Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a method of treating, and improving survival in, critically ill patients, and the use of certain sterile sedative pharmaceutical compositions for the manufacture of a medicament for improving the survival of such patients.
• Propofol is an intravenous sedative agent and can be used for the induction and maintenance of general anaesthesia and for sedation, for example in Intensive Care Units.
• Propofol is a highly successful anaesthetic and is marketed under the trademark 'Diprivan' for use in treating humans and under the trademark 'Rapinovet' for veterinary use.
• modified formulation 'Diprivan' i.e. 2,6-diisopropylphenol (propofol) when administered in a formulation containing 0.005% disodium edetate, possesses previously unrecognised properties and is effective in significantly improving survival in certain critically ill patients.
• ICUs intensive care units
• compositions containing a free radical scavenging sedative agent (such as propofol) and a metal ion chelating agent (such as edetate) may be of value as a therapy for the improving survival in certain critically ill patients.
• the present invention provides a method of improving survival in critically ill patients which comprises administration of a pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent, in association with a pharmaceutically-acceptable diluent or carrier.
• the present invention further provides a method of improving survival in critically ill patients which comprises administration of a pharmaceutical composition comprising a free- radical scavenging sedative agent and a metal ion chelating agent, which pharmaceutical composition is described and claimed in United Kingdom Patent 2,298,789.
• the invention provides a method of improving survival in critically ill patients which comprises administration of a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises a metal ion chelating agent.
• the invention provides a method of improving survival in critically ill patients which comprises administration of a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises edetate.
• the invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent, in association with a pharmaceutically-acceptable diluent or carrier, for use as a medicament for improving survival in critically ill patients.
• the invention further provides a pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent, which pharmaceutical composition is described and claimed in United Kingdom Patent 2,298,789, for use as a medicament for improving survival in critically ill patients.
• the invention provides a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises a metal ion chelating agent, for use as a medicament for improving survival in critically ill patients.
• the invention provides a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises edetate, for use as a medicament for improving survival in critically ill patients.
• the invention further provides the use of a pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent, in association with a pharmaceutically-acceptable diluent or carrier, for the manufacture of a medicament for improving survival in critically ill patients.
• the invention further provides the use of a pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent, which pharmaceutical composition is described and claimed in United Kingdom Patent 2,298,789, for the manufacture of a medicament for improving survival in critically ill patients.
• the invention provides the use of a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises a metal ion chelating agent, for the manufacture of a medicament for improving survival in critically ill patients.
• the invention provides the use of a sterile pharmaceutical composition for parenteral administration, which composition comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilised by means of a surfactant, and which further comprises edetate, for the manufacture of a medicament for improving survival in critically ill patients.
• the methods and uses of the present invention relate to use in warm-blooded animals, such as man, in sedation.
• a clinically significant time such as 7 days post sedation.
• a further clinically significant time is 28 days post-sedation.
• the post-sedation time may be determined from the point at which sedation was commenced (as in the clinical trial programme) or from the point at which sedation was stopped.
• the critically ill patient demonstrates a reduction, or absence, in condition related problems and/or does not require further mechanical ventilation and/or is deemed by a physician to be less likely to die and/or is deemed by a physician to have an improved probability of surviving.
• the patient populations which benefit the most from the invention are 'critically ill patients' and are those not receiving sedation for a chronic disease, i.e. 'critically ill patients' are those, for example, suffering an acute insult, injury or trauma and requiring sedation following, for example, (elective or emergency) surgery, medical treatment or post-trauma.
• critically ill ventilated patients in ICUs are included.
• Patients with a probability of dying e.g. from an underlying disease condition such as severe renal failure
• the benefit from the invention will also be less marked for patients who are intrinsically reasonably healthy, with a probability of dying of about 5% or less.
• the invention thus provides, in one embodiment, a potential treatment for certain patients in danger of suffering multiple organ dysfunction/failure.
• the use and method of the invention are provided for surgical patients requiring sedation following elective and/or emergency surgery.
• the use and method of the invention are provided for critically ill patients with an APACHE II score of below 24, preferably below 19.
