CN1430511A - Method of improving survival of patients - Google Patents

Abstract

The 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; in particular such use of pharmaceutical compositions comprising a free radical scavenging sedative agent (such as propofol) and a metal ion chelating agent (such as edetate) in association with a pharmaceutically-acceptable diluent or carrier, especially such composition comprising 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 (such as disodium edetate).

Description

survival benefit

The invention relates to a method for treating and improving the survival rate of critical patients, and the use of certain sterile sedative pharmaceutical compositions in the preparation of medicaments for improving the survival rate of such patients.

Despite advances in research on emergency medicine, survival rates for critically ill patients remain low and variable, with a typical mortality rate of 10%-40%. In addition to the development of antibiotics and advances in medical technology (such as newer resuscitation techniques, such as ventilation and fluid administration), although many medical studies involving drugs and treatments have been conducted over the years, the impact on critical patient survival is still very small. Accordingly, there remains a substantial medical need to increase the survival rate of critically ill patients.

Propofol is an intravenously administered sedative used for induction and maintenance of general anesthesia and for sedation in intensive care units. Propofol is a very successful anesthetic sold under the trademark 'Diprivan' for the treatment of humans and 'Rapinovet' for the treatment of animals.

Once the anesthetic properties of propofol were recognized, the applicant filed UK patent application 13739/74 and was granted UK patent 1,472,793. Corresponding patents are also granted in the USA (USP4,056,635, USP 4,452,817 and USP 4,798,846) and many other territories.

Occasional external microbial contamination due to non-sterile handling of the original formulation of 'Diprivan' could lead to 'clustering' of post-operative infections, and the development of an improved formulation with suitable additives capable of Delay the growth of common microorganisms to no more than 1 log (i.e. 10-fold) within 24 hours of exposure to external contamination. After developing an improved propofol preparation containing ethylenediamine tetraacetate, applied for and authorized the British patent 2,298,789, and corresponding patents in the United States (USP 5,714,520; USP 5,731,355; USP5,731,356 and USP 5,908,869) and other regions Also authorized. A modified formulation of 'Diprivan' is sold containing 0.005% disodium edetate.

In order to meet the FDA regulations, a clinical trial procedure was carried out in the United States during 1993-1998 using a modified formulation of 'Diprivan'. The aim was to find out what adding 0.005% disodium edetate to 'Diprivan' would do to its pharmacokinetics, efficacy and safety profile. No differences in pharmacokinetics or efficacy were expected. However, it is estimated that it may produce differences in serum calcium and magnesium concentrations, and probably also differences in renal function. Therefore, these safety parameters are the main measures in the clinical trial procedure.

The described program, which included ten independent clinical trials, demonstrated that the addition of disodium edetate (0.005% w/v) did not affect the pharmacokinetics or efficacy of 'Diprivan'. With regard to safety, no clinically significant effects on calcium or magnesium levels have been seen, and it has been reported that neither short-term nor long-term use of the improved formulation produces calcium or magnesium due to the introduction of disodium edetate Disorders of homeostasis. In fact, clinically, the overall adverse event distribution of the modified "Diprivan" was no different from that of "Diprivan". The only significant effect was higher urinary excretion of zinc in intensive care unit (ICU) patients who received the modified formulation for long-term sedation compared with those who received standard sedation. The clinical significance of this finding is unclear, but modified 'Diprivan' may be considered as a prophylactic measure of zinc supplementation when given chronically in patients prone to zinc deficiency.

The nature and pattern of all adverse events spontaneously exposed when using 'Diprivan' has been monitored and although exact values cannot yet be determined, in addition to a reduction in infectious 'clusters' associated with occasional external microbial contamination, the introduction of improved formulations The pattern of reported adverse events was similar to that before introduction. No new or undesired adverse reactions occurred, indicating that the addition of disodium edetate did not affect the safe profile of 'Diprivan'. In particular, there was no increase in the number of reports of symptoms attributable to disodium edetate, such as hypocalcemic symptoms or renal injury.

Raw data from clinical trial procedures have not previously been publicly available. Furthermore, as mentioned above, the primary objective of these trials was to see if there were any (clinically) significant inappropriate differences in the distribution of adverse events with the modified formulation of 'Diprivan'.

We can now report that data from four of our clinical trials have shown improved survival in certain critically ill patients. In addition, a more specific survival/outcome analysis (not previously requested) has been performed on these clinical trial data. Here we report for the first time the new results obtained from this particular, concrete analysis. Medical advances are often made through this up-to-date analysis of medical data. Thus, the conclusions and applications of the present analysis represent previously unpublished, novel and surprising results.

In short, we have now surprisingly found that the improved formulation 'Diprivan', 2,6-diisopropylphenol (propofol) It has previously unrecognized properties and is effective in significantly improving the survival rate of certain critically ill patients. These novel properties observed may provide an opportunity to treat selected patient populations in intensive care units (ICUs) with established propofol-containing formulations and, in doing so, significantly improve survival rates during selective sedation/anesthesia. Results reported here for the first time show that 2,6-diisopropylphenol (propofol) in the modified formulation 'Diprivan' has a real benefit in improving survival in critically ill patients and provides a basis for the treatment of such patients. A new therapeutic strategy is provided.

Therefore, a pharmaceutical composition comprising a free radical scavenger sedative (such as propofol) and a metal ion chelator (such as edetate) is of great value as a therapy to improve survival in certain critically ill patients of.

