WO2009009907A1 - Utilisation d'agonistes du récepteur de la vasopressine pour le traitement d'un choc septique - Google Patents

Utilisation d'agonistes du récepteur de la vasopressine pour le traitement d'un choc septique Download PDF

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WO2009009907A1
WO2009009907A1 PCT/CA2008/001346 CA2008001346W WO2009009907A1 WO 2009009907 A1 WO2009009907 A1 WO 2009009907A1 CA 2008001346 W CA2008001346 W CA 2008001346W WO 2009009907 A1 WO2009009907 A1 WO 2009009907A1
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vasopressin
septic shock
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baseline
patients
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James Russell
Keith Walley
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University of British Columbia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to the field of septic shock. More specifically, the present invention relates to a method of using vasopressin-receptor agonists for the treatment of patients with septic shock.
  • ICU International Health Organization
  • Sepsis is a systemic infection that may be caused by primary bacteremia; however it is often triggered by events such as trauma, surgery, perforated bowel and burns, or by conditions such as pneumonia, urinary tract infection, wound infection, peritonitis, cholangitis, cellulitis, intra-abdominal abscess and post-surgery infection. It may progress to more severe conditions such as septic shock and result in multiple organ failure and death. Septic shock is a serious medical condition characterized by hypotension, hyperventilation and eventually organ dysfunction. Refractory septic shock is very serious with the patient not responding to increasing doses of vasopressors and often accompanied by multiple organ failures or near-failures. Death and organ dysfunction/ failure are caused by poor tissue perfusion and reduced oxygen delivery.
  • a compromised immune system can be caused by for example surgery, tissue transplantation and chemotherapy.
  • Large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension.
  • Hypotension reduces tissue perfusion pressure and thus tissue hypoxia ensues.
  • ventricular dilatation and myocardial dysfunction may occur.
  • the impact of sepsis is particularly devastating to patients with compromised cardiac, hepatic and immune-defense function.
  • the Acute Physiology and Chronic Health Evaluation (APACHE) II 3 scoring system is used to predict morbidity for ICU patients 15 years of age or older. The score is based on age, routine physiological measurements, information about immunocompromisation or chronic organ failure and the Glasgow Coma Score (a neurological measure of consciousness).
  • the Apache II score ranges from 0-71; 71 indicating the highest risk of death.
  • the physiological measurements include: body temperature, heart rate, blood pressure, mean arterial pressure, respiratory rate, pulmonary function (PaO 2 /FiO 2 ), white blood cell count, arterial pH, blood oxygenation and serum levels of creatinine, sodium, potassium and HCO 3 .
  • the APACHE II score can be used to determine the severity of septic shock.
  • Resuscitation strategies include intravenous fluid and the use of vasopressors including catecholamines such as norepinephrine, epinephrine, dopamine and dobutamine.
  • catecholamines such as norepinephrine, epinephrine, dopamine and dobutamine.
  • catecholamines have important adverse effects and may even increase mortality.
  • norepinephrine a potent, commonly-used ⁇ -adrenergic agent in septic shock may decrease cardiac output, oxygen delivery, and blood flow to vulnerable organs despite adequate perfusion pressure.
  • Corticosteroids may also be used in resuscitation strategies for subjects with septic shock. Reducing the subject's inflammatory response may be beneficial and aid in restoring cytokine homeostasis, however a review of various clinical studies (Delliner, 2004), suggests these may be several opinions on the matter, with respect to dose and timing of administration.
  • Arginine vasopressin is a human peptide hormone that is released in response to hypotension or when the body is low on water. AVP causes the kidneys to conserve water, but not salt, by concentrating the urine and reducing urine volume. It also raises blood pressure by inducing moderate vasoconstriction. Ethanol and caffeine increase urination by reducing vasopressin secretion, whereas angiotensin II increases water reabsorption by stimulating the secretion of vasopressin.
  • Vasopressin is currently used as a second-line and add-on therapy to treat severe vasodilatory hypotension that is unresponsive or refractory to one or more adrenergic agents (eg, high-dose dopamine, epinephrine, norepinephrine, phenylephrine) 5 . Its use has been associated with side-effects such as bradycardia, gut ischemia, digital ischemia and myocardial ischemia 6 .
  • adrenergic agents eg, high-dose dopamine, epinephrine, norepinephrine, phenylephrine
  • Vasopressin binds to vasopressin-specific membrane-bound Vl receptors (also known as AVPRlA) on vascular smooth muscle 6 , stimulating vasoconstriction because of contraction of vascular smooth muscle. Furthermore, vasopressin binds V2 receptors on the distal convoluted tubule and collecting ducts in the kidney, and V3 receptors in the pituitary gland that modify adrenocorticotropin hormone synthesis and release.