• the use and method of the invention are provided for patients early in the course of their critical illness (i.e. when the systemic inflammatory response is not fully activated).
• a free-radical scavenging sedative agent and a metal ion chelating agent may be administered simultaneously (as in the case of 'Diprivan' with the results reported herein, i.e. combined in one formulation), separately (for example via separate infusion lines) or sequentially (provided that sedation is maintained and an adequate metal-ion chelating agent dose and concentration is maintained in-vivo at the same time).
• An adequate level of a metal- ion chelating agent is a function of a number of factors, including the patient, their overall & metal ion homeostasis condition and whether the patient is receiving any additional metal ion supplementation.
• the metal ion chelating properties and concentrations are those as obtained from disodium edetate in the modified formulation of 'Diprivan' used in the accompanying Experimental & Results.
• the components may be administered continuously by infusion (together as a co- infusion or separately) or via intermittent bolus injections.
• propofol formulations without a metal ion chelating agent may be administered with an independent administration of a metal ion chelating agent.
• the effects described herein may arise from a beneficial synergy resulting from a reduction in physiological stress caused by use of the free radical scavenging sedative agent, and a beneficial effect on acute stress responses resulting from use of the metal ion chelating agent.
• the beneficial synergy is believed to result in lower levels of stress-related agents and/or an anti-oxidative effect.
• the benefit reported herein is believed to arise, in part, from the free radical scavenging/anti-oxidative effects of the sedative propofol.
• formulations containing other free radical scavenging/anti-oxidative sedatives may also show benefit.
• a 'free radical scavenging sedative agent we mean a sedative agent that also has the ability to scavenge free radicals in-vivo (with the ability to counteract free radical mediated oxidative stress processes).
• other such agents may include, for example, barbiturates such as phenobarbitol.
• the free radical scavenging sedative agent is preferably lipophilic in nature.
• Benefit is also believed to arise, in part, from the metal ion chelator chelating (trace) metal ions involved in oxidative processes, for example, divalent metal ions involved in enzyme free radical mechanisms leading to apoptosis and cell death.
• metal ions include calcium, iron, zinc and copper.
• the metal ion chelating agent is preferably hydrophilic in nature. Benefit may be observed by suitable inhibition of calcium influx induced apoptosis (Ca channel blockers, such as Nifedapine, may also be useful in this context) and/or enhanced hypo-zincaemia and/or a reduction in iron serum levels.
• lipid component of an oil-in-water emulsion used as a pharmaceutically-acceptable carrier may also provide part of a beneficial synergy.
• concentrations of components may vary, provided that sedation and adequate metal-ion chelating agent dose and concentration are maintained.
• antioxidants such as VitaminE
• the time to sedation should preferably be as soon as possible after injury for the most benefit to be observed (typically within 1 to 2 hours), but the time may vary depending on the nature of the particular patient and injury.
• the duration of treatment should be as long as is considered necessary by an attending physician.
• the duration of treatment for a benefit to be observed may be longer than that normally required or used in routine practice for mechanical ventilation.
• a beneficial effect may be evidenced by, for example, an improvement in, or maintenance of (if a deterioration is usually expected), organ function and/or standard physiological measures such as blood pressure, body temperature and/or a normalisation of immune function. Treatment would usually be for 24 hours or greater.
• the depth of sedation may be light, moderate or deep depending on the particular patient and the extent of their illness. Sub-sedative doses may also be usefully administered in certain patients.
• the dose of components should be sufficient to achieve the desired level of sedation and achieve an adequate metal-ion chelating agent dose. Based on 'Diprivan' dosage levels in the range 0.3-8.0 mg/Kg/hr, doses of disodium edetate in the range 5xl0 "5 g/hr to about 0.05 g/hr are appropriate for particular benefit. Equivalent doses of other metal ion chelating agents may be calculated based on these figures.
• a further feature of the invention is therefore, a pharmaceutical composition comprising a free-radical scavenging sedative agent, such as a barbiturate, and a metal ion chelating agent, in association with a pharmaceutically-acceptable diluent or carrier.