The purpose of comparing the use of propofol with other sedatives (such as midazolam) in ICUs was to focus on cost, independent of ventilation and nutrition. Such studies failed to reveal any benefit on survival or mortality associated with the use of any particular sedative. Eighteen trials comparing midazolam with propofol (without EDTA) for ICU sedation showed similar mortality rates between propofol and midazolam (Intensive Care Medicine, 1999, 25 1999-Suppl 1pp S158Abs. ^-12th Annual Congress of European Society of Intensive Care Medicine, Berlin, 3-6 Oct. 1999). Previously, no studies have shown improved survival benefits of 'Diprivan' over other sedatives.

Processes known to involve death and multiple organ dysfunction/failure are particularly complex, and the effectiveness of the improved 'Diprivan' in combating complex events involving death was particularly surprising.

Accordingly, the present invention provides a method of improving the survival rate of critically ill patients comprising administering a pharmaceutical composition comprising a free radical scavenging sedative and a metal ion chelating agent, and a pharmaceutically acceptable Accepted diluent or carrier.

The present invention also provides a method for improving the survival rate of critically ill patients, which comprises administering a pharmaceutical composition containing a free radical scavenging sedative and a metal ion chelating agent. The pharmaceutical composition is patented in the UK 2,298,789 described and claimed.

In particular, the present invention provides a method of improving the survival rate of critically ill patients comprising administering a sterile pharmaceutical composition for parenteral administration comprising an aqueous solution emulsified with water and stabilized with a surfactant. An oil-in-oil emulsion in which propofol is dissolved in a water-immiscible solvent and said composition also contains a metal ion sequestrant.

More particularly, the present invention provides a method of improving the survival rate of critically ill patients, which comprises administering a parenterally administered sterile pharmaceutical composition containing a An oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent and the composition also contains ethylenediaminetetraacetate.

The present invention also provides a pharmaceutical composition that can be used as a drug for improving the survival rate of critical patients, which contains a free radical scavenging sedative, a metal ion chelating agent, and a pharmaceutically acceptable diluent or carrier.

The present invention also provides a pharmaceutical composition comprising a free radical scavenging sedative and a metal ion chelating agent useful as a medicament for improving survival in critically ill patients, said pharmaceutical composition being described and claimed in British Patent 2,298,789.

In particular, the present invention provides a sterile pharmaceutical composition for parenteral administration useful as a medicament for improving the survival rate of critically ill patients, said composition comprising an oil-in-water emulsified with water and stabilized by a surfactant. type emulsion in which propofol is dissolved in a water immiscible solvent and said composition also contains a metal ion chelating agent.

More particularly, the present invention provides a sterile pharmaceutical composition for parenteral administration useful as a medicament for improving the survival rate of critically ill patients, said composition comprising a water-in-water emulsified and stabilized by a surfactant. An oily emulsion in which propofol is dissolved in a water-immiscible solvent and the composition also contains ethylenediaminetetraacetate.

The present invention also provides the use of the pharmaceutical composition in the preparation of a medicament for improving the survival rate of critically ill patients, wherein the pharmaceutical composition contains a free radical scavenging sedative and a metal ion chelating agent, and a pharmaceutically acceptable diluent agent or carrier.

The present invention also provides the use of a pharmaceutical composition for the preparation of a medicament for improving the survival rate of critically ill patients, wherein said pharmaceutical composition contains a free radical scavenging sedative and a metal ion chelating agent, said pharmaceutical composition is disclosed in British Patent 2,298,789 Describe and claim protection.

In particular, the present invention provides the use of a sterile pharmaceutical composition for parenteral administration, wherein said composition contains an oil-in-water emulsified with water and stabilized by a surfactant, in the preparation of a medicament for improving the survival rate of critically ill patients type emulsion in which propofol is dissolved in a water immiscible solvent and said composition also contains a metal ion chelating agent.

More particularly, the present invention provides the use of a sterile pharmaceutical composition for parenteral administration in the preparation of a medicament for improving the survival rate of critically ill patients, wherein said composition contains a water-encapsulated drug emulsified with water and stabilized by a surfactant. An oily emulsion in which propofol is dissolved in a water-immiscible solvent and the composition also contains ethylenediaminetetraacetate.

In addition, the methods and uses fully described herein are also provided with reference to the experiments and results.

The methods and uses of the invention relate to sedation for warm-blooded animals, such as humans.

'Increased survival rate' and 'increased survival rate' refer to a critical patient still alive at a clinically important time, such as 7 days after sedation. Another clinically important time is 28 days after sedation. Post-sedation time can be determined from the point at which sedation is initiated (as in a clinical trial procedure) or from the point at which sedation is discontinued. If a critically ill patient is demonstrated to have fewer or no health-related problems and/or no longer requires mechanical ventilation and/or is less likely to die and/or has a higher likelihood of survival as certified by the attending physician raised, they are also included in these terms.

The patient population that would benefit most from the present invention are 'critical patients', and those who do not receive sedation because of chronic illness, i.e. 'critical patients' are those who, for example, have suffered an acute impairment, injury or trauma and are in (elective or emergency ) those requiring sedation following surgery, drug therapy, or trauma. This specifically includes critically ventilated patients in ICUs. Patients with a probability of death of about 70% or higher (eg, from an underlying disease condition, such as severe renal failure) would benefit little from the present invention. Likewise, patients who are otherwise reasonably healthy, with a probability of death of about 5% or less, will benefit less from the invention. Thus, in one of its embodiments, the present invention provides an effective treatment for patients with multiple organ dysfunction/failure. In another embodiment, the uses and methods of the present invention are provided to surgical patients requiring sedation following elective and/or emergency surgery. In another embodiment, the uses and methods of the present invention are administered to critically ill patients with an APACHE II value below 24, preferably below 19. The uses and methods of the present invention are preferably provided to patients in the early stages of critical illness (ie when the systemic inflammatory response has not yet been fully activated).