  • Vl receptors also known as AVPRlA
  • Vasopressin is synthesized in the hypothalamus. Most of it is stored in the posterior part of the pituitary gland to be released into the blood stream in response to a reduced plasma volume or an increase in plasma osmolality. Steady state normal plasma levels of vasopressin is about 5 - 10 pmol/L. The half-life of vasopressin is approximately 5-15 minutes.
  • Exogenous vasopressin and other vasopressin-receptor agonists are used to prevent or control polyuria, polydipsia, and dehydration in patients with central diabetes insipidus. It is also used to prevent nocturnal enuresis, or nocturnal involuntary emptying of the bladder (Nocturia), mostly affecting children.
  • Intravenous vasopressin is included in the Advanced Cardiac Life Support (ACLS) algorithm as an alternative to epinephrine for the treatment of cardiac arrest associated with asystole or pulseless electrical activity. Vasopressin also has been used in the treatment of intestinal paresis, postoperative abdominal distention, and upper GI tract hemorrhage, although this practice has been abandoned.
  • ACLS Advanced Cardiac Life Support
  • Terlipressin is a long-acting synthetic vasopressin analogue.
  • vasopressin or AVP when used (herein and elsewhere), it may refer to terlipressin or any other vasopressin-receptor agonist.
  • vasopressin for the treatment of severe septic shock has been discussed, for example by D ⁇ nser et al 7 , Patel et al 8 , Landry et al 9 ' 10 and Russell & Landry 11 , and the opinions, comments and election of whether or not to use vasopressin and when, and under what conditions, are many and varied.
  • Russell & Landry n have indicated that vasopressin may be beneficial in extreme cases of sepsis, but should not be used routinely, and there is suggestion that vasopressin may be harmful.
  • the present invention provides, in part, improved uses of vasopressin or vasopressin-receptor agonists for the treatment of septic shock.
  • the present invention relates to a use of vasopressin, or a vasopressin-receptor agonist for the treatment of septic shock.
  • Vasopressin may be used as an adjunct to catecholamines, corticosteroids or norepinephrine to support blood pressure in refractory septic shock.
  • Infusion of low-dose vasopressin as a first-line of treatment significantly decreases mortality in patients with less severe septic shock, and in septic shock-patients treated with steroids.
  • a method of preventing organ failure in a subject having septic shock comprising administering to the subject vasopressin, or a vasopressin-receptor agonist, for sufficient time to prevent organ failure.
  • the organ failure may be renal failure.
  • the septic shock may be less severe septic shock.
  • a method of treating a subject having less severe septic shock comprising administering to the subject vasopressin, or a vasopressin-receptor agonist, for sufficient time to treat septic shock.
  • the methods may further comprise administering to the subject one or more corticosteroids.
  • the vasopressin or vasopressin- receptor agonist may be administered in a dose of 0.01 to 0.03 U / min.
  • kits for use in treating a subject having less severe septic shock comprising vasopressin or a vasopressin-receptor agonist, and instructions for use.
  • the instructions may further comprise dosing information, or instructions for selecting a subject having less severe septic shock.
  • a method of determining the eligibility of a subject for treatment of septic shock with vasopressin or a vasopressin-receptor agonist comprising: (i) determining the subject's requirement for vasopressor support; (ii) determining the subject's requirement for one or less vasopressors at baseline; (iii) determining the subject's baseline lactate levels; (iv) determining the subject's APACHE II score at baseline; and (v) determining the subject's signs of renal dysfunction at baseline; wherein the subject is eligible for treatment of septic shock with vasopressin or a vasopressin-receptor agonist if the subject meets one or more of the following criteria: (i) requiring less than or equal to 14 ⁇ g norepinephrine /min);.
  • vasopressin as a catecholeamine-sparing agent for the treatment of less severe septic shock, wherein the catecholamine is norepinephrine, and administered at a dose of less than 14 ug/minute.
  • Such methods of treatment or prevention, or uses of one or more aspects of the invention may provide for an advantageous reduction in the subject's requirement for corticosteroids relative to a subject not receiving vasopressin or a vasopressin-receptor agonist.
  • a subject receiving vasopressin or a vasopressin-receptor agonist may demonstrate a "Days Alive and Free" (DAF) score (corticosteroid) of >16), while a subject not receiving vasopressin or a vasopressin-receptor agonist may demonstrate a "Days Alive and Free" (DAF) score (corticosteroid) of >16), while a subject not receiving vasopressin or a vasopressin-receptor agonist may demonstrate a "Days Alive and Free" (DAF) score (corticosteroid) of >16), while a subject not receiving vasopressin or a vasopressin-receptor agonist may demonstrate a "Days A
  • DAF score (corticosteroid use) of 16 or less.