• a preferred pharmaceutically-acceptable diluent or carrier is an oil-in-water emulsion using a water-immiscible solvent (see elsewhere herein for further details).
• compositions in which the free radical scavenging sedative (such as propofol) and the metal chelating agent (such as edetate) are present in a composition suitable for administration other additives may also be present (see later under "Combination with other therapeutic agents").
• Suitable pharmaceutical compositions containing propofol for use in the present invention are described and claimed in United Kingdom Patent 2,298,789 and US Patent 5,714,520 (the contents of which are hereby incorporated by reference), and corresponding applications/patents in other territories.
• an 'oil-in-water emulsion' we mean a distinct two-phase system that is in equilibrium and in effect, as a whole, is kinetically stable and thermodynamically unstable.
• 'edetate' we include metal ion chelating/sequestering agents, such as polyaminocarboxylate chelators, such as 'edetate' (ethylenediaminetetraacetic acid -EDTA), diethylenetriaminepentaacetic acid (DTP A) and EGTA, and derivatives thereof.
• 'edetate' ethylenediaminetetraacetic acid -EDTA
• DTP A diethylenetriaminepentaacetic acid
• EGTA EGTA
• suitable metal ion chelating agents are those salts having lower affinity for the free acid form than calcium, and in particular those derivatives descibed in UK Patent No. 2,298,789.
• a particular, preferred metal ion chelating agent is disodium edetate.
• Desferroxime is a further suitable metal ion chelating agent.
• the metal ion chelating agent will be present in the compositions in a molar concentration (with respect to the metal ion chelating agent free acid) in the range 3xl0 "5 to 9xl0 "4 .
• the metal ion chelating agent free acid is present in the range 3xl0 "5 to 7.5x10 " , for example in the range 5xl0 "5 to 5x10 " and more preferably in the range 1.5xl0 '4 to 3.0xl0 "4 , most preferably about 1.5xl0 "4 .
• the metal ion chelating agent free acid is present in the range from about 0.0005% to 0.1% w/v.
• the 0.005 % concentration of disodium edetate used in modified 'Diprivan' was selected to prevent significant growth of microorganisms for at least 24 hours in the event of adventitious, extrinsic contamination (see UK Patent No. 2,298,789 - the relevant information from which is hereby incorporated by reference).
• the benefit of the present invention may be achieved using lower than a 0.005 % concentration.
• a propofol composition suitable for use according to the present invention typically comprises from 0.1 to 5%, by weight, of propofol.
• the composition comprises from 1 to 2% by weight of propofol and, in particular, about 1% or about 2%.
• Propofol alone may be emulsified with water by means of a surfactant, but it is preferred that propofol is dissolved in a water-immiscible solvent prior to emulsification.
• the water-immiscible solvent is suitably present in an amount that is up to 30% by weight of the composition, more suitably 5-25%, preferably 10-20% and in particular about 10%.
• water-immiscible solvents can be used in the compositions suitable for use in the present invention.
• the water-immiscible solvent is a vegetable oil, for example soy bean, safflower, cottonseed, corn, sunflower, arachis, castor or olive oil.
• the vegetable oil is soy bean oil.
• the water-immiscible solvent is an ester of a medium or long-chain fatty acid for example a mono-, di-, or triglyceride; or is a chemically modified or manufactured material such as ethyl oleate, isopropyl myristate, isopropyl palmitate, a glycerol ester or polyoxyl hydrogenated castor oil.
• the water-immiscible solvent may be a marine oil, for example cod liver or another fish-derived oil.
• Suitable solvents also include fractionated oils for example fractionated coconut oil or modified soy bean oil.
• the compositions suitable for use in the present invention may comprise a mixture of two or more of the above water-immiscible solvents.
• Propofol is emulsified by means of a surfactant.
• Suitable surfactants include synthetic non-ionic surfactants, for example ethoxylated ethers and esters and polypropylene-polyethylene block co-polymers, and phosphatides for example naturally occuring phosphatides such as egg and soya phosphatides and modified or artificially manipulated phosphatides (for example prepared by physical fractionation and/or chromatography), or mixtures thereof.