We believe the effects described here are produced by the combination of a free radical scavenger sedative and a metal ion chelator. These respective components may be combined simultaneously (as in the case of 'Diprivan' with the results reported here, i.e., combined in one formulation), separate (e.g., via separate infusion lines) or sequentially (assuming sedation is maintained, At the same time, maintain the appropriate dosage and concentration of the metal ion chelating agent in the body) administration. The appropriate level of metal ion chelator is a function of several factors including the patient, their total & metal ion homeostasis and whether the patient is being supplemented with any other metal ions. In one of these embodiments, the chelating properties and concentrations of said metal ions are those obtained from disodium edetate in the modified formulation of 'Diprivan' used in the Tests & Results.

The components can be administered continuously by infusion (co-infusion or separately) or via intermittent bolus injections. For example, a formulation of propofol without a metal ion chelator can be co-administered with a separate administration of the metal ion chelator.

Without wishing to be bound by theory, we believe that the effects described here may result from a beneficial synergy resulting from a reduction in the physiological stress response induced by the use of free radical scavenging sedatives, And the effects described here may be caused by a beneficial effect on the acute stress response produced by the use of metal ion chelating agents. The beneficial synergy is believed to result in lower levels of stress-related agents and/or antioxidant effects.

The beneficial effects reported here are believed to result in part from the free radical scavenging/antioxidative effects of sedating propofol. Therefore, formulations containing other free radical scavenging/antioxidant sedatives may also exhibit this benefit. 'Free radical scavenging sedative' means a sedative with the ability to scavenge free radicals in the body (with the ability to counteract free radical-mediated oxidative stress processes). In addition to propofol, other such agents may include, for example, barbiturates such as phenobarbital. The free radical scavenging sedative is preferably lipophilic.

The benefit is believed to be due in part to metal ion chelators that sequester (trace amounts) metal ions involved in oxidative processes, for example, enzymatic free radical functions leading to apoptosis and cell death of divalent metal ions. Such metal ions include calcium, iron, zinc and copper. Preferably the metal ion sequestrant is hydrophilic. The benefit may also be through appropriate inhibition of calcium influx-induced apoptosis (calcium channel blockers, such as nifedipine, which are also beneficial in the present invention) and/or elevation of hypo-blood zinc and/or A reduction in iron serum levels was observed. It is believed that the specific combination of (lipophilic) free radical scavenger/antioxidant sedatives and (hydrophilic) metal ion chelators is very important for balancing the resistance to oxidative stress. The lipid component of the oil-in-water emulsion used as a pharmaceutically acceptable carrier may also provide part of the beneficial synergistic effect. The relative concentrations of the components can be varied assuming that sedation and appropriate doses and concentrations of the metal ion chelator are to be maintained. The addition of other antioxidants (such as vitamin E) can also exert other beneficial effects.

Particular attention should also be paid to the following factors:

1. The timing of sedation is preferably as soon as possible after the injury to observe the most beneficial effect (usually within 1-2 hours), but this time can vary according to the nature of the injury and the particular patient.

2. The duration of treatment is as long as the attending surgeon deems necessary. The duration of treatment for a beneficial effect to be observed may be longer than typically used or required in routine practice of mechanical ventilation. Therefore, if one wishes to see or observe a treatment effect, one can proceed with the treatment. Beneficial effects may be demonstrated, for example, by an increase or maintenance of organ function and/or standard physiological measures such as blood pressure, body temperature (if decline is normally desired) and/or restoration of immune function. Treatment time is usually 24 hours or longer.

3. Depending on the particular patient and the extent of his disease, the depth of sedation can be mild, moderate or deep. Often, sub-sedative doses are also given to specific patients.

4. The doses of the ingredients should generally be sufficient to achieve the desired level of sedation and to achieve a suitable metal ion sequestrant dose. Dosage levels of 'Diprivan' of 0.3-8.0 mg/Kg/hr, disodium edetate doses of about 5 x 10 ^-5 g/hr-0.05 g/hr are particularly beneficial. Equivalent doses of other metal ion chelating agents can be calculated from these values.

'Pharmaceutical composition comprising a free radical scavenging sedative and a metal ion chelating agent' includes compositions comprising both agents (allowing the simultaneous administration of the ingredients), and wherein the individual ingredients may be administered separately or sequentially system. Accordingly, another feature of the present invention is a pharmaceutical composition comprising a free radical scavenging sedative, such as a barbiturate, and a metal ion chelating agent, and a pharmaceutically acceptable diluent or carrier. Preferred pharmaceutically acceptable diluents or carriers are oil-in-water emulsions using water-immiscible solvents (see elsewhere for further details).

In a pharmaceutical composition suitable for administration, containing a free radical scavenging sedative (such as propofol) and a metal ion chelating agent (such as ethylenediaminetetraacetic acid salt), other additives (see later "with combination of other therapeutic agents"). Suitable pharmaceutical compositions containing propofol for use in the present invention are described and claimed in UK Patent 2,298,789 and US Patent 5,714,520 and corresponding applications/patents elsewhere (the contents of which are incorporated herein by reference).