  • Such methods of treatment or prevention, or uses of one or more aspects of the invention may provide for an advantageous reduction in the subject's requirement for mechanical ventilation relative to a subject not receiving vasopressin or a vasopressin- receptor agonist.
  • a subject receiving vasopressin or a vasopressin- receptor agonist may demonstrate a "Days Alive and Free" (DAF) score (mechanical ventilation) of >14), while a subject not receiving vasopressin or a vasopressin-receptor agonist may demonstrate a DAF score (mechanical ventilation) of 14 or less.
  • DAF Days Alive and Free
  • Such methods of treatment or prevention, or uses of one or more aspects of the invention may provide for an advantageous reduction in the subject's requirement for mechanical ventilation relative to a subject not receiving vasopressin or a vasopressin- receptor agonist.
  • a subject receiving vasopressin or a vasopressin- receptor agonist may demonstrate a "Days Alive and Free" (DAF) score (renal failure) of >4), while a subject not receiving vasopressin or a vasopressin-receptor agonist may demonstrate a DAF score (renal failure) of 4 or less.
  • DAF Days Alive and Free
  • the vasopressin-receptor agonist is selected from the group comprising, arginine vasopressin (AVP), lysine vasopressin (LVP), triglycil-lysine vasopressin, octopressin, ornipressin, and desmopressin (DDAVP).
  • AVP arginine vasopressin
  • LVP lysine vasopressin
  • DDAVP desmopressin
  • a method is provided for treating patients with septic shock, wherein the method may involve the use of vasopressin-receptor agonists on a selected subset of patients with septic shock.
  • vasopressin-receptor agonist may be used for the treatment of patients with less severe septic shock.
  • vasopressin-receptor agonist may be used for the treatment of patients with septic shock and requiring low dose vasopressor support (such as ⁇ 14 ⁇ g norepinephrine /min).
  • vasopressin-receptor agonist may be used for the treatment of patients with septic shock and low baseline lactate levels (such as ⁇ 1.4mmol/L).
  • vasopressin-receptor agonist may be used for the treatment of patients with septic shock treated with one or less vasopressors at baseline.
  • a method whereby a vasopressin-receptor agonist may be used for the treatment of patients with septic shock that show no signs of renal dysfunction at baseline.
  • a method whereby a vasopressin-receptor agonist may be used for the treatment of patients with septic shock at increased risk of developing renal failure or renal dysfunction.
  • a vasopressin-receptor agonist may be used for the treatment of patients with septic shock in conjunction with treatment using corticosteroids, including but not limited to the administration of one or more doses of cortisone, hydrocortisone, prednisone, and methylprednisolone.
  • the dose of vasopressin-receptor agonist that is used may be low, such as corresponding to 0.01-0.03U of vasopressin /min.
  • the vasopressin-receptor agonist may be used in combination with other vasopressors and/or any agents that may improve the outcome for the patient.
  • FIGURE 1 Flowchart of subject enrollment and outcomes.
  • NYHA denotes New York Heart Association classification.
  • OR denotes operating room.
  • MI denotes myocardial infarction.
  • FIGURE 3 Comparison of mean arterial pressure (A) and heart rate (B) in the norepinephrine group (grey circles) and vasopressin group (black squares). Values are mean +/- standard deviation.
  • FIGURE Rates of total norepinephrine infusion (open-label and study drug) in the vasopressin treated group (black squares) and the norepinephrine treated group (grey circles) amongst all patients who were treated with open-label norepinephrine at baseline. Values are median + interquartile range.
  • Solid black line is the vasopressin treated group
  • the dotted line is the norepinephrine treated group
  • the vertical line marks day 28. P values were calculated using the log rank statistic.
  • FIGURE 7 Renal function at enrollment for all VASST patients according to RIFLE criteria.
  • FIGURE 8 28-day mortality according to baseline RIFLE criteria. The presence of any renal dysfunction was associated with increased mortality compared to no renal dysfunction (44.3% vs 27.0%, respectively, * P ⁇ 0.001).
  • a 'subject' refers to an animal, such as a bird or a mammal. Specific animals include rat, mouse, dog, cat, cow, sheep, horse, pig or primate.
  • a subject may further be a human, alternatively referred to as a patient.
  • a subject may further be a transgenic animal.
  • a subject may further be a rodent, such as a mouse or a rat.
  • a 'vasopressin-receptor agonist' is any compound that has the ability to bind and activate any vasopressin-receptor and induce constriction of smooth muscle and blood vessels and/ or returning a reduced blood pressure to normal levels.
