Vanadyl and vanadates for use in alleviating stress-induced metabolic disorders - Patents.com

Abstract

The present invention relates to the use of physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as bis(maltolato)oxovanadium (BMOV), in the prevention or amelioration of stress-induced metabolic disorders in a subject. More particularly, the present invention relates to physiologically acceptable organic and / or inorganic vanadium compounds or complexes for use in the amelioration of hyperglycemia in a subject experiencing stress, such as that induced by trauma, wherein the physiologically acceptable organic and / or inorganic vanadium compounds or complexes are administered to the subject before the trauma is inflicted on the subject. [Selection diagram] None

Description

FIELD OF THE INVENTION

[0001] The present invention relates to the use of physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as bis(maltolato)oxide vanadium (BMOV), in the prevention or amelioration of stress-induced metabolic disorders in a subject. More specifically, the present invention relates to physiologically acceptable organic and / or inorganic vanadium compounds or complexes for use in the amelioration of hyperglycemia in a subject experiencing stress, such as that induced by trauma, wherein the physiologically acceptable organic and / or inorganic vanadium compounds or complexes are administered to the subject before the trauma is inflicted on the subject. Furthermore, the present invention relates to physiologically acceptable organic and / or inorganic vanadium compounds or complexes for use in the prevention of hyperglycemia in a subject having trauma, wherein the physiologically acceptable organic and / or inorganic vanadium compounds or complexes are administered to the subject before the trauma is inflicted on the subject. In one embodiment, a physiologically acceptable organic and / or inorganic vanadium compound or complex is administered to a human subject 0-96 hours, preferably 2-24 hours, before the human subject undergoes surgery for the prevention or amelioration of trauma-induced hyperglycemia associated with surgery. Part of the invention is that the physiologically acceptable organic and / or inorganic vanadium compound or complex is the starting material for vanadyl or vanadate in the patient to whom such compound or complex is administered. BACKGROUND OF THE INVENTION

[0002] Metabolic abnormalities are an important and common feature of stress to which a subject is exposed. Examples of such stress that induce metabolic abnormalities in a subject include trauma-related stress, exposure to body radiation, such as radiotherapy in cancer treatment, and administration of a contrast fluid or agent to a subject for imaging (part of) the body. For example, when trauma is inflicted on a subject, such as a human subject, metabolic abnormalities in plasma are identified, which are triggered by the trauma and further triggered by shock, such as hemorrhagic shock. Metabolic alterations associated with catabolic reactions, acidosis, and hyperglycemia have been identified. For example, trauma can trigger severe metabolic abnormalities, resulting in elevated glucose levels and ultimately leading to hyperglycemia in the plasma of a subject experiencing such a stressful event, among other things. Conventional measures of post-stress biochemical imbalances, such as trauma-related stress, have been shown to correlate with patient outcomes. Catabolic responses, acidosis, and insulin resistance along with the resulting hyperglycemia are examples of defined metabolic phenotypes that contribute to post-traumatic secondary injury.

[0003] Stress hyperglycemia (also called stress diabetes or injury diabetes) refers to a transient elevation of blood glucose due to the stress of illness or trauma. Such hyperglycemia is a significant problem in patients undergoing trauma or in patients who have undergone, for example, traumatic surgery, radiation therapy, infection acquisition, medication administration, or psychological stress. Hyperglycemia has been shown to be associated with increased morbidity and mortality. As noted, for example, hyperglycemia in trauma patients is caused by a hypercatabolic response to stress. Stress-induced hyperglycemia underlies numerous health-threatening effects in patients suffering from elevated blood glucose levels. Hyperglycemia, for example, increases apoptosis through the exacerbation of both calcium imbalance and the accumulation of reactive oxygen species (ROS) in neurons; amplifies anaerobic energy production and causes lactic acidosis, which further stresses neurons in the penumbra; reduces blood perfusion after ischemic stroke by reducing the availability of nitric oxide (NO), a critical mediator of vasodilation; and enhances the inflammatory response after stroke, causing edema and hemorrhage due to blood-brain barrier disruption and white matter degradation, which leads to impaired functional outcome.

[0004] Surgical patients commonly develop hyperglycemia associated with a hypercatabolic stress response, which increases glucose production and leads to insulin resistance. Although hyperglycemia is associated with worsening outcomes, treating hyperglycemia with insulin infusion has not consistently provided benefits. Despite initial results suggesting reduced mortality and other benefits of relatively tight glucose control, further investigations have either identified no benefit or increased mortality when hyperglycemia is aggressively treated with insulin. Because of these conflicting data, the optimal glucose concentration that improves outcomes is unknown. However, there is agreement that hypoglycemia is an undesirable complication of intensive insulin therapy and should be avoided. Furthermore, the risk of increased glucose variability is recognized due to the associated increased risk for worsening outcomes.

[0005] Stress hyperglycemia is particularly common in patients with hypertonic dehydration, elevated catecholamine levels (e.g., after emergency department treatment of acute asthma with epinephrine), elevated hormone levels such as corticosteroids or growth hormone, and increased heart rate and / or decreased blood pressure after blood loss, trauma, or physical or infectious attacks, but there are many more examples, such as ischemic stress, e.g., stroke. Stress hyperglycemia increases the risk of postoperative infectious complications after surgery. For example, subjects suffering from acute myocardial infarction may have blood glucose levels exceeding 180 mg / dL, and high levels are associated with an increased risk of congestive heart failure or cardiogenic shock. Furthermore, acute stroke, i.e., the acute phase of stroke, is accompanied by hyperglycemia, which has been established as a predictor of poor outcome in non-diabetic patients. In hospitalized patients, hyperglycemia has also been shown to be an independent marker of mortality during hospitalization in intensive care units, as well as in patients admitted to general wards. Overall mortality was significantly higher in such patients with hyperglycemia (16%) than in diabetic (3%) and normoglycemic patients (1.7%).

[0006] People who experience stress hyperglycemia during critical illness have a threefold increased risk of developing diabetes in the following years, making screening for diabetes feasible in survivors of critical illness.

[0007] From the issues outlined above regarding the occurrence of hyperglycemia in subjects exposed to stress, such as surgical patients, and the risk for the subsequent occurrence of hypoglycemia due to very strict glucose level control in surgical patients, it is clear that the current standard of care regarding the treatment of hyperglycemia in traumatic patients is less than optimal. While such subjects are undergoing stress that induces metabolic abnormalities, or shortly thereafter, the current standard of care focuses more on managing the glucose levels in the subject's blood, and therefore, in most cases, management of blood glucose levels relates to the treatment of existing hyperglycemia.

[0008] Therefore, there is a great need to develop therapeutic modalities to limit metabolic abnormalities in stress-induced patients, such as those undergoing traumatic surgery, so as to design therapeutic strategies tailored to the severity of the stress- and trauma-induced procedure on metabolic alterations and the patient's health. In particular, the devastating consequences of hyperglycemia as a result of trauma require significant attention, and therefore, there is a great need to address the problem of hyperglycemia, especially in patients who have undergone trauma, such as trauma associated with surgery. Summary of the Invention

[0009] The current standard of care for managing hyperglycemia associated with stress-induced metabolic disorders in patients focuses on lowering blood glucose levels in patients after they begin to be exposed to stress, such as stress associated with illness or trauma during a surgical procedure. Treating hyperglycemia after an already stressed patient then carries the risk of damage already caused in the patient by the hyperglycemic state before glucose levels drop to normal in the patient's blood and / or carries the risk of being so uncomfortable that glucose levels drop to the point where hypoglycemia is induced.