By 'oil-in-water emulsion' is meant a separated two-phase system which is in equilibrium and, indeed, kinetically stable and thermodynamically unstable.

The term 'ethylenediaminetetraacetate' includes metal ion chelating/sequestering agents such as polyaminocarboxylate chelating agents such as 'ethylenediaminetetraacetic acid' (ethylenediaminetetraacetic acid-EDTA), Diethylenetriaminepentaacetic acid (DTPA) and EGTA, and their derivatives. For example, the disodium derivative of EDTA is known as disodium EDTA. In general, suitable metal ion sequestrants are those salts which have a lower affinity for the free acid than calcium, especially the derivatives described in British Patent No. 2,298,789. A particularly preferred metal ion sequestrant is disodium edetate. Desferroxime is another suitable metal ion sequestrant.

In propofol compositions containing ethylenediaminetetraacetate, generally the metal ion chelating agent is present in the composition at a molar concentration of 3×10 ⁻⁵ to 9×10 ⁻⁴ . Preferably, the free acid of the metal ion chelating agent is 3×10 ^-5 -7.5×10 ^-4 , such as 5×10 ^{-5 -5} ×10 ^-4 , more preferably 1.5×10 ^-4 -3.0×10 ^-4 , most preferably Preferably about 1.5 x 10 ^-4 is present. In particular, the metal ion sequestrant free acid is present at about 0.0005% to 0.1% w/v. EDTA at a concentration of 0.005% was chosen to be used in the modified 'Diprivan' to prevent significant microbial growth for at least 24 hours in the event of accidental external contamination (see British Patent 2,298,789, its Relevant information is incorporated here by reference). Depending on the properties of the selected metal ion sequestrant, the benefits of the present invention may be obtained using concentrations below 0.005%.

Propofol compositions suitable for use in the present invention typically contain 0.1 to 5% by weight propofol. Preferably the composition contains 1-2% by weight, especially about 1% or about 2% by weight of propofol. Propofol may be emulsified in water alone with the aid of a surfactant, preferably the propofol is dissolved in a water-immiscible solvent prior to emulsification. The water-immiscible solvent constitutes 30% by weight of the composition, preferably 5-25%, more preferably 10-20%, especially 10%.

A wide variety of water-immiscible solvents are suitable for use in the compositions of the present invention. Typical water immiscible solvents are vegetable oils such as soybean, safflower, cottonseed, corn, sunflower, peanut, castor or olive oil. A preferred vegetable oil is soybean oil. Optionally, the water immiscible solvent is an ester of medium or long chain fatty acids, such as monoglycerides, diglycerides, or triglycerides; or a chemically modified or manufactured substance, such as oleic acid Ethyl esters, isopropyl myristate, isopropyl palmitate, glycerides or polyoxyl hydrogenated castor oil. In another alternative, the water-immiscible solvent may be an oil from a marine product, such as cod liver oil or oil derived from other fish. Suitable solvents also include fractionated oils, such as fractionated coconut oil or modified soybean oil. In addition, compositions suitable for the present invention may contain mixtures of two or more of the aforementioned water-immiscible solvents.

Propofol, alone or dissolved in a water-immiscible solvent, is emulsified with the aid of surfactants. Suitable surfactants include synthetic nonionic surfactants, such as ethoxylated ethers and esters and polypropylene-polyethylene block copolymers, and phospholipids, such as naturally occurring phospholipids such as lecithin and soybean phospholipids and modified phospholipids (prepared, for example, by physical fractionation and/or chromatography), or mixtures thereof. Preferred surfactants are lecithin and soy lecithin.

The compositions of the present invention are suitably formulated at a physiologically neutral pH, typically 6.0-8.5, using a base such as sodium hydroxide if desired.

The compositions of the present invention can be made isotonic with blood by admixture with a suitable toxicity modifier, such as glycerol.

The compositions of the invention are generally sterile preparations which are prepared according to conventional techniques of manufacture using aseptic manufacture or terminal sterilization by autoclaving. A detailed description of the preparation of the compositions of the present invention is also included in the patent, which is incorporated herein by reference.

The compositions of the present invention are effective as anesthetic agents, including sedation, induction and maintenance of general anesthesia, and this property can be effectively exploited in the process of the present invention to improve critical patient survival. Propofol is a short-acting anesthetic indicated for induction and maintenance of general anesthesia, for sedation to supplement local anesthetic techniques, for sedation of ventilated patients under surveillance, and for surgical and diagnostic procedures in the intensive care unit. Conscious sedation. Propofol can be administered as a single or repeated intravenous bolus injection or continuous infusion. It is rapidly removed from the bloodstream and metabolized. As a result, the depth of sedation is easily controlled, and the patient recovers quickly after discontinuation of the drug and is significantly more alert than with other anesthetics.

Dosage levels of the present invention suitable for improving survival in critically ill patients are generally within those used for sedation. For 'Diprivan', the dosage level for adults is 0.3-8.0 mg/Kg/hr, but in any particular patient, those skilled in the art can optimize the dosage to obtain the desired effect. Usually about 0.3-4.0 mg/Kg/hr is used as a continuous infusion for partial-to-moderate sedation. Additional information on dosing can be found in US 5,714,520, the contents of which are incorporated herein by reference.