  • vasopressin-receptor agonists or vasopressin-like peptides include, but are not limited to: arginine vasopressin (also known as AVP, argipressin, antidiuretic hormone or ADH), lysine vasopressin triglycil-lysine vasopressin (also known as glycopressin or terlipressin), octopressin, ornipressin, and l-deamino-8-D-arginine vasopressin (also known as desmopressin or DDAVP).
  • arginine vasopressin also known as AVP, argipressin, antidiuretic hormone or ADH
  • lysine vasopressin triglycil-lysine vasopressin also known as glycopressin or terlipressin
  • octopressin octopressin
  • ornipressin octopressin
  • vasopressin-receptor agonists includes analogues of arginine vasopressin, including but not limited to such analogues extended by 1-3 amino acids such as AIa-AVP, Ser-Ala-AVP and Thr-Ser-Ala-AVP as well as other compounds including but not limited to3-beta-(2-thienyl)-L-alanine)-8-lysine-, N-alpha-glycyl-glycyl- glycyl-[8-lysine]-vasopressin l-deamino-6-carba-[8-arginine] -vasopressin and analogues thereof.
  • Other examples of vasopressin-receptor agonists are described in, for example, PCT Publication WO 2006/020491, incorporated herein by reference.
  • Baseline' refers to the level of a physiological measure before treatment was initiated, such as treatment with an adrenergic agent or a vasopressin-receptor agonist such as the study drug.
  • treatment In the context of the present invention, the terms “treatment,” , “treating”, “therapeutic use,” or “treatment regimen” as used herein may be used interchangeably are meant to encompass prophylactic, palliative, and therapeutic modalities of the methods, uses and kits of the present invention.
  • any prevention, amelioration, alleviation, reversal, or complete elimination of septic shock, SIRS or less severe septic shock, or criteria of septic shock, SIRS or less severe septic shock is encompassed by the present invention.
  • 'Septic shock' is herein defined by the presence of two or more of the systemic inflammatory response syndrome (SIRS) criteria 13 (including fever or hypothermia, tachypnea or need for mechanical ventilation, tachycardia and abnormal white blood cell count), proven or suspected infection, at least one new organ dysfunction, and hypotension despite adequate fluid resuscitation requiring vasopressor support of at least 5 ⁇ g/min of norepinephrine (or equivalent).
  • SIRS systemic inflammatory response syndrome
  • 'Less severe septic shock' is herein defined as septic shock and with at least one of the following characteristics:
  • baseline vasopressor support such as less than or equal to 14 ⁇ g norepinephrine /min.
  • b) requiring one or less vasopressors at baseline c) low baseline lactate levels (such as ⁇ 1.4mmol/L)
  • a low APACHE II score at baseline such as ⁇ 25
  • 'Hypotension' is herein defined by: systolic blood pressure (SBP) less than 90 mmHg or decrease in SBP by at least 40 mmHg for more than one hour while central venous pressures (CVP) remained adequate ( ⁇ 12 mmHg) or at least 500 mL of saline was infused or if vasopressors were infused to maintain blood pressure.
  • SBP systolic blood pressure
  • CVP central venous pressures
  • a "vasopressor” is an agent, factor or composition, frequently a pharmaceutical composition, that causes vasoconstriction.
  • 'Vasopressor requirement' or a 'patient requiring vasopressors' is herein defined as patients in need of >5 ⁇ g/min of norepinephrine or equivalent in the preceeding 24 hours, OR patients requiring high vasopressor doses (norepinephrine equivalent >15 ⁇ g/hr) to maintain a mean arterial pressure of 65-75 mmHg.
  • 'Norepinephrine equivalent dose' is herein calculated as [norepinephrine ( ⁇ g/min)] + [dopamine ( ⁇ g/kg/min) ⁇ 2] + [epinephrine ( ⁇ g/min)] + [phenylephrine ( ⁇ g/min) ⁇ 10] after the study of Patel et al. 8
  • Acutely ill subjects may experience dysfunction or failure of one or more organs (e.g. heart, liver, lung, kidney, pancreas, and the like), necessitating mechanical intervention to maintain life. Monitoring of physiological indicators (e.g.
  • urine output, heart rate, blood pressure, body temperature, respiratory rate, and blood or plasma enzymes, metabolites and the like) may provide an indication of risk, injury, failure or complete loss of organ function.
  • the subject's degree of organ dysfunction may be described using a scoring system, such as the Sepsis-Related Organ Failure Assessment (SOFA) (Moreno et al,., 1999) or Brussels score 16 , while individual organ function/dysfunction/failure may be assessed using other defining features, e.g. acute renal failure and the RIFLE criteria.