[0010] A first aspect of the present invention relates to a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex and further comprising a pharmaceutically acceptable excipient for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient. Stress induces a state of physiological tension in the patient, and the stress may be of a physical nature (e.g., trauma, infection, radiation therapy) and / or psychological origin (e.g., acute distress, exposure to a future threat to the subject's physical or mental well-being). Preferably, the physiologically acceptable organic and / or inorganic vanadium compound or complex is an insulin-mimetic vanadium compound. Preferably, the physiologically acceptable organic and / or inorganic vanadium compound or complex is bis(maltolato)oxide vanadium (BMOV). Also according to the present invention, the physiologically acceptable organic and / or inorganic vanadium compound or complex for use in the present invention is a compound or complex capable of providing a vanadate moiety or vanadyl moiety in the body of a subject, e.g., a human subject, after administration of the compound or complex to the subject.

[0011] It is now the inventors' contribution that a subject, such as a human subject, can receive a preventative measure, i.e., administration of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, before the subject is exposed to stress, so that glucose levels in the subject's blood do not rise to high ranges and hyperglycemia does not occur during the subject's exposure to stress.

[0012] In one embodiment, the pharmaceutical composition is administered to the patient before the patient is subjected to stress.

[0013] In one embodiment the pharmaceutical composition for use according to the invention is for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient, wherein the metabolic disorder comprises hyperglycemia, preferably the metabolic disorder is hyperglycemia.

[0014] Trauma associated with surgery is a representative type of stress that can lead to hyperglycemia in patients, which can cause damage, sometimes even irreversible damage, to the patient. Thus, in one embodiment, the pharmaceutical composition is administered to a patient before the patient is exposed to stress, for example, before undergoing surgery. Further types of stress according to the present invention are, for example, trauma caused by a medical procedure, trauma caused by iatrogenic injury, and / or stress caused by one or more of infections, administration of one or more medications, long-term or short-term acute psychological stress due to a life-threatening condition, for example, a potentially life-threatening condition, and an accident.

[0015] Typically, according to the present invention, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a subject, for example, 0 to 96 hours before surgery, for example, twice, once about 16 to 24 hours, or about 16 to 20 hours before surgery and once about 3 hours before said surgery.

[0016] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention is administered orally or parenterally, for example intravenously or intraperitoneally or subcutaneously or intramuscularly or intradermally, to a subject about to be stressed, for example a subject undergoing surgery.

[0017] In one embodiment, a pharmaceutical composition for use according to the present invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered to a patient so that the increase in the glucose content of the patient's blood during the first 1 to 8 hours of a period in which the patient is stressed, preferably during the first approximately 3 hours of a period in which the patient is stressed, is between about -25% and about 100%, preferably between about 0% and about 75%, more preferably between about 5% and about 65%, and most preferably about 30%, compared to the glucose content in the patient's blood at a time point between 3 hours and 0 minutes before the patient is stressed, preferably compared to the glucose content in the patient's blood at the time the patient begins to be stressed.

[0018] A second aspect of the present invention is a kit of parts comprising a container containing at least two doses of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention, the kit further comprising instructions for use of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, provided in said container in the prevention or alleviation of stress-induced metabolic disorders (stress inducing a state of physiological tension in a patient) in a patient who becomes stressed.

[0019] As stated, it is also part of the present invention that physiologically acceptable organic and / or inorganic vanadium compounds or complexes are the starting material for vanadyl or vanadate in the patient to whom such compounds or complexes are administered, when used in the prevention or alleviation of stress-induced metabolic disorders in a stressed patient.

[0020] The term "stress" has its ordinary scientific meaning, such as that outlined in Dorland's Pocket Medical Dictionary, 26th Edition, and herein refers to internal or external adverse physical and / or mental stimuli that induce a stress response and / or a state of physiological tension that interferes with the functioning of an organism, such as a subject herein, e.g., a human subject.

[0021] The term "metabolic abnormalities" has its ordinary scientific meaning and herein refers to, among other things, blood sugar, lactic acidosis and hyperlipidemia.

[0022] The term "hyperglycemia" has its ordinary scientific meaning, such as that outlined in Dorland's Pocket Medical Dictionary, 26th Edition, and is used herein to mean an abnormally increased content of glucose in the blood.

[0023] The term "trauma" has its ordinary scientific meaning and is used herein to refer to injury to a subject's body, e.g., a human subject. Typically, injury refers to damage to a subject's body that originates from internal damage caused by, for example, infection, surgery, accident, stroke and / or ischemia, an internal condition that leads to acute organ failure.

[0024] As used herein, the term "excipient" has its conventional meaning, meaning a pharmaceutically acceptable ingredient commonly used in the pharmaceutical arts to prepare formulations, e.g., dosage formulations for oral, intradermal, intravenous administration, etc.

[0025] As used herein, the term "pharmaceutical composition" has its conventional meaning, meaning a pharmaceutically acceptable composition.

[0026] As used herein, the term "pharmaceutically acceptable" has its conventional meaning and means compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment suitable for contact with the tissues of mammals, particularly humans, without undue toxicity, irritation, allergic response and other problems, complications with a reasonable benefit / risk ratio.

[0027] "Bis(maltolato)oxovanadium" is also referred to as "bis(maltolato)oxovanadium(IV)" and "bis(maltolato)oxo-vanadium" and "bis(maltolato)oxidovanadium", and "BMOV" generally refers to a vanadium(IV) complex having the molecular structure outlined in FIG. 7.

[0028] "Bis(ethylmaltolato)oxovanadium(IV)" and "bis(ethylmaltolato)oxidovanadium(IV)" and "bis(ethylmaltolato)oxidovanadium", "BEOV" in summary refer to vanadium(IV) complexes having the molecular structure outlined in FIG. 8. [Brief explanation of the drawings]

[0029] [Figure 1] Figure 1 shows the experimental design for adrenaline / saline and BMOV / vehicle administration and blood sampling. Figure 2 shows BMOV dose 1 starting 120 min after the start of adrenaline or saline infusion. [Figure 2] FIG. 1 shows blood glucose levels (mean + / - SEM) after administration of low, medium and high doses of adrenaline infusion (n=4-5 animals / group). [Figure 3] FIG. 1 shows blood glucose levels (mean + / - SEM) in series 2 (n = 1 to 2 rats / group). [Figure 4] Figure 1 shows the experimental design applied to adrenaline administration and BMOV administration and blood sampling. The dose of adrenaline infusion was 0.3 micrograms / kg / min. [Figure 5]Pre-treating subjects with BMOV before the onset of a stressful insult (herein, adrenaline infusion starting at t=0 min) (3 h before the onset of stress, or 16-24 hours thereafter 3 h before the onset of stress) shows a surprisingly high reduction in the onset of hyperglycemia in stressed subjects. [Figure 6] 1 shows that pre-treating subjects with BMOV (3 h before the onset of stress, or 16-24 hours thereafter 3 h before the onset of stress) before the onset of a stressful insult (herein, adrenaline infusion starting at t=0 min) significantly reduces the incidence of hyperglycemia in stressed subjects. Here, glucose levels in the blood of stressed subjects are shown at 180 min after the start of adrenaline infusion. [Figure 7] FIG. 1 shows the molecular structure of bis(maltolato)oxovanadium (BMOV). [Figure 8] FIG. 1 shows the molecular structure of bis(ethylmaltolato)oxovanadium(IV) (BEOV). Detailed Description of the Invention

[0030] The present invention will be described with respect to particular embodiments and with reference to certain examples but the invention is not limited thereto but only by the claims.