When used, the propofol compositions of the present invention can be administered for a longer period of time than for simple sedation, ie, the patient can be maintained sedated until effective therapy is deemed to have been achieved. Artificial ventilation requires sedation, so the propofol formulations of the present invention can be used for this purpose. At the same time, the propofol formulations of the present invention may increase the likelihood of survival through a mechanism independent of artificial ventilation.

Combination with other therapeutic agents

As another feature of the present invention, there is provided a pharmaceutical composition containing a free radical scavenging sedative (such as propofol) suitable for parenteral administration of the present invention, the pharmaceutical composition contains an oil-in-water emulsion, the The emulsion contains the therapeutic agent or agent alone or dissolved in a water-immiscible solvent, and the emulsion is emulsified with water and a free radical scavenging sedative such as propofol, stabilized by a surfactant, and the The pharmaceutical composition also contains a metal ion chelating agent.

Suitable therapeutic agents or agents are those capable of parenteral administration in the form of oil-in-water emulsions. Usually such agents (which may be administered separately, sequentially or simultaneously with the propofol composition) are lipophilic compounds which may be antifungal agents, anesthetics, antibacterial agents, anticancer agents, anti-emetic agents, antioxidants, Agents acting on the central nervous system, such as diazepam, steroids, barbiturates, and vitamin preparations. The most beneficial agents are those with added benefit in treating or preventing multiple organ dysfunction and death, eg, antibacterials, NSAIDs, vitamin E, fluid therapy and vasoactive amines. Supportive therapy for organ insufficiency may include artificial ventilation and dialysis.

Therefore, the use of a parenterally administered pharmaceutical composition containing a free radical scavenging sedative (such as propofol) in the preparation of a medicament for improving the survival rate of critically ill patients is provided, the pharmaceutical composition contains an oil-in-water type Emulsions containing therapeutic agents or agents alone or dissolved in water-immiscible solvents emulsified with water and a free radical scavenging sedative such as propofol and stabilized by surfactants, And the pharmaceutical composition also contains a metal ion chelating agent. Also provided are methods of improving survival in critically ill patients comprising the use of such compositions. In particular, this feature of the invention relates to such oil-in-water emulsions, which are administered over a period of one day or longer when required by the patient.

The comments made herein concerning typical and preferred propofol compositions of the invention and their preparation also apply mutatis mutandis to oil-in-water emulsions containing additional therapeutic agents or agents.

Experiment & Results

In Table 1 are summarized data from four clinical trials showing improved survival in some critically ill patients.

The procedure included four studies performed in adult ICU sedation. Three of these studies compared a 1% original 'Diprivan' formulation with a modified 'Diprivan' formulation. These are Study 53: Surgical ICU patients (SICU), Study 54: Medical ICU patients (MCIU) and Study 60: Renal failure patients. A fourth study, Study 69, compared a modified 'Diprivan' formulation with standard sedatives (SSAs, without EDTA) in medical, trauma and surgical ICU patients.

Table 1 ICU survival data for original and modified 'Diprivan' formulations Trial Treatment No. Preparation Patient   Track 7 days No. % % % p-Death Dead Alive Value Tracking 28 days No % % p-Death Dead Survival value 53 Improved 59 0 0 100 0.006 1 2 98 0.004 Original 63 8 13 87 11 17 83 54 Improved 42 9 21 79 0.459 19 45 55 1.000 Original 43 13 30 70 19 44 56 60 Improved 18 4 22 78 1.000 5 28 72 0.728 original 19 4 21 79 7 37 63 69 Improved 106 18 17 83 0.303 33 31 69 0.768 SSA 104 24 23 77 35 34 66

Follow-up is timed from the end of ICU sedation.

The analysis of mortality derived from these studies was not the primary measure. Among the surgical patients in Study 53, after 7 days of follow-up, those patients who received the improved 'Diprivan' formulation had a greater mortality rate (0/59 patients) than those who received the original 'Diprivan' formulation (8/63 patients) at Statistically significant reduction (p=0.006). Mortality after 28 days of follow-up was also significantly lower in the modified formulation group.

In other studies, the improvement in mortality may have been less statistically significant for various reasons. Such reasons include lower patient numbers, patients considered very serious (e.g., patients with severe renal failure), and patients who are unlikely to benefit from the invention (which is particularly beneficial for critically ill patients), or the duration of treatment is too long. short. Furthermore, in Study 53, propofol formulations were administered to each patient during the early stages of their illness (i.e., immediately after surgery), whereas in the other studies it was administered later in the illness . Thus, greater benefit can be obtained when the improved 'Diprivan' formulation is administered early in the disease, ie when the inflammatory inflammatory response has not yet been fully activated.

The dosing of propofol and EDTA in these studies is summarized below (ZD#1 = modified formulation; DIP = original formulation).

Table 2A: Infusion Rate of Propofol (mcg/kg/min) Trial No. Treatment Group N Mean Range 53 ZD#1 59 31.64 2.37-79.31

DIP 62 32.18 4.5-72.8554 ZD#1 42 40.27 2.84-105.26

DIP 40 34.51 6.43-123.6760 ZD#1 18 7.89 1.99-17.09

DIP 19 12.62 0.86-45.9169 ZD#1 106 36.0 3.3-154.3 All ZD#1 0.86-154.3

DIP 1.99-123.67

Table 2B: EDTA infusion rate (ng/kg/min) test number treatment group N mean range 53 ZD#1 59 158.18 11.86-396.5454 ZD#1 42 201.33 14.18-526.3160 ZD#1 18 39.47 9.93-85.4469 ZD# 1 106 179.8 16.7-771.3 All ZD#1 9.93-771.3 In Study 53, the mean total dose of EDTA received was 39.1 ± 82.91 mg.