• Preferred surfactants are egg and soya phosphatides.
• the compositions suitable for use in the present invention are suitably formulated to be at physiologically neutral pH, typically in the range 6.0-8.5, if necessary by means of alkali such as sodium hydroxide.
• compositions suitable for use in the present invention may be made isotonic with blood by the incorporation of a suitable tonicity modifier for example glycerol.
• suitable tonicity modifier for example glycerol.
• the compositions suitable for use in the present invention are typically sterile formulations and are prepared according to conventional manufacturing techniques using for example aseptic manufacture or terminal sterilisation by autoclaving. Further details on the preparation of compositions suitable for use in the present invention are included in the Patents referred to herein in the introduction, and are hereby incorporated by reference.
• the compositions suitable for use in the present invention are useful as anaesthetics, which includes sedation and induction and maintenance of general anaesthesia, and such properties may be usefully exploited during the improvement in survival in critically ill patients according to the present invention.
• Propofol is a short-acting anaesthetic, suitable for both induction and maintenance of general anaesthesia, for sedation to supplement regional analgesic techniques, for sedation of ventilated patients receiving intensive care and for conscious sedation for surgical and diagnostic procedures in Intensive Care Units.
• Propofol may be administered by single or repeated intravenous bolus injections or by continuous infusion. It is very rapidly removed from the blood stream and metabolised. Thus the depth of sedation is easily controlled and patient recovery on discontinuing the drug is usually rapid and the patient is often significantly more clear headed as compared to after administration of other anaesthetics.
• the dosage levels suitable for improving survival in critically ill patients according to the invention are generally within those typically used for sedation.
• dose levels in the range 0.3-8.0 mg/Kg/hr for adult humans may be used, but may be optimised to achieve the desired effect in any particular patient, in accordance with normal skill in the art.
• a continuous infusion at about 0.3-4.0 mg/kg/hr for sub- to moderate sedation is typically used. See US 5,714,520 for further information on dosing, the contents of which are hereby incorporated by reference.
• the propofol composition of the present invention may be administered for longer than is used for simple sedation, i.e. a patient may thus be maintained under sedation until it is considered that effective treatment has been delivered.
• Artificial ventilation requires sedation, and the present propofol formulations can be used for this purpose. Simultaneously, the present propofol formulations can improve survival potential by a mechanism that is independent of the artificial ventilation.
• Suitable therapeutic or pharmaceutical agents are those capable of being administered parenterally in an oil-in-water emulsion.
• agents are lipophilic compounds and may for example be antif ⁇ ngal agents, anaesthetics, antibacterial agents, anti- cancer agents, anti-emetics, antioxidants, agents acting on the central nervous system such as diazepam, steroids, barbiturates and vitamin preparations.
• the agents most useful are those which may have additional benefit in the treatment or prevention of multiple organ dsyfunction and death and its causes, for example, antibacterial agents, NSAIDs, Vitamin E, fluid therapy and vasoactive amines.
• Supportive treatment of organ insufficiency may include artificial ventilation and dialysis.
• compositions containing a free radical scavenging sedative for parenteral administration which comprises, for example, an oil-in-water emulsion, containing a therapeutic or pharmaceutical agent, in which the agent, either alone or dissolved in a water-immiscible solvent, is emulsified with water and a free radical scavenging sedative (such as propofol), and stabilised by means of a surfactant and which further comprises an amount of a metal ion chelating agent, for the manufacture of a medicament for improving survival in critically ill patients.
• a method of improving survival in critically ill patients comprising the use of such compositions.
• this feature of the present invention relates to such oil-in-water emulsions which typically are administered, to patients in need thereof, over periods of a day or more.
• the programme included four studies in adult ICU sedation. Three of these studies compared 1% original formulation 'Diprivan' versus modified formulation 'Diprivan' . These were Study 53: in surgical ICU patients (SICU), Study 54: in medical ICU patients (MICU) and Study 60: in patients with renal failure. The fourth study, Study 69 was a comparison of modified formulation 'Diprivan' against standard sedative agents (SSAs, without EDTA) in0 medical, trauma and surgical ICU patients.