  • SOFA Sepsis-Related Organ Failure Assessment
  • R-Risk Increased serum creatinine xl.5 patient baseline I-Injury; Increased serum creatinine x2 patient baseline F-Failure; Increased serum creatinine x3 patient baseline or if patient baseline creatinine is >350umol/l (4mg/dl) and acute rise is > 44 umol/1 (0.5 mg/dl).
  • L-Loss Complete loss of renal function (dialysis) for at least 4 weeks.
  • E-End stage Renal failure (dialysis) for at least 3 months.
  • 'New organ dysfunction' is herein defined as respiratory (ventilated and
  • PaO 2 ZFiO 2 ⁇ 300 mmHg renal (urine output ⁇ 30 mL/hour or less than 0.5 mL/kg body weight, for at least one hour), coagulation (platelet count ⁇ 80,000/mm 3 ), and neurologic (Glasgow Coma Score ⁇ 12, prior to receiving sedation).
  • 'Serious adverse events' that could occur and may warrant discontinuing treatment with catecholamine vasopressors and vasopressin-receptor agonist includes: (1) acute S-T segment elevation confirmed by 12-lead electrocardiogram, (2) serious or life-threatening (hemodynamically unstable) cardiac arrhythmias, (3) acute mesenteric ischemia, (4) digital ischemia, or (5) hyponatremia (serum sodium ⁇ 130 mmol/L).
  • 'Open-label catecholamine vasopressors' include epinephrine, norepinephrine, dopamine and dobutamine that were initiated at baseline or as an adjunct to the main treatment, such as the study drug.
  • 'Corticosteroids' refers to any analogues of Cortisol, corticosterone or aldosterone as well as any compounds that resemble or mimic their function in a subject, including but not limited to cortisone, hydrocortisone, prednisone and methylprednisolone.
  • a "sufficient time to treat less severe septic shock” or “sufficient time to prevent organ failure” in reference to the duration of time that a subject was administered vasopressin, arginine vasopressin (AVP), lysine vasopressin (LVP), triglycil-lysine vasopressin, octopressin, ornipressin, and desmopressin (DDAVP), or a vasopressin- receptor agonist is the time period from when the first administration commenced to when administration discontinued,, including the initiation of weaning of the subject from vasopressin, arginine vasopressin (AVP), lysine vasopressin (LVP), triglycil-lysine vasopressin, octopressin, ornipressin, and desmopressin (DDAVP), or a vasopressin- receptor agonist.
  • vasopressin treatment does not improve 28-day or 90-day mortality rates for patients with septic shock in general. Neither does vasopressin treatment improve 28-day or 90-day mortality rates for patients with more severe septic shock, hi sharp contrast with the current use and knowledge of vasopressin treatment for septic shock, low-dose vasopressin treatment significantly reduces 28-day and 90-day mortality rates for patients with less severe septic shock and for patients treated with corticosteroids.
  • vasopressin treatment reduces the rate of progression to renal failure or loss in patients with no baseline renal dysfunction, including patients at risk of developing such.
  • Patients with less severe septic shock differ from patients with more severe septic shock in at least two significant ways:
  • corticosteroids have been shown to reverse tachyphylaxis against exogenous vasopressors, providing an explanation for why vasopressin becomes more efficient in septic shock when used in conjunction with corticosteroids.
  • a vasopressin-receptor agonist may be used for the treatment of septic shock in patients who have less severe septic shock.
  • the method may include one of the following: [0084]
  • a vasopressin-receptor agonist may be used for the treatment of septic shock in patients with septic shock requiring low dose vasopressor support at baseline (such as ⁇ 14 ⁇ g norepinephrine /min).
  • a vasopressin-receptor agonist may be used for the treatment of septic shock in patients with septic shock and with low lactate levels (such as ⁇ 1.4mmol/L).
  • a vasopressin-receptor agonist may be used for the treatment of septic shock in patients with septic shock that require support from only one or less vasopressors at baseline.
  • a vasopressin-receptor agonist may be used for the treatment of septic shock that show no signs of renal dysfunction at baseline.
  • a vasopressin-receptor agonist may be used for the treatment of patients with septic shock at increased risk of developing renal failure or renal dysfunction.
  • a vasopressin-receptor agonist may be used for the treatment of patients with septic shock in conjunction with treatment using corticosteroids, including but not limited to the administration of one or more doses of cortisone, hydrocortisone, prednisone and methylprednisolone.
  • a vasopressin-receptor agonist may be used in combination with other vasopressors and/or any agents that may improve the outcome for the patient.
  • a vasopressin-receptor agonist may be infused into the subject, for example in a vein.
  • vasopressin or a vasopressin receptor agonist
  • the dose of vasopressin, or a vasopressin receptor agonist may be expressed as an infusion rate e.g "per minute".