Table 3: Duration of sedation (hours) Trial No. Treatment Group N Mean Range 53 ZD#1 59 41.51 2.0-308.5

DIP 63 43.74 0.92-503.2554 ZD#1 42 111.31 7.83-362.42

DIP 40 95.57 12.25-483.7760 ZD#1 18 74.07 4.0-265.42

DIP 19 69.58 23.0-122.3369 ZD#1 106 149.1 6.7-645.0 All ZD#1 2.0-645.0

DIP 0.92-503.25

Analysis of Survival Rates for Studies 53, 54 & 60

Each patient in the three studies was randomized to receive 1% propofol in aqueous emulsion, the original 'Diprian' formulation (control group) or propofol-EDTA, the modified 'Diprian' formulation (treatment group). All trials were performed with informed consent and were approved by the Institutional Review Boards of all participating institutions. All patients provided written consent before joining this study.

For all three studies, patients with a history of hypersensitivity to the trial drug or any of its components, or who participated in other drug trials within 30 days of entry into the study, were excluded.

Study 53

SICU patients aged 17 years or older who were hemodynamically stable and required intubation and mechanical ventilation for at least 2 hours were eligible for this trial. Patients who were unable to respond to stimuli due to prolonged paralysis due to trauma or neuromuscular blockade were not eligible for this study.

Research 54

Eligible patients were males and females 13 years or older who were admitted to the ICU with adult respiratory distress syndrome (ARDS) or pulmonary dysfunction as a primary diagnosis or comorbidity, and whose hemodynamic Medically stable, requiring at least 48 hours of sedation and mechanical ventilation.

Study 60

Eligible patients consisted of SICU or MICU patients with impaired renal function (estimated creatinine clearance ≤40 mL/min), aged 17 years or older, hemodynamically stable, and requiring intubation and Mechanical ventilation ≥ 24 hours, and has reached the appropriate level of analgesia after surgery (only SICU patients). Criteria for exclusion included head trauma and inability to respond to stimuli due to paralysis.

Patients were randomized to receive propofol or propofol-EDTA. Sedation was initiated by a continuous infusion at an initial rate of 5 μg/kg/min, which was then adjusted until the patient achieved the desired level of sedation. The sedation dose is adjusted to vary the short-term sedation level, and the investigator may change the sedation level if a different sedation level is deemed more appropriate for the patient.

If possible, continue to administer the test drug to the patient until extubation is required. During extubation, propofol or propofol-EDTA may be given to provide a slight level of sedation. If the patient met the eligibility criteria for weaning, the study drug was discontinued and the patient was insufflated during the later period of weaning from mechanical ventilation.

For all studies, standard non-sedating drug therapy was provided at the investigator's discretion, considered necessary and expected not to interfere with trial medications or affect trial measurements. Enteral nutrition is the preferred form of nutritional support, but parenteral nutrition is also permitted.

For SICU and MICU patients, only morphine sulfate and fentanyl are allowed for pain relief. For patients with renal failure, provide appropriate analgesia after surgery and before starting propofol or propofol-EDTA infusions. During sedation, the patient was given an epidural or intravenous infusion of fentanyl for pain relief. In patients receiving lipid infusions for nutritional supplementation, the amount of lipid administered concurrently was reduced to compensate for the amount of lipid infused as part of the propofol and propofol-EDTA formulations.

Demographic variables and treatment descriptors were compared to assess comparability of the propofol and propofol-EDTA groups. Categorical variables (sex) were analyzed using chi-square analysis, and continuous variables (eg, age, body weight, APACHE II value, total propofol dose, mean propofol infusion rate, and duration of infusion) were analyzed using the Wilcoxon test (using positive state approximation and a continuous correction number of 0.5). There were no significant differences in sex, age, body weight, and disease severity expressed by APACHE II values between the propofol and propofol-EDTA groups.

The median total propofol dose, median infusion duration, and mean infusion rate did not differ significantly between the two groups. There were no significant differences in any laboratory measurements between the propofol and propofol-EDTA groups. Serum ionized calcium and magnesium, intact PTH, 1,25-dihydroxyvitamin D, sodium, potassium, and phosphate levels, and renal function (assessed by BUN and serum creatinine levels) were similar in both groups. Blood pressure and heart rate were also similar between the propofol and propofol-EDTA groups.

Survival rates were summarized by counting the number of patients alive and calculating descriptive statistics of how long patients died. Product-Limit (Kaplan-Meier) estimates as a function of survival were calculated relative to the propofol and propofol-EDTA groups within each study population (SICU, MICU, and patients with renal failure). Survival curves were also compared between two groups within each study population using the log-rank test and Wilcoxon's test.

Figure 1 shows survival curves for treatment group (propofol or propofol-EDTA), study population (SICU, MICU, or renal failure), and baseline APACHE II value (<15, 15-24, or >24).