[0031] Furthermore, although various embodiments are referred to as "preferred," this does not limit the scope of the invention, but rather should be construed as exemplary ways in which the invention may be practiced.

[0032] The term "comprising," as used in the claims, should not be construed as being limited to the elements or steps listed thereafter; it does not exclude other elements or steps. As mentioned, it must be construed as specifying the presence of a certain feature, integer, step, or component, but need not be construed as excluding the presence or addition of one or more other of those features, integers, steps, or components, or groups. Thus, the scope of the expression "a composition comprising A and B" should not be limited in the present invention to a composition consisting solely of components A and B, but rather, the recited components of the composition are merely A and B, and the claims should be construed to include equivalents of these components, e.g., their derivatives.

[0033] As used herein, the term "may" encompasses the word "can," and the term "may be" encompasses the words "is" or "are," depending on the context. Furthermore, the presence of the word "may" is intended to describe options for performing or practicing the present disclosure without limitation.

[0034] In addition to the above-mentioned physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as vanadium-based insulin-mimetics or e.g. BMOV, the pharmaceutical compositions according to the invention also comprise pharmaceutically acceptable additives.

[0035] For purposes of oral administration of the pharmaceutical compositions of the present invention, such additives are selected from ingredients commonly used in the pharmaceutical arts for preparing granulated, solid, or liquid oral dosage forms. Similarly, such additives are selected from ingredients commonly used in the pharmaceutical arts for preparing formulations for intravenous administration, intramuscular administration, and the like.

[0036] Examples of excipient categories include, but are not limited to, binders, disintegrants, lubricants, gradants, fillers, and fillers. For oral administration of the pharmaceutical composition of the present invention, one skilled in the art can select one or more of the aforementioned excipients based on the specific desired characteristics of the granulation, e.g., tablets or pills, from which they will be produced through routine experimentation and without undue burden. The amount of each excipient used can vary within ranges conventional in the art. The following references, all of which are incorporated herein by reference, disclose techniques and excipients used to formulate pharmaceutical compositions, e.g., pharmaceutical compositions for oral administration: "The Handbook of Pharmaceutical Excipients," 4th ed., Rowe et al., eds., American Pharmaceuticals Association (2003); and "Remington: The Science and Practice of Pharmacy," 20th ed., Gennaro, ed., Lippincott Williams & Wilkins (2000).

[0037] A first aspect of the invention relates to a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex and further comprising a pharmaceutically acceptable excipient for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient.

[0038] One aspect of the present invention relates to a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex and further comprising a pharmaceutically acceptable excipient, for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient. The physiologically acceptable organic and / or inorganic vanadium compound or complex for use in the present invention is a compound or complex capable of providing a vanadate or vanadyl moiety in the body of a subject, e.g., a human subject, which compound or complex is then administered to the subject. Thus, according to the present invention, the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use in the present invention is a pharmaceutical composition that is the starting material for vanadyl or vanadate in the body of the subject to which the pharmaceutical composition is administered. According to the present invention, an amount of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to the present invention is administered to a subject such that said amount provides a plasma exposure level of elemental vanadium in said subject of between 25 ng / ml and 2500 ng / ml, or more preferably between 100 ng / ml and 1000 ng / ml.

[0039] In one embodiment, the pharmaceutical composition for use according to the present invention is administered to a patient before the patient is subjected to stress. In many cases, it is known what day and time a subject, such as a human subject, will be subjected to stress, such as trauma associated with surgery. Such situations, where knowledge of when trauma will be experienced by the subject, provide an opportunity to benefit from the present invention. That is, for example, a subject undergoing surgery is administered at least one dose, preferably two doses, of a pharmaceutical composition comprising BMOV before stress is induced in the subject. In this way, the subject is then prevented from developing metabolic disorders during the period when stress is induced, for example, during surgery, and in particular, a subject undergoing surgery is prevented from suffering from hyperglycemia according to the present invention. As previously mentioned, preventing or reducing elevated blood glucose levels improves mortality and morbidity, and therefore this is one of the many benefits of the present invention.

[0040] Therefore, one aspect of the present invention relates to a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex and further comprising a pharmaceutically acceptable additive for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient, the pharmaceutical composition being administered to the patient before the patient is stressed. According to the present invention, the vanadium compound is an insulin mimetic, preferably selected from BMOV and BEOV, preferably BMOV. Also according to the present invention, the physiologically acceptable organic and / or inorganic vanadium compound or complex is a compound or complex that is capable of providing a vanadate moiety or a vanadyl moiety in the body of a subject, e.g., a non-diabetic human subject, after the compound or complex is administered to the subject. According to the present invention, the physiologically acceptable vanadium compound or vanadium complex preferably has a valence of +4 or +5, i.e., V 4+ or V 5+ Preferably, the vanadate portion of the vanadium complex or compound is 4+ Cation or V 5+ cation, preferably V 5+ Preferably, the vanadyl portion of the vanadium complex or compound is V 4+ It is a positive ion.