  • the quantity of vasopressin, or vasopressin receptor agonist may be described as "units” or abbreviated as "U”.
  • a unit of vasopressin or a vasopressin receptor agonist is known in the art, and may be described as equivalent to the pressor activity of 0.5 mg of the USP Posterior-pituitary Reference Standard. As an example, 1 mg of synthetic vasopressin corresponds to 600 units.
  • a subject may receive a dose from about 0.001 to about 0.1 units or any amount therebetween, or from about 0.001 to about 0.05 units or any amount therebetween, or from about 0.005 to about 0.004 units or any amount therebetween, or from about 0.01 to about 0.03 units or any amount therebetween.
  • a suitable dose may be determined based on standard protocols used in the particular institution or medical facility, or may be provided by the manufacturer or supplier of the vasopressin or vasopressin receptor agonist, or other drug used for the treatment of the subject. Alternately, a suitable dose may be determined empirically and adjusted by a practitioner as needed.
  • vasopressin or vasopressin receptor agonist is provided (e.g. concentration), the mode of administration, or the like.
  • the dose of a vasopressin-receptor agonist that is used may be low, such as corresponding to 0.01-0.03U of vasopressin /min.
  • a vasopressin-receptor agonist may be infused in the form of a liquid, for example corresponding to 0.12U vasopressin/mL.
  • the drugs, agonists and other pharmaceuticals that may be used for treatment of a subject with septic shock or less severe septic shock may be administered alone or in combination, in any of several ways - including, for example, continuous intravenous infusion, continuous intraarterial infusion, intermittent intravenous infusion, intermittent intraarterial infusion, subcutaneous injection, intraperitoneal injection, intramuscular injection, intravenous injection, epidermal or transdermal administration, mucosal membrane administration, orally, nasally, rectally, or vaginally. See, for example, Remington- The Science and Practice of Pharmacy, 21 st edition. Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia. Carrier formulations may be selected or modified according to the route of administration.
  • Dosage schedules may be dependent on, for example, the subject's condition, age, gender, weight, route of administration, formulation, or general health. Dosage schedules may be calculated from measurements of adsorption, distribution, metabolism, excretion and toxicity in a subject, or may be extrapolated from measurements on an experimental animal, such as a rat or mouse, for use in a human subject. Optimization of dosage and treatment regimens are discussed in, for example, Goodman & Gilman's The Pharmacological Basis of Therapeutics 11 th edition. 2006. LL Brunton, editor. McGraw- Hill, New York, or Remington- The Science and Practice of Pharmacy, 21 st edition. Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia.
  • vasopressin or a vasopressin-receptor agonist is described in the following infusion protocol: Infusion may be started at 5 mL/hr, and increased over the first hour by 2.5 mL/hr every 10 minutes, to a constant target rate of 15 mL/hr while the bedside nurse can titrate open-label catecholamine vasopressors to maintain a constant target mean arterial pressure (MAP) (such as 65 - 75 mmHg). If this protocol is used, the vasopressin infusion would be starting at 0.01 U/min and titrated to a maximum of 0.03 U/min.
  • MAP mean arterial pressure
  • the target MAP may not be needed.
  • An initial target MAP of 65 - 75 mmHg is recommended; however, the target MAP may be set by the individual ICU physician.
  • Infusion of study drug may be continued at 15 mL/hr until the patient improves such that open-label catecholamine vasopressors are no longer required, or until the patient develops serious adverse events or dies.
  • Weaning of the study medication may for example be commenced when the target MAP has been maintained while off all vasopressors for a time-period such as eight hours.
  • vasopressin-receptor agonist may for example be decreased in 2.5 mL decrements every hour while the target MAP is maintained.
  • MAP > 85 mmHg open-label catecholamine vasopressors and the vasopressin-receptor agonist may be weaned more rapidly.
  • the invention may further comprise a kit for use in treating a subject with septic shock, or less severe septic shock.
  • the kit may comprise vasopressin, or a vasopressin- receptor agonist, and instructions for its use.
  • the instructions may comprise steps involving assessment of the severity of the subject's sepsis or suspected sepsis, or SIRS, or other clinical events associated with sepsis.
  • the instructions may provide information with respect to characteristics of a recommended subject, e.g. a subject with less severe septic shock as described herein, or a contraindicated subject.
  • the kit may further provide a vasopressor for use in combination with the vasopressin or vasopressin-receptor agonist, along with information of reduced or alternate doses suitable for treatment of a subject with septic shock, or less severe septic shock.
  • a vasopressor for use in combination with the vasopressin or vasopressin-receptor agonist, along with information of reduced or alternate doses suitable for treatment of a subject with septic shock, or less severe septic shock.