Figure 2 shows predictions of survival based on a model that incorporates the effects of study population, baseline APACHE II value, and treatment effect. For patients with an APACHE II value equal to 11, the model predicted improved survival in SICU patients receiving propofol-EDTA (Fig. 2A). For patients with an APACHE II value of 21, overall survival was worse than for patients with an APACHE II value of 11, but the use of the modified 'Diprivan' formulation was predicted to improve survival in SICU and renal failure patients (Fig. 2B). For patients with an APACHE II value equal to 30, the model predicted that the improved 'Diprivan' formulation would significantly improve survival in SICU patients (Fig. 2C).

Cox proportional hazards regression analysis was used to model the effect on survival predictors. The model predicts the survival time T based on the survival function S(t)=Pr(T>t), where the hazard rate, h(t)>>Pr(t<T, t+dt|T>t)/dt. The actual hazard model is log h(t) = log h ₀ (t) + bx, where the baseline hazard is unaccounted for.

A null model is a model that divides the patient population into strata (ie, a model that allows patients in the SICU, MICU, and renal failure groups to have different baseline hazard functions and does not restrict the proportionality of these three hazard functions). APACHE II values and treatment variables (propofol only vs. propofol-EDTA) were added to the null model with different slopes and intercepts for each of the three studies. Treatment effects varied among the three studies. Other factors that significantly affected survival were by age, sex, height, body weight, serum albumin level, total dose of propofol, mean propofol infusion rate, median infusion duration, SAPS II, Patient type (Medical vs. Surgical) and medical history (Malignant vs. Other) were incrementally added to the model. Statistical calculations were performed using SAS for Windows version 6.12.

Figure 3 summarizes the results of the Cox proportional hazards model. The linear predictors on the y-axis are the extension of the increase in mortality with each predictor. The x-axis reflects the broad effect of APACHE II values on survival. In the SICU study population, the effect of adding EDTA was equivalent to that of reducing the APACHE II value from 38 to 10. In patients with renal failure, the effect of the modified 'Diprivan' formulation was dependent on the APACHE II value. The improved 'Diprivan' formulation was predicted to improve survival in patients with APACHE II values <25; whereas survival in patients with APACHE II values > 30 became worse.

The results of this analysis showed that the modified formulation of 'Diprivan' significantly improved survival in critical surgical patients; its effect on survival in patients with renal failure was variable, with improved survival in patients with APACHE II values <24, whereas APACHE Patients with II values >24 had a lower survival rate.

In this study, we found no EDTA-induced nephrotoxicity assessed by BUN and creatinine.

The main finding of this study was that SICU patients who received the improved 'Diprivan' formulation had improved survival compared to patients who received the original 'Diprivan' formulation.

Mortality in the SICU propofol group was close to predicted, whereas mortality in the SICU propofol-EDTA (modified 'Diprivan' formulation) group was lower than expected, thus demonstrating a beneficial treatment effect.

It is not entirely clear why patients in MICU and severe renal failure could not achieve the benefits seen in SICU patients from the modified 'Diprivan' formulation. The onset of critical illness was more acute in SICU patients, and after severe injury, treatment with the modified formulation of 'Diprivan' had a faster onset of action in SICU patients than in MICU patients. It is likely that MICU and renal failure patients have further developed organ damage compared to SICU patients, making the improved 'Diprivan' formulation less effective. MICU and renal failure patients had more severe and longer-lasting illnesses before ICU admission. It is likely that malnutrition was more severe in these patients. Furthermore, it is likely that MICU patients had underlying trace mineral deficiencies compared with SICU patients, and renal failure patients with higher APACHE II values had more severe renal disease.

The results of this study show that the improved formulation of 'Diprivan' has beneficial therapeutic effects in a selected group of critically ill patients, with the greatest impact on SICU patient survival. The benefit of the improved 'Diprivan' formulation in SICU patients is sufficient to demonstrate that the improved 'Diprivan' formulation could represent an effective new therapy for critically ill patients with systemic inflammatory response syndrome.

Overview of the drawings:

Figure 1: Survival curves for treatment groups (A), study population (B) and APACHE II values (C) : ZD = improved formulation; DIPRIVAN = original formulation

Figure 2: Prediction of Survival Rate Based on the Model, Where the Model Reflects the Study Population Body effects and therapeutic effects at APACHE II values of 11(A), 21(B), and 30(C) fruit

SICU-no EDTA = SICU patients receiving propofol;

SICU-EDTA = SICU patients receiving propofol-EDTA;

Renal failure - no EDTA = renal failure patient receiving propofol;

Renal failure-EDTA = Renal failure patient receiving propofol-EDTA;

MICU = MICU patients receiving propofol or propofol-EDTA (all MICU patients pooled together).

Figure 3: Results of the Cox proportional hazards model

The linear predictors on the y-axis are the extension of the mortality rate increasing with each predictor. Broad effects of APACHE II values on survival were evident in all groups.

SICU-no EDTA = SICU patients receiving propofol;

SICU-EDTA = SICU patients receiving propofol-EDTA;

Renal failure - no EDTA = renal failure patient receiving propofol;

Renal failure-EDTA = Renal failure patient receiving propofol-EDTA;

MICU = MICU patients receiving propofol or propofol-EDTA (all MICU patients pooled together).

Clinical Trials

The benefits disclosed here may be demonstrated in future studies comparing the improved 'Diprivan' formulation with the original 'Diprivan' formulation, with mortality as the primary objective.

The experimental treatment was an intravenous infusion of propofol at 5 μg/kg/min at the beginning, and was titrated to obtain the appropriate depth of sedation considered by the investigator. Randomization of patients was performed postoperatively and the study used a 1% strength modified 'Diprivan' formulation. It is believed that the beneficial effect can also be achieved at 2% strength (wherein the amount of disodium edetate is that of 1% strength, which is half the dose of propofol).