[0041] According to the present invention, the physiologically acceptable organic and / or inorganic vanadium compound or complex comprised by the pharmaceutical composition for use according to the present invention is selected from the group consisting of BMOV, BEOV, insulin mimetics, vanadyl acetylacetonate (VAC), organic vanadium compounds that have demonstrated insulin-mimetic activity in a subject, e.g., a human, in type 1 and / or type 2 diabetes, organic vanadium compounds having a pharmacological activity selected from the group consisting of inhibition of gluconeogenesis, reduction of glutamate dehydrogenase activity, and antilipolysis; vanadyl sulfate (VS), vanadyl 3-ethylacetylacetonate (VET); oxovanadium, orthovanadium; keto-enol tautomers having a keto and an enol group at adjacent carbon atoms forming a 5-membered ring with the metal, and beta-diketones in which two keto groups are separated by one carbon atom, forming a 6-membered ring with the metal, and preferably comprising a vanadium(IV) coordinate covalently bonded to an organic moiety, preferably in the keto-enol tautomer. For example, the organic moiety is maltol, 2-hydroxy-2,4,6-cycloheptatrien-1-one, 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-methyl-2,4,6-cycloheptatrien-1-one, 3-hydroxy-1,2-dimethyl-4(1H)-pyridone, 3-ethyl-2-hydroxy-2-cyclopenten-1-one, 3,4-dihydro- 2-hydroxy-3-cyclobutene-1,2-dione, ethyl 2-hydroxy-4-oxo-2-pentenone, 2,3,5,6-tetrahydroxy-1,4-benzoquinone, 2',4'-dihydroxy-2-methoxyacetophenone, 4-hydroxy-5-methyl-4-cyclopentene-1,3-dione, 2-chloro-3-hydroxy-1,4-naphthoquinone, 2-(4-bromophenyl)-3-hydroxymaleimide, 2-hydroxy-3-methyl-2-cyclopenten-1-one, 2',3',4'-Trihydroxyacetophenone, furoin, 2-hydroxy-2-methylpropiophenone, maklurin, 6-(pyrrolidinomethyl)kojic acid, α-acetyl-4-hydroxy-β-(hydroxymethyl)-3-methoxycinnamic acid γ-lactone, 4-hydroxy-5-phenyl-4-cyclopentene-1,3-dione, 6-(morpholinomethyl)kojic acid, 1-(4,5-dimethoxy-2-hydroxyphenyl)-3-methyl-2-buten-1-one, purpurogallin, 2,3-dihydroxy-1,4-phenazinedione, alizarin orange, 1-hydroxy-1-methylnaphthalen-2(1H)-one, alizarin, 6-(piperidinomethyl)kojic acid, 1,2,7-trihydroxyanthraquinone, 6-(4-methylpiperazinomethyl)kojic acid, fisetin, 3-oxo-4,5,6-trihydroxy-3(H)-xanthene-9-propionic acid, benzoin, 4'-chlorobenzoin, quercetin, morin, myricetin, and 4,4'-dimethylbenzoin, more preferably, the organic moiety is selected from the group consisting of maltol or a β-diketone, and the organic moiety is acetylacetone. , 2-acetyl-1-tetralone, benzoylacetone, 1-benzoylacetylacetone, 1,1,1-trifluoro-2,4-pentanedione, S-methyl-4,4,4-trifluoro-3-oxothiobutyrate, 2-acetyl-1,3-cyclopentanedione, 3-chloro-2,4-pentanedione, 1,1,1,5,5,5-hexafluoro-2,4-pentanedione, 3-ureidomethylene-2,4-pentanedione, 2-acetylcyclopentanone, 2-acetylcyclohexanone, 3-methyl-2,4-pentanedione, 2,4 ,6-heptatrione, 3-ethyl-2,4-pentanedione, thianoyltrifluoroacetone, St-butyl-acetothioacetate, 3-acetyl-5-methylhexan-2-one, 3-acetyl-2-heptanone, 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedione, 4-hydroxy-5-phenyl-4-cyclopentene-1,3-dione, 4,4,4-trifluoro-1-phenyl-1,3-butanedione, 3-acetyl-2-octanone, 1(2-hydroxy-4-methylphenyl)-1,3-Butanedione, 1-(2-hydroxy-5-methylphenyl)-1,3-butanedione, 3-benzylidene-2,4-pentanedione, 1-(2-hydroxy-5-methylphenyl)-1,3-pentanedione, 2,2,6,6-tetramethyl-3,5-heptanedione, 3-acetyl-5-hydroxy-2-methylchromone, (+)-3-(trifluoroacetyl)camphor, 4,9-dihydro-6-methyl-5H-furo(3,2-g)(1)benzopyran-4,5,9-trione, 3-(2-nitrobenzylidene)-2,4-pentanedione 1,3-bis-(4-chlorophenyl)-1,3-propanedione, 1,3-bis-(4-fluorophenyl)-1,3-propanedione, 4,4,4-trifluoro-1-(2-naphthyl)-1,3-butanedione, 1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)-1,3-propanedione, 2-bromo-1,3-diphenyl-1,3-propanedione, dibenzoylmethane, 2-(4-chlorobenzylidene)-1-phenyl-1,3-butanedione, 2-(2-nitrobenzylidene)-1-phenyl-1,3-butanedione and a coordination-covalent complex comprising a vanadium(V) metal ion, an oxo group covalently bonded to the metal ion, two peroxo groups covalently bonded to the metal ion, and at least one organic moiety covalently bonded to the metal ion by at least one N-containing or O-containing functional group capable of donating electrons via a coordination-covalent bond, the coordination-covalent complex being selected from the group consisting of (1,10-phenanthroline). (oxodiperoxovanadium(V), oxalato-oxodiperoxovanadium(V), (2,2'-bipyridine)oxodiperoxovanadium(V), (4,7-dimethyl-1,10-phenanthroline)oxodiperoxovanadium(V), (3,4,7,8-tetramethyl-1,10-phenanthroline)oxodiperoxovanadium(V), (pyridine-2-carboxylic acid)oxodiperoxovanadium(V), (5-hydroxypyridine-2-carboxylic acid)oxodiperoxovanadium(V), (pyridine-2,and derivatives thereof, preferably the coordination-covalent complex is (1,10-phenanthroline)oxodiperoxovanadium(V); a coordination-covalent complex comprising a vanadium(V) metal ion, an oxo group covalently bonded to the metal ion, one peroxo group covalently bonded to the metal ion, and at least one organic moiety covalently bonded to the metal ion by at least one N-containing or O-containing functional group capable of donating electrons via the coordination-covalent bond, wherein the coordination-covalent complex is selected from the group consisting of (pyridine-2,6-dicarboxylato)(hydrato)oxoperoxovanadium(V); (1,10-phenanthroline)oxodiperoxovanadium(IV), oxalatooxodiperoxovanadium(V), (2,2'-bipyridine)oxodiperoxovanadium(V), (4,7-dimethyl-1,10-phenanthroline)oxodiperoxovanadium(V), (3,4,7,8-tetramethyl-1,10-phenanthroline)oxodiperoxovanadium(V), (pyridine-2-carboxylic acid)oxodiperoxovanadium(V), (5-hydroxypyridine-2-carboxylic acid)oxodiperoxovanadium(V), (pyridine-2,6-dicarboxylic acid)oxodiperoxovanadium(V), (pyridine-2,Coordination-covalent complexes selected from the group consisting of (6-dicarboxylato)(hydrato)oxoperoxovanadium(V) and derivatives thereof substituted with hydroxy or lower alkyl substituents that do not interfere with the formation of the coordination-covalent bond; coordination-covalent complexes comprising a vanadium(V) metal ion, an oxo group coordinatively covalently bonded to the metal ion, and at least one organic moiety coordinatively covalently bonded to the metal ion by at least one N-containing or O-containing moiety capable of donating electrons to the coordination-covalent bond, the coordination-covalent complex being meso-tartrateoxovanadium(V); picolinate and phenanthroline pentavalent complexes. The vanadium complexes and vanadium compounds are preferably selected from the group of vanadium complexes and vanadium compounds which are peroxide vanadium compounds, preferably bisperoxovanadium-picolinate (bpV(pic), bpV(HOpic), bpV(phen), VO(OPT). Preference is given to physiologically acceptable vanadium complexes or vanadium compounds which are capable of releasing or forming vanadyl and / or vanadate and / or bis-peroxovanadate according to the invention. Without wishing to be bound by theory, it is believed that the active moiety of the different vanadium compounds in the subject to which the pharmaceutical composition is administered according to the use of the present invention is vanadyl (VO, 2+ ) or vanadate (H2VO4 - ) in a subject when a pharmaceutical composition comprising said vanadium compound or complex is administered to the subject in accordance with the present invention. 2+ ) or vanadate (H2VO4 - ) is any physiologically acceptable vanadium complex or compound that provides

[0042] In one embodiment, the pharmaceutical composition for use according to the present invention is administered to a subject, wherein the subject is an animal, such as a mammal, preferably the subject is a human, such as a healthy human, a non-diabetic human, or a diabetic human, preferably a non-diabetic human, such as a healthy non-diabetic human.

[0043] Representative pharmaceutical compositions of the present invention are those containing bis(maltolato)oxide vanadium (BMOV) or bis(ethylmaltolato)oxovanadium(IV) (BEOV), preferably those containing BMOV, or a combination thereof. Preferably, the physiologically acceptable organic and / or inorganic vanadium compound or complex is a vanadium compound, such as a vanadium-based insulin-mimetic.