• SSAs standard sedative agents
• the mortality benefit although perhaps not statistically significant, may be less apparent for a number of reasons. For example, such reasons may include low patient numbers, patients considered to be severely ill (such as severe renal failure patients) and so unlikely to benefit from the invention (which is of particular benefit for critically ill patients), or the duration of treatment is too short for a benefit to be observed.
• Futhermore in Study 53 patients were administered with the propofol formulations early in the course of each patient's illness (i.e. immediately post-operatively), whereas administration was later in the course of illness in the other studies. Thus, greater outcome benefit may be provided when the modified formulation 'Diprivan'is administered early in the course of critical illness (i.e. when the systemic inflammatory response is not fully activated).
• SICU patients who were 17 years of age or older, hemodynamically stable, and expected to require intubation and mechanical ventilation for at least 2 hours were eligible for inclusion in the trial. Patients were ineligible for the study if they were unable to respond to 15 stimuli because of prolonged paralysis due to trauma or neuromuscular blockade.
• Eligible patients were men and women 13 years of age or older who were admitted to the ICU with pulmonary dysfunction or adult respiratory distress syndrome (ARDS) as one of their primary diagnoses or complications, hemodynamically stable, expected to require at least 20 48 hours of sedation and mechanical ventilation.
• ARDS adult respiratory distress syndrome
• Eligible patients consisted of SICU or MICU patients with documented impaired renal function (estimated creatinine clearance ⁇ 40 mL/min) who were 17 years of age or older, hemodynamically stable, and expected to require intubation and mechanical ventilation for 25 >24 hours, and who had achieved adequate levels of postoperative analgesia (SICU patients only). Exclusion criteria included head trauma and an inability to respond to stimuli because of paralysis.
• Demographic variables and treatment descriptors were compared to assess comparability of the propofol and propofol-EDTA groups.
• Chi-square analysis was used for the categorical variable (sex), and Wilcoxon test (using normal approximations and continuity corrections of 0.5) was used for continuous variables (such as age, body weight, APACHE II score, total propofol dose, mean propofol infusion rate, and duration of infusion). Gender, age, body weight, and severity of illness as indicated by APACHE II score did not differ significantly between the propofol and propofol-EDTA groups.
• Figure 1 shows survival curves by treatment group (propofol or propofol-EDTA), study population (SICU, MICU, or renal failure), and baseline APACHE II score ( ⁇ 15, 15-24, or >24).
• Figure 2 shows predictions of survival based on a model incorporating the influence of study population, baseline APACHE II score, and treatment effect.
• the model predicts an improvement in survival for SICU patients receiving propofol-EDTA (Figure 2A).
• Figure 2B For patients with an APACHE II score of 21, the model predicts that modified formulation 'Diprivan' will considerably improve survival in SICU patients ( Figure 2C).
• Cox proportional hazards regression analysis was used to model the influence of predictors of survival.
• the null model was a model stratified by patient population (i.e. a model that allowed a different baseline hazard function for patients in the SICU, MICU, and renal failure groups, without the restriction that these three hazards be proportional).
• To the null model was added APACHE II score, with a different slope and intercept for each of the three studies, and the treatment variable (propofol only versus propofol-EDTA). The treatment effect was allowed to differ among the three studies.
• Figure 3 summarizes the results of the Cox proportional hazards model.
• the linear predictor on the y-axis is the extent to which mortality is expected to increase with each predictor.
• the x-axis reflects the widespread influence of APACHE II score on survival.
• the addition of EDTA produced an effect equivalent to decreasing the APACHE II score from 38 to 10.
• the effect produced by use of modified formulation 'Diprivan' depended on APACHE II score. In patients with an APACHE II score ⁇ 25, survival is predicted to improve with modified formulation 'Diprivan'; in patients with an APACHE II score >30, survival is expected to worsen.
• the major finding of this study is the improved survival rate in SICU patients receiving modified formulation 'Diprivan', compared with original formulation 'Diprivan'.
• the mortality rate for the SICU propofol group was close to that predicted, whereas the rate for the SICU propofol-EDTA (modified formulation 'Diprivan') group was lower than expected, thereby indicating a beneficial therapeutic effect.