The trial was carried out on 250 patients (providing 80% probability and p<0.05 significance level), after 28 days, the mortality rate of the original 'Diprivan' formulation was 17.5%, and the mortality rate of the improved 'Diprivan' formulation was 8.6%. % (ie, an absolute reduction of 8.9% and a relative reduction of 51%).

Trial overview:

A multicentre randomized comparison of mortality in adult surgical ICU patients (minimum 18 years old, because tracheal intubation required at least 24 hours of sedation) with the original 'Diprivan' formulation and modified 'Diprivan' formulation compared with the original 'Diprivan' 28-day mortality in adult surgical ICU patients treated with formulations and modified 'Diprivan' formulations. Patients with head injury or those sedated with agents other than Diprivan prior to the study were excluded.

The primary objective was strictly-assessed 28-day mortality, ie sedation procedure and death within 28 days from the start of sedation (post-surgery), independent of the duration of sedation (but a minimum treatment duration of 24 hours). Therefore, the primary objective also included patients who were sedated for 1 day and died on day 27 from the start of sedation, and patients who were sedated for 10 days and died on day 27 from the start of sedation.

The secondary objective was to assess subsequent organ failure 7- & 28-days after initiation of sedation and ventilation.

Data recorded included patient demographics, past medical history, drug therapy (limited to secondary drug therapy without EDTA), reason for surgery, type of anesthesia (limited to surgical anesthetics without EDTA), SAPS II and SOFA at baseline , 7- and 28-days, duration of sedation (and ventilation), and total dose of propofol and side effects.

Claims (16)

1. one kind is used as the pharmaceutical composition that improves urgent patient's survival rate medicament, and it contains a kind of free radical scavenging sedative and a kind of metal ion chelation agent, and a kind of pharmaceutically acceptable diluent or carrier.

2. one kind as improving urgent patient's survival rate medicament, the sterile pharmaceutical composition of parenterai administration, wherein said compositions contains a kind of water emulsifying and by the stable emulsion oil-in-water of surfactant, in this emulsion, propofol is dissolved in the immiscible solvent of water, and described compositions also contains a kind of metal ion chelation agent.

3. the sterile pharmaceutical composition that improves urgent patient's survival rate medicament that can be used as according to claim 1 and 2, wherein said metal ion chelation agent is an edetate.

4. sterile pharmaceutical composition improves purposes in the medicament of urgent patient's survival rate in preparation, and wherein said sterile pharmaceutical composition contains a kind of free radical scavenging sedative and a kind of metal ion chelation agent.

5. the purposes of sterile pharmaceutical composition according to claim 4 in the medicament of preparation raising urgent patient survival rate, wherein said sterile pharmaceutical composition contains a kind of free radical scavenging sedative and a kind of metal ion chelation agent, and a kind of pharmaceutically acceptable diluent or carrier.

6. improve purposes in the medicament of urgent patient's survival rate according to claim 4 or 5 described compositionss in preparation, wherein said compositions contains a kind of water emulsifying and by the stable emulsion oil-in-water of surfactant, in this emulsion, propofol is dissolved in the immiscible solvent of water, and described compositions also contains a kind of metal ion chelation agent.

7. according to any one described purposes of claim 4-6, wherein said metal ion chelation agent is an edetate.

8. according to any one described purposes of claim 4-7, wherein said sterile pharmaceutical composition is the form of emulsion oil-in-water, and it contains:

(a) propofol of 1 weight %,

(b) soybean oil of 10 weight %,

(c) lecithin of 1.2 weight %,

(d) glycerol of 2.25 weight %,

(e) sodium hydroxide,

(f) water,

(g) disodiumedetate of 0.005 weight %.

9. according to any one described purposes of claim 4-7, wherein said sterile pharmaceutical composition is the form of emulsion oil-in-water, and it contains:

(a) propofol of 2 weight %,

(b) soybean oil of 10 weight %,

(c) lecithin of 1.2 weight %,

(d) glycerol of 2.25 weight %,

(e) sodium hydroxide,

(f) water,

(g) disodiumedetate of 0.005 weight %.

10. according to any one described purposes of claim 4-9, wherein said urgent patient is a surgical patient.

11. a method that improves urgent patient's survival rate comprises the pharmaceutical composition that gives this patient's effective dose, wherein said pharmaceutical composition contains a kind of free radical scavenging sedative and a kind of metal ion chelation agent.

12. the method for raising urgent patient survival rate according to claim 11, comprise and give pharmaceutical composition, wherein said pharmaceutical composition contains a kind of free radical scavenging sedative and a kind of metal ion chelation agent, and a kind of pharmaceutically acceptable diluent or carrier.

13. according to claim 11 or 12 described methods, comprise and give pharmaceutical composition, wherein said pharmaceutical composition contains a kind of water emulsifying and by the stable emulsion oil-in-water of surfactant, in this emulsion, propofol is dissolved in the immiscible solvent of water, and described pharmaceutical composition also contains a kind of metal ion chelation agent.

14. according to any one described method of claim 11-13, wherein said metal ion chelation agent is an edetate.

15. according to any one described method of claim 11-14, wherein said pharmaceutical composition is the pharmaceutical composition that limits in claim 8 or 9.

16. according to any one described method of claim 11-15, wherein said urgent patient is a surgical patient.

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