[0044] Stress to which a subject is exposed or suffered induces a state of physiological tension in the patient, the stress being of a physical nature (e.g., trauma, infection, radiation therapy) and / or psychological origin (e.g., acute distress, exposure to a future threat to the physical or mental well-being of the subject). In one embodiment, the pharmaceutical composition for use according to the present invention comprises a physiologically acceptable organic and / or inorganic vanadium compound or complex, said vanadium compound or complex being bis(maltolato)oxide vanadium (BMOV) or bis(ethylmaltolato)oxovanadium(IV) (BEOV), preferably BMOV.

[0045] In one embodiment the pharmaceutical composition for use according to the invention is for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient, wherein the metabolic disorder comprises hyperglycemia, preferably the metabolic disorder is hyperglycemia.

[0046] Stress that induces metabolic abnormalities, such as hyperglycemia, can be caused by multiple events and causes. In physical therapy, a primary trauma is damage to a biological organism caused by injury or physical harm from an external source. A primary trauma is also an injury that can potentially result in serious long-term consequences, such as chronic pain. A primary trauma is an example of stress that induces hyperglycemia.

[0047] Surgery is a major stress that induces hyperglycemia. Non-limiting examples of surgical procedures and diseases and health problems that are examples of acute stress that induce hyperglycemia are myocardial infarction (MI), stroke, multiple trauma, burn wounds, pressure ulcers, endotracheal intubation, glaucoma and other eye surgeries (laser, eye correction), anesthesia, cosmetic surgery, liposuction, sepsis, shock, hemorrhage, acute kidney injury, acute ischemic bowel injury, and traumatic brain injury (TBI).

[0048] Traumatic illness is an injury caused by an external force, but which does not rise to the level of a major trauma. Traumatic illness is distinguished from other causes of injury, e.g., iatrogenic injury (see below).

[0049] Iatrogenesis refers to any effect on a person resulting from one or more individuals working as healthcare professionals or through any activity promoting a product or service as beneficial to health that does not support the goals of the affected individual. Some iatrogenic effects are clearly defined and easily recognized, such as complications after a surgical procedure (e.g., lymphedema as a result of breast cancer surgery). Less obvious ones, such as complex drug interactions, may require significant investigation to identify. While some advocate using "iatrogenesis" to mean any "event caused by the healthcare delivery team," whether positive or negative, consensus restricts the use of "iatrogenesis" to harmful or, most broadly, unintended outcomes. Thus, iatrogenesis can be an iatrogenic injury, which is stress capable of inducing hyperglycemia in a patient.

[0050] Causes of iatrogenic illness include possible side effects of drug interactions, adverse effects of prescribed medications, complications arising from procedures or treatments, medical errors such as drug abuse, prescription errors, hospital-acquired infections, incorrect procedures, incorrect techniques, incorrect information, incorrect methods, or incorrect devices.

[0051] Acute psychological stress is a further cause of hyperglycemia. Acute distress or exposure to situations that are dangerous to the body, even to life, are examples of acute psychological stress that are known to be capable of inducing hyperglycemia.

[0052] Furthermore, postoperative infectious complications are stressful, hyperglycemic, and carry the risk of morbidity and mortality.

[0053] The inventors have surprisingly found that BMOV has the potential to prevent the development of stress-induced hyperglycemia in a subject when administered before the subject is exposed to stress. Preventing the accumulation of hyperglycemic conditions in a subject exposed to stress includes maintaining normal blood glucose levels in the subject and preventing the rise of blood glucose levels in the subject to a level designated as hyperglycemia. Furthermore, after pre-treatment of the subject with BMOV before exposure to stress, preventing hyperglycemia due to stress exposure can also result in a reduction in the initial blood glucose level in the subject, for example, at the beginning of the period during which the subject is exposed to stress, before stress is induced in the subject. Normal blood glucose levels are defined as blood glucose levels between 70 mg / dL and 100 mg / dL in a fasting (pre-meal) state in a healthy human subject (4 mmol / L to 6 mmol / L) and blood glucose levels below 140 mg / dL two hours after a meal (post-meal state in a healthy subject) (less than 7.8 mmol / L). In a series of tests conducted by the inventors, normal, healthy subjects (mammals, here, rats) exposed to stress without pretreatment with BMOV experienced an average increase in blood glucose levels of about 260%. In contrast, subjects receiving a treatment regimen involving the administration of two doses of BMOV at different times before stress induction experienced a maximum increase in blood glucose levels of only about +28%, i.e., a maximum average blood glucose level of about 6.4 mmol / L. Thus, even when subjects are subjected to stressful conditions, such as stress induced after injection of adrenaline, pretreatment of the subjects with BMOV, according to the present invention, prevented the accumulation of hyperglycemia and largely reduced the increase in blood glucose levels. The introduction of adrenaline into an organism, e.g., a subject, such as a human subject, has long been known as a stressor that induces hyperglycemia.See, for example, Rizza RA, Cryer PE, Haymond MW, "Adrenergic mechanisms of catecholamine action on glucose homeostasis in man," in Metabolism. 1980 Nov;29(11Suppl 1):1155-63.

[0054] Reference is now made to the examples outlined in the Examples section.

[0055] In one embodiment, the pharmaceutical composition for use according to the present invention comprises BMOV or BEOV as the sole active pharmaceutical ingredient, or a combination of BMOV and BEOV as the active pharmaceutical ingredients. Preferred according to the present invention are pharmaceutical compositions of the present invention comprising BMOV as the sole active pharmaceutical ingredient. The inventors have surprisingly discovered that administering an organic vanadium compound, i.e., BMOV, to a subject before the subject is exposed to stress, e.g., elevated circulating adrenaline levels, can prevent or reduce increases in blood glucose levels in the subject during periods of specific stress. Thus, according to the present invention, by administering a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and BMOV to a subject before the subject is subjected to stressful conditions, hyperglycemia is adequately and sufficiently prevented, or the degree of increase in blood glucose levels during periods of stress is largely reduced.

[0056] In one embodiment, the pharmaceutical composition for use according to the invention comprises a vanadium compound, wherein the ligand of vanadium(IV) is an antioxidant other than maltol.

[0057] In one embodiment, the pharmaceutical composition for use according to the present invention comprises a vanadium compound, said vanadium compound being combined with an antioxidant.

[0058] In an alternative embodiment, the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to the invention comprises a further active pharmaceutical ingredient in addition to the physiologically acceptable organic and / or inorganic vanadium compound or complex.

[0059] In one embodiment, the pharmaceutical composition comprising BMOV or BEOV or a combination of BMOV and BEOV for use according to the invention comprises a further active pharmaceutical ingredient in addition to said BMOV or BEOV or a combination of BMOV and BEOV. Typically, such a further active pharmaceutical ingredient comprised by the pharmaceutical composition of the invention is a compound for lowering blood glucose levels when administered to a subject, such as a human subject. Examples of such blood glucose lowering compounds include insulin for oral administration or parenteral administration, including intradermal and intramuscular injection.