• critical illness was of more acute onset, and treatment with modified formulation 'Diprivan' began sooner after the critical insult than in MICU patients.
• organ injury was more advanced in MICU and renal failure patients than in SICU patients, causing modified formulation 'Diprivan' to have a decreased therapeutic benefit.
• MICU and renal failure patients also appeared to have more serious and longer duration of disease prior to admission to the ICU. It is also likely that malnutrition was greater in these patients.
• modified formulation 'Diprivan' may have a beneficial therapeutic effect in select groups of critically ill patients, with the greatest effect on survival occurring in SICU patients.
• the benefits of modified formulation 'Diprivan' in SICU patients were sufficiently large to suggest that modified formulation 'Diprivan' may represent a potential new therapy for the treatment of critically ill patients with systemic inflammatory response syndrome.
• Figure 2 Prediction of survival based on a model incorporating the influence of study population and treatment effect for APACHE II scores of 11 (A), 21 (B), and 30 (O
• SICU-no EDTA SICU patients who received propofol
• the linear predictor on the y-axis is the extent to which mortality is expected to increase with each predictor.
• the widespread influence of APACHE II score on survival in all groups is evident.
• SICU-no EDTA SICU patients who received propofol
• SICU-EDTA SICU patients who received propofol-EDTA
• renal failure-no EDTA renal failure patients who received propofol
• renal failure-EDTA renal failure patients who received propofol-EDTA
• MICU MICU patients who received either propofol or propofol-EDTA (all MICU patients grouped together).
• the benefits disclosed herein can be demonstrated in a prospective study with mortality as the primary endpoint, comparing modified formulation 'Diprivan' against e.g. original formulation 'Diprivan'.
• the trial treatment is intravenous infusion of propofol commencing at 5 ⁇ g/kg/min. and titrated to achieve the depth of sedation considered appropriate by the investigator. Randomisation of patients is post-operative and the study uses 1% strength modified formulation 'Diprivan'. Note that the benefit is also believed to attach to 2% strength (in which the amount of disodium edetate is half that in an equivalent propofol dose of the 1% strength).
• trial is designed with 250 patients in each arm (to give an 80% probability and p ⁇ 0.05 significance level), for 28-day mortality in the original formulation 'Diprivan' arm of 17.5% and in the modified formulation 'Diprivan' arm of 8.6% (i.e. an absolute reduction of 8.9% or a relative reduction of 51%).
• Trial summary :
• Patients with head injury or those who have had an established regimen of sedation with agents other than Diprivan in the period immediately preceding consideration for the study will be excluded.
• the primary endpoint is severity-adjusted 28-day mortality, i.e. death during sedation and within 28 days from start of (post-operative) sedation irrespective of duration of sedation (but with a minimum duration of treatment of 24 hours).
• the primary endpoint thus includes patients sedated for 1 day and then dying on day 27 since commencement of sedation, as well as patients sedated for 10 days and dying on day 27 since commencement of sedation.
• Secondary endpoints include sequential organ failure assessment 7- & 28-days following start of sedation and time on ventilation.
• Data to be recorded include patient demographics, past history, medications (with a restriction on concomitant medication having no EDTA), reason for surgery, type of anaesthesia (with a restriction on the surgical anaesthetic having no EDTA), SAPS II and SOFA at baseline, 7- and 28-days, duration of sedation (and ventilation) and total dose of propofol and adverse events.

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• 2001
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  • 2001-05-22 EP EP01931901A patent/EP1289518A2/en not_active Ceased
  • 2001-05-22 CA CA002408033A patent/CA2408033A1/en not_active Abandoned
  • 2001-05-22 WO PCT/GB2001/002267 patent/WO2001089514A2/en not_active Application Discontinuation
  • 2001-05-22 MX MXPA02011531A patent/MXPA02011531A/es unknown
  • 2001-05-22 AU AU2001258592A patent/AU2001258592A1/en not_active Abandoned
• 2002
  • 2002-11-22 NO NO20025628A patent/NO20025628L/no not_active Application Discontinuation

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