  • SIRS criteria were:
  • tachypnea (respiratory rate > 20 breaths per minute or PaCO 2 ⁇ 32 mmHg) or need for mechanical ventilation
  • abnormal leukocyte count > 12,000 cells/mm 3 , ⁇ 4000 cells/mm 3 , or > 10% immature [band] forms).
  • the study drug infusion was started at 5 mL/hr, and increased over the first hour by 2.5 mL/hr every 10 minutes, to a constant target rate of 15 mL/hr while the bedside nurse titrated open-label catecholamine vasopressors to maintain a constant target
  • MAP 65 - 75 mmHg
  • the blinded vasopressin infusion was started at 0.01 U/min and titrated to a maximum of 0.03 U/min while the blinded norepinephrine infusion was started at 5 ⁇ g/min and titrated to a maximum of 15 ⁇ g/min.
  • An initial target MAP of 65 - 75 mmHg was recommended; however, the attending ICU physician could modify the target blood pressure in each patient.
  • Infusion of study drug was continued at 15 mL/hr until the patient died, developed a serious adverse event, or improved such that open-label catecholamine vasopressors were no longer required. Neither crossover to the alternate arm nor open-label vasopressin was permitted.
  • Study drug infusion was discontinued or interrupted if any of the following predetermined serious adverse events occurred: (1) acute S-T segment elevation confirmed by 12-lead electrocardiogram, (2) serious or life-threatening (hemodynamically unstable) cardiac arrhythmias, (3) acute mesenteric ischemia, (4) digital ischemia, or (5) hyponatremia (serum sodium ⁇ 130 mmol/L). If the clinical team noted an adverse event that they considered to be related to study drug, then the study drug was discontinued for at least eight hours and a serious adverse event was reported. Study drug could be restarted if, in the judgment of the investigator or attending physician, the adverse event had been treated, the condition had reversed and the event was not thought to be a result of the study drug or study protocol.
  • vasopressor support was required during the same ICU admission after a patient had been weaned from study drug, the study drug was preferentially re- infused, providing no exclusion criteria were met.
  • study drug details [00114] After receiving the allocation code from the central randomization system, study pharmacists at each center were responsible for preparation of the study drug. Both vasopressin (30 U) and norepinephrine (15 mg) were mixed in and infused from identical 250 mL D5W intravenous bags to give final concentrations of 0.12 U/mL of vasopressin and 60 ⁇ g/mL of norepinephrine.
  • DAF Days alive and free calculations: DAF was scored as 1 if the patient was alive and free of organ dysfunction (normal or mild dysfunction). DAF was scored as 0 if the patient had organ dysfunction (moderate, severe, or extreme) or was not alive. A low DAF score indicates more organ dysfunction because a low score indicates fewer days alive and free of organ dysfunction. Each of the 28 days after meeting the inclusion criteria was scored. For any 24-hour period in which there is no measurement of a variable, we carried forward the value from the previous 24-hour period. If any variable was never measured, it was assumed to be normal. Once a patient was discharged home they were considered free of organ or failure. [00135] The data analyst and investigators remained blinded to treatment allocation while undertaking the final analyses. The primary analysis comparing 28-day mortality between the two treatment groups was performed using an unadjusted Chi-square test and all patients were analyzed according to the treatment group allocated at randomization. Results are presented as absolute and relative risks and 95% confidence intervals. Kaplan-
  • Meier curves describing the estimated probability of survival in the two treatment arms as a function of time from admission into the study were compared using the log-rank test statistic. Because of the complex nature of septic shock patients and to adjust for any imbalances between the two treatment groups at baseline, a logistic regression procedure was used to adjust raw values for 28 day mortality using significant covariates predicting outcomes. Age, illness severity (APACHE II score at baseline), serious co-morbid illness and other baseline covariates predicting outcome (at a threshold p value of 0.2) were entered into the model. Results are presented as odds ratios (OR) and 95% confidence intervals.
  • COPD chronic obstructive pulmonary disease
  • APACHE II Acute Physiology and Chronic Health Evaluation II *Ethinicity was determined by the local study coordinators
  • **Other sites of infection included the blood, skin, central nervous system, bones and joints, cardiac system and reproductive organs.
  • Ventilation 6 (0, 20) 8.5 (0, 20) 0.24
  • ***ARR denotes absolute risk reduction (mortality rate in norepinephrine group minus mortality rate in vasopressin group).
  • CI denotes confidence interval.
  • Organ dysfunction for each organ system is defined as being present during each 24-hour period if there was evidence of moderate, severe, or extreme organ dysfunction according to the Brussels criteria. 16 A low score indicates more organ dysfunction because a low score indicates fewer days alive and free of organ dysfunction. Values are median (interquartile range), P values are based on Wilcoxon Rank Sum test.