[0060] Examples of blood glucose lowering agents that can be combined with physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, BEOV, or a combination of BMOV and BEOV, in pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes for use according to the invention are numerous and varied. As mentioned, such blood glucose lowering agents, including insulin, are compounds suitable for parenteral administration and / or oral administration, or compounds suitable for inhalation, for example when presented as a mist or the like. Without wishing to be limited to the following examples, pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes according to the present invention may further comprise any one or more of the following list of compounds for lowering blood glucose levels in a (human) subject, to name a few: biguanides, such as metformin, metformin liquid and metformin extended release formulations; sulfonylureas, such as glimepiride, glyburide, glipizide, micronized glyburide, meglitinide, repaglinide; D-phenylalanine derivatives, such as nateglinide; thiazolidinediones, such as pioglitazone, pioglitazone; DPP-4 inhibitors, such as sitagliptin, saxagliptin, sinagliptin; α-glucosidase inhibitors, such as acarbose, miglitol; bile acid sequestrants, to name a few. Sequestrant), such as colesevelam; combination preparations including, for example, pioglitazone and metformin, glyburide and metformin, glipizide and metformin, sitagliptin and metformin, saxagliptin and metformin, repaglinide and metformin, pioglitazone and glimepiride, metformin-alogliptin, metformin-canagliflozin, metformin-dapagliflozin, metformin-empagliflozin, metformin-glipizide, metformin-glyburide, metformin-linagliptin, metformin-pioglitazone, metformin-repaglinide, metformin-rosiglitazone, metformin-saxagliptin, metformin-sitagliptin,Injectable insulins, such as short-acting insulins and rapid-acting insulins, for example insulin aspart, insulin glulisine, insulin lispro, or intermediate-acting insulins, for example insulin isophane, long-acting insulins, for example insulin degludec, insulin detemir, insulin glargine, combination insulins, for example NovoLog® Mix 70 / 30 (insulin aspart protamine-insulin aspart), Humalog Mix 75 / 25 amylinomimetics such as (insulin lispro protamine-insulin lispro), Humalog® Mix 50 / 50 (insulin lispro protamine-insulin lispro), Humulin® 70 / 30 (human insulin NPH-regular human insulin), Novolin® 70 / 30 (human insulin NPH-regular human insulin), and Ryzodeg® (insulin degludec-insulin aspart); dopamine agonists, such as bromocriptine; any one or more of alogliptin, alogliptin-metformin, alogliptin-pioglitazone, linagliptin, linagliptin-empagliflozin, linagliptin-metformin, saxagliptin, saxagliptin-metformin, sitagliptin, sitagliptin-metformin, sitagliptin, and simvastatin; glucagon-like peptides (e.g., Retinomimetics), such as albiglutide, dulaglutide, exenatide, exenatide extended-release, liraglutide meglitinide; nateglinide, repaglinide and / or repaglinide-metformin; sodium-glucose cotransporter (SGLT) 2 inhibitors, such as dapagliflozin, dapagliflozin-metformin, canagliflozin, canagliflozin-metformin, empagliflozin, empagliflozin-linagliptin, empagliflozin-metformin, etc.;Sulfonylureas, such as glimepiride, glimepiride-pioglitazone, glimeperide-rosiglitazone, gliclazide, glipizide, glipizide-metformin, glyburide, glyburide-metformin, chlorpropamide, tolazamide, tolbutamide, etc.; thiazolidinediones, such as rosiglitazone, rosiglitazone-glimepiride, rosiglitizone-metformin, pioglitazone, pioglitazone-alogliptin, pioglitazone-glimepiride, pioglitazone-metformin;

[0061] Of course, a dosage regimen according to the present invention may also consist of providing a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention, and separately providing any one or more of the physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, that lower blood glucose, other than BMOV. In one embodiment, a dosage regimen encompasses providing a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, and separately providing any one or more of the physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, that lower blood glucose, other than BMOV, as the sole pharmaceutical ingredients for use according to the present invention.

[0062] In one embodiment, the pharmaceutical composition of the invention comprises a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, and further comprises a second active pharmaceutical ingredient for use according to the invention. Preferred is a pharmaceutical composition of the invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, and further comprises a second active pharmaceutical ingredient for use according to the invention, wherein the second active pharmaceutical ingredient is insulin.

[0063] In one embodiment, the pharmaceutical composition of the present invention comprises a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, and further comprises a second active pharmaceutical ingredient for use according to the present invention, wherein insulin is administered to a patient separately from the pharmaceutical composition. Typically, then, insulin is administered according to the present invention before and during the onset of stress-induced hyperglycemia, or before, during and after the onset of stress-induced hyperglycemia, or before the onset of stress-induced hyperglycemia, at the same time(s) as the pharmaceutical composition for use according to the present invention is administered, and / or insulin is administered at a separate time. Also preferred is a similar administration regime for a second active pharmaceutical ingredient other than insulin, which, according to the present invention, has blood glucose-lowering activity after a single administration to a patient.

[0064] In one embodiment, the pharmaceutical composition of the present invention comprises a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention, or the physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is the sole active pharmaceutical ingredient, and insulin is also administered to the subject, i.e., patient, during stress. Without wishing to be bound by theory, for example, the blood glucose-lowering ability of BMOV is enhanced when insulin is present in the patient's circulation, i.e., at levels above a threshold level for enhancing the effect of BMOV. Thus, if a patient to whom a pharmaceutical composition for use according to the present invention is administered has, for example, circulating insulin levels below such a threshold for enhancing the activity of BMOV, those skilled in the art will recognize that the patient will benefit from the administration of an amount of insulin that approximates the normal level of insulin in the patient's circulation. According to the present invention, when such patients are treated with insulin therapy alone, the amount of insulin required to raise insulin levels in the patient's circulation, e.g., to a level at which BMOV activity is enhanced, is lower than the amount of insulin required to treat hyperglycemia, e.g., in a patient undergoing acute stress.

[0065] A subject, e.g., an animal, e.g., a mammal, preferably a human subject, e.g., a diabetic or non-diabetic human subject, to whom a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to the present invention, such as BMOV, BEOV, or a combination of BMOV and BEOV, is administered before the subject is subjected to stress, is, according to the present invention, a healthy subject. Alternatively, the subject is, according to the present invention, a diabetic patient, i.e., suffering from type I diabetes or type II diabetes. Furthermore, some stress-induced human subjects, as well as human subjects to whom a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to the present invention, such as BMOV, is administered before the subject is subjected to stress, may be a patient suffering from a health problem or disease, with or without a breakdown in glycemic control in the subject's body, such as, for example, cardiovascular disease, atherosclerosis, or dysfunction of any organ, e.g., kidney, liver, lung, brain, skin, intestine, etc.

[0066] In one embodiment, the pharmaceutical composition for use according to the present invention is administered to a patient at least once between 96 h and 0 h before the patient is stressed, preferably between 72 h and 1 h, more preferably between 48 h and 2 h, and most preferably between 24 h and 3 h before the patient is stressed. For example, BMOV is active in preventing or reducing stress-induced metabolic disorders in a stressed patient when the dosage of BMOV is administered for at least 72 days, e.g., 4-5 days, depending on the dosage administered to the subject. In one embodiment, the pharmaceutical composition for use according to the present invention is administered to a patient at least once between 30 h and 0 h before the patient is stressed, preferably between 24 h and 2 h, more preferably between 24 h and 3 h before the patient is stressed. Preferably, the pharmaceutical composition for use according to the present invention is administered to a patient at least twice: at a first time point between 30 h and 10 h before the patient is stressed, preferably between 24 h and 12 h, more preferably between 24 h and 16 h before the patient is stressed, at a second time point between 8 h and 0 h before the patient is stressed, preferably between 5 h and 2 h, more preferably about 3 h before the patient is stressed. Preferably, the pharmaceutical composition for use according to the present invention is administered to a patient at least twice: at a first time point between 96 h and 10 h before the patient is stressed, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, most preferably between 24 h and 16 h before the patient is stressed, and at a second time point between 8 h and 0 h before the patient is stressed, preferably between 5 h and 2 h, more preferably about 3 h before the patient is stressed.

[0067] As is evident from the illustrative experimental in vivo results in mammals, e.g., rats (see the Experimental Section), when a subject is pretreated with a pharmaceutical composition comprising BMOV, e.g., a pharmaceutical composition comprising BMOV (BMOV being the sole active pharmaceutical ingredient), before exposure to stress according to the present invention, the subject is prevented from developing hyperglycemia. As exposure of a subject to stress is, of course, not in all cases predicted and / or predictable, chronic treatment with a pharmaceutical composition comprising BMOV is a means for preventing or ameliorating the induction of hyperglycemia as a result of exposure to stress. That is, before the subject is subjected to stress, the subject is administered a dose of a pharmaceutical composition comprising BMOV, and the dosage regimen includes administering BMOV once or twice daily one day before the predicted stress is induced, or over a long period of time as a preventative measure when stress is likely to be induced in the subject, or even for lifelong periods when exposure to stress is predictable or when the subject has an (increased) risk of experiencing stress in the (near) future, e.g., within a few days, weeks, or months. For example, workers, such as those deployed to life-threatening situations, such as soldiers, firefighters, paramedics, police officers, or athletes, who are at relatively high risk of experiencing stress, e.g., trauma-related stress, may receive a dosing regimen involving chronic administration of a pharmaceutical composition containing BMOV for an extended period of time during which they are at high risk of experiencing trauma. For example, a human subject at risk of experiencing trauma may receive a pharmaceutical composition containing BMOV twice daily according to the present invention. Preferably, the pharmaceutical composition of the present invention is administered to a subject in need thereof by injection, although oral administration is also suitable. Of course, monitoring blood glucose levels is part of such a dosing regimen to monitor whether normoglycemia is maintained and whether hypoglycemia occurs.

[0068] In one embodiment, the pharmaceutical composition for use according to the present invention is used for the prevention or reduction of hyperglycemia in a subject, such as a human subject, such as a healthy subject, that is subjected to stress, wherein said stress is trauma, such as trauma caused by surgery, trauma, such as medical trauma caused by a medical procedure, trauma caused by iatrogenic injury, and / or the stress experienced by the patient is, according to the present invention, caused by any one or more of an infection, the administration of one or more medication(s), long or short term acute psychological stress due to a life-threatening condition, such as a potentially life-threatening condition, and an accident, such as a car accident or a collapsed building in which the subject is trapped. When a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered to a subject before the subject experiences stressful conditions, the origin and cause of the stress resulting in hyperglycemia in the subject exposed to such stress is unrelated to the mechanism of action of the pharmaceutical composition of the present invention comprising the physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV. Thus, stress may be associated with trauma due to any cause (e.g., surgery, accident, sporting event, etc.), or may be associated with infection, sepsis, inflammation, organ failure, organ or tissue dysfunction, burns (e.g., sunburn), cancer, undercooling of a subject, overheating of a subject, dehydration of a subject, shock, heart failure, blood loss, low blood pressure, high blood pressure, elevated adrenaline in the blood, asphyxiation, reperfusion (e.g., after a heart attack or surgery), ischemia, bone damage and fractures, etc.

[0069] In one embodiment, the pharmaceutical composition for use according to the present invention, the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered orally to a patient, or intravenously, or intraperitoneally, or intramuscularly, or intradermally, preferably the pharmaceutical composition comprising is administered intravenously, or intradermally, or intraperitoneally to a patient.

[0070] The pharmaceutical composition of the present invention is suitable for many of the commonly applied routes of administration of pharmaceutical compositions to a subject, such as a human subject. The pharmaceutical composition of the present invention is applicable for administration to a subject in need thereof by non-invasive routes, such as oral, nasal, vaginal, rectal, pulmonary, ocular (eye drops), sublingual, intraotic, transdermal (TD), etc., and by invasive routes, such as intradermal (ID), subcutaneous (SC), intramuscular (IM), intravenous (IV), intraarterial (IA), intrathecal (IT), intraperitoneal (IP), intra-articular (synovial), and intracerebroventricular.

[0071] One of the many benefits of the present invention is that subjects who are predictably about to undergo stress in the near future, e.g., within one or a few days, can benefit from pretreatment with a pharmaceutical composition containing a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to the present invention, such as BMOV, before the subject is stressed. Most conveniently, such pretreatment comprises a dosage regimen consisting of a formulation containing a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV or BEOV, or a combination of BMOV and BEOV, which can be administered orally. Thus, a pharmaceutical composition containing a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as the BMOV of the present invention, is provided as a formulation for oral use, such as a tablet, powder, pill, etc. Preferably, the dosage regimen of the present invention comprises the oral administration of a single pill or tablet, etc., containing a pharmaceutical composition for use according to the present invention. Of course, a single tablet, pill, etc. containing a complete single dose of a physiologically acceptable organic and / or inorganic vanadium compound or complex, e.g., BMOV, is preferred, but the dosing regimen can also include administering at least two tablets, etc., to administer a single dose of a pharmaceutical composition for use according to the present invention to a subject. Part of the present invention is administering a dose of a physiologically acceptable organic and / or inorganic vanadium compound or complex, e.g., BMOV, in a time frame between 0 h and 96 h before the onset of stress, before the subject succumbs to stress. In accordance with the present invention, the pharmaceutical composition is administered as multiple dosage units to reduce the risk of side effects, such as gastrointestinal side effects, imparted by the pharmaceutical composition. Of course, those skilled in the art will understand that the optimal dose and number of administered amounts will be selected with respect to the desired effective plasma level of a physiologically acceptable organic and / or inorganic vanadium compound or complex, e.g., BMOV, at the time and thereafter stress is induced in the subject.

[0072] In one embodiment, the pharmaceutical composition for use according to the present invention is an aqueous solution, preferably comprising between about 0.001 mg and 10 mg of a physiologically acceptable organic and / or inorganic vanadium compound or complex per ml of pharmaceutical composition, preferably between about 0.5 mg / ml and 5 mg / ml, more preferably about 2 mg of a physiologically acceptable organic and / or inorganic vanadium compound or complex per ml. Such an aqueous solution is advantageously applied in a dosing regimen comprising oral administration, intravenous administration, transdermal administration by injection, or intramuscular administration, for example, by injection, of a single dose of the pharmaceutical composition for use according to the present invention to a subject in need thereof, for pre-treating the subject before stress is induced in the subject.

[0073] In one embodiment, the pharmaceutical composition for use according to the invention is an aqueous solution, preferably comprising between about 0.5 mg BMOV per ml and 5 mg BMOV per ml of pharmaceutical composition, preferably about 2 mg BMOV per ml. In an alternative embodiment, the physiologically acceptable organic and / or inorganic vanadium compound or complex is BEOV or a combination of BMOV and BEOV.