  • vasopressin and norepinephrine groups were low in the vasopressin and norepinephrine groups (approximately 10% in each). Previous studies raised the possibility that vasopressin infusion may increase the incidence of cardiac arrest. 5 In contrast, we found that of 11 cardiac arrests reported in this study, eight occurred in the norepinephrine group while three occurred in the vasopressin group. Our selection of a low dose of vasopressin (0.03 U/min) and careful exclusion of patients who had acute coronary syndromes or severe heart failure could account for the lack of adverse cardiovascular effects of vasopressin infusion.
  • vasopressin becomes routine therapy and is given to septic shock patients with co-morbid heart disease, the adverse reactions to vasopressin could be increased.
  • Other reported adverse effects of both vasopressin and norepinephrine include decreased cardiac output, 5 ' 10> 17 mesenteric ischemia, 18 ' 19 hyponatremia (vasopressin), skin necrosis 10 ' 20 and digital ischemia. 21 More patients in the vasopressin group had digital ischemia compared to the norepinephrine group (2.0% vs
  • Norepinephrine ( ⁇ g/min) 9.8 ⁇ 5.5 (n 310) 30.0 ⁇ 23.3 ⁇ 0.001
  • Epinephrine ( ⁇ g/min) 7.8 ⁇ 6.1 (n 8) 12.6 ⁇ 15.1 0.14
  • COPD chronic obstructive pulmonary disease
  • APACHE II Acute Physiology and Chronic Health Evaluation II *Other sites of infection included the blood, skin, central nervous system, bones and joints, cardiac system and reproductive organs
  • ***ARR denotes absolute risk reduction (mortality rate in norepinephrine group minus mortality rate in vasopressin group).
  • CI denotes confidence interval.
  • Renal replacement therapy 28 (9, 28) 28(13,28) 0.17 19 (2.5, 28) 15.5(1,28) 0.44 Hepatic 27 (9, 28) 27.5(13,28) 0.12 22 (2, 28) 18(1,28) 0.23 Hematologic 25 (9, 28) 27 (14.5, 28) 0.10 22 (2, 28) 20(1,28) 0.38 Neurologic 15.5(1,24) 18 (4,24) 0.22 15 (0, 25) 7 (0, 23) 0.04
  • Organ dysfunction for each organ system is defined as being present during each 24-hour period if there was evidence of moderate, severe, or extreme organ dysfunction according to the Brussels criteria. 16 A low score indicates more organ dysfunction because a low score indicates fewer days alive and free of organ dysfunction. Values are median (interquartile range), P values are based on Wilcoxon Rank Sum test.
  • VASST Vasopressin And Septic Shock Trial
  • Acute renal failure was defined according to the consensus RIFLE serum creatinine criteria (urine output data was not available):
  • R-Risk Increased serum creatinine xl.5 patient baseline I-Injury; Increased serum creatinine x2 patient baseline F-Failure; Increased serum creatinine x3 patient baseline or if patient baseline creatinine is >350umol/l (4mg/dl) and acute rise is > 44 umol/1 (0.5 mg/dl).
  • L-Loss Complete loss of renal function (dialysis) for at least 4 weeks.
  • vasopressin treatment is associated with a reduction in mortality and progression to renal failure in patients at risk.
  • Vasopressin does not seem to improve the outcome for patients who have already sustained significant renal injury.

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Abstract

L'invention porte sur un procédé consistant à traiter un sujet ayant un choc septique, le procédé comprenant l'administration au sujet de vasopressine, ou d'un agoniste du récepteur de la vasopressine. Le procédé peut en outre comprendre l'administration d'un corticostéroïde, ou d'une dose réduite d'un vasopresseur, tel que la norépinéphrine. L'invention porte également sur des procédés pour accéder à l'admissibilité d'un sujet à un traitement d'un choc septique par la vasopressine.
PCT/CA2008/001346 2007-07-18 2008-07-18 Utilisation d'agonistes du récepteur de la vasopressine pour le traitement d'un choc septique Ceased WO2009009907A1 (fr)

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EP2976646B1 (fr) * 2013-03-20 2020-08-19 sphingotec GmbH Adrénomédulline pour guider la thérapie du déclin de la pression sanguine
CN111920939A (zh) * 2013-12-18 2020-11-13 乔治华盛顿大学国会特许非营利公司 血管紧张素ii单独或以组合方式用于治疗低血压
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CN113164550A (zh) * 2018-11-15 2021-07-23 费灵有限公司 用于治疗败血症的化合物、组合物和方法

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