[0074] In one embodiment, the pharmaceutical composition for use according to the invention comprises at least one pharmaceutically acceptable excipient, said pharmaceutically acceptable excipient comprising phosphate buffered saline comprising 1.86 g / L NaH2PO4.H2O, 9.50 g / L Na2HPO4.2H2O, and 4.40 g / L NaCl; preferably, said pharmaceutically acceptable excipient comprises phosphate buffered saline consisting of about 1.86 g / L NaH2PO4.H2O, about 9.50 g / L Na2HPO4.2H2O, and about 4.40 g / L NaCl. Such phosphate buffered saline compositions are particularly suitable pharmaceutically acceptable excipients for administration of pharmaceutical compositions comprising BMOV for use according to the invention, particularly when the composition is for intravenous, intramuscular, or intradermal administration, although oral administration is also a possibility. Typically, the pH of phosphate buffered saline for use as a pharmaceutically acceptable excipient in a pharmaceutical composition for use according to the invention is near physiological, e.g., between pH 6 and 8, preferably between pH 6.5 and 7.5. Typically, the pH of such a pharmaceutically acceptable excipient is between about 7.2 and 7.4.

[0075] Of course, other aqueous solutions may similarly serve as pharmaceutically acceptable additives in pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, for use according to the invention. For example, pharmaceutically acceptable additives suitable for application by intravenous and / or intradermal administration and / or inhalation as a mist in the lungs and / or intramuscular and / or oral administration are, according to the invention, equally suitable for application in pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, for use according to the invention. Such pharmaceutically acceptable additives are well known in the art.

[0076] In one embodiment, the pharmaceutical composition for use according to the invention is administered orally to a patient, and the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is provided as a capsule, tablet, pill or water-soluble powder for oral administration. Of course, any other formulation of the pharmaceutical composition for use according to the invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, that is suitable for oral administration is equally suitable according to the invention for the purpose of preventing or ameliorating metabolic disorders, in particular hyperglycemia, in patients who will be subject to stress in the future, for example trauma associated with surgery.

[0077] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV or BEOV, for use according to the present invention is used as a single dose of the pharmaceutical composition administered to a patient or in a dosing regimen in which at least two doses of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV or BEOV, are administered to a patient every 12 to 96 hours, preferably two doses every 16 to 72 hours. In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV or BEOV, for use according to the present invention is used as a single dose of the pharmaceutical composition administered to a patient or in a dosing regimen in which at least two doses of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV or BEOV, are administered to a patient every 12 to 24 hours, preferably two doses every 16 to 24 hours.

[0078] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient at a dosage of between 7.5 mg and 30 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, preferably between 12 mg and 20 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, more preferably about 15 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, wherein the physiologically acceptable organic and / or inorganic vanadium compound or complex is preferably BMOV.

[0079] In one embodiment, pharmaceutical compositions for use according to the present invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, are administered to a subject, e.g., a human, at a dosage of between 0.01 mg and 30 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, preferably between 0.1 mg and 15 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, more preferably between 0.15 mg / kg and 10 mg / kg, and most preferably between 0.5 mg and 2.5 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, where the physiologically acceptable organic and / or inorganic vanadium compound or complex is preferably BMOV. It should be recognized that these dosage levels (in mg) are based on the molecular weight of BMOV; for other vanadium-containing compounds or complexes, absolute dosage levels should reflect an equimolar amount of vanadium. Furthermore, these dosage levels reflect intravenous administration. Regardless of the particular vanadium-containing compound and / or route of administration, dosage levels and administration should preferably result in general plasma exposure levels of elemental vanadium between 25 ng / ml and 2500 ng / ml, more preferably between 100 ng / ml and 1000 ng / ml, although peak plasma levels may exceed these limits. Typically, such plasma exposure levels are achieved in subjects, preferably human subjects, after oral, subcutaneous, intraperitoneal, or intravenous administration of a physiologically acceptable vanadium compound or vanadium complex, such as BMOV or BEOV. Typically, such plasma exposure levels of between 25 ng / ml and 2500 ng / ml, e.g., 100 ng / ml to 1000 ng / ml, are obtained, for example, by intravenous administration of BMOV to human subjects. Alternatively, such levels are achieved after oral administration of BEOV or vanadium sulfate to human diabetic subjects.In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a subject, such as a human, at a dosage of between 0.5 mg and 4 mg of the pharmaceutical composition per kg of patient body weight.

[0080] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention is administered to a subject, e.g., a human, at a dosage of between 0.001 mg and 30 mg of the pharmaceutical composition per kg of patient body weight, such that the plasma exposure level of the vanadium compound or complex, e.g., BMOV or BEOV, in the subject, e.g., a human subject, is between 25 ng / ml and 2500 ng / ml, or more preferably between 100 ng / ml and 1000 ng / ml, of elemental vanadium. These listed plasma exposure levels are notwithstanding, peak plasma levels may exceed these limits.

[0081] In one embodiment, pharmaceutical compositions containing a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention are administered at a dosage of between 1 mg and 30 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, preferably between 4 mg and 20 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, and more preferably between about 6 mg and 12 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, where the physiologically acceptable organic and / or inorganic vanadium compound or complex is preferably BMOV. As previously noted, these dosage levels (in mg) according to the present invention are based on the molecular weight of BMOV; it should be recognized that for other vanadium-containing compounds or complexes, absolute dosage levels should reflect an equimolar amount of vanadium. Furthermore, these dosage levels reflect intravenous administration of pharmaceutical compositions for use according to the present invention. Regardless of the particular vanadium compound or vanadium complex and / or chosen route of administration, the particular dosage level and particular route of administration should preferably result in general plasma exposure levels of between 25 ng / ml and 2500 ng / ml, and even more preferably between 100 ng / ml and 1000 ng / ml, of elemental vanadium, although peak plasma levels may exceed these limits.

[0082] It is highly preferred to administer a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention to a patient before the patient is subjected to stress, such as stress related to trauma during surgery. In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient during a period when the patient is subjected to stress. Alternatively, in one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient before the patient is subjected to stress, and then again during a period when the patient is subjected to stress, such as stress related to undergoing surgery which involves the induction of trauma in the patient. Of course, if the stressed patient needs it, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention may also be administered to said patient after the patient has been relieved of stress, e.g., induced by surgery, e.g., after recovery from said stress (e.g., after an accident, wound healing after surgery). The effect of pretreatment of a patient who will be stressed or who is undergoing or recovering from stress with a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is the same as follows: maintenance of normoglycemia or a reduction in the degree of elevation of glucose levels in the patient's blood during and / or after the stress. As mentioned, said pre-treatment with a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, can according to the invention be supplemented with a continuous treatment with a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention during the patient's exposure to stress and / or after said period of stress.

[0083] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention is administered to a patient during a period before the patient is stressed and optionally thereafter, also during a period when the patient is stressed and optionally thereafter, also during a pre-treatment period when the patient is recovering from stress and its consequences, e.g., stroke, trauma, acute attack, tissue regeneration and / or wound healing, e.g., after trauma caused by, e.g., infection, surgery, accident, etc.

[0084] In one embodiment, a pharmaceutical composition for use according to the present invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered to the patient as a first single dose between 96 h and 10 h, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, and most preferably between 24 h and 16 h, before the patient is subjected to stress, and a second single dose of the pharmaceutical composition is administered to the patient between 8 h and 0 h, preferably between 5 h and 2 h, before the patient is subjected to stress, preferably the first single dose is administered between 24 h and 16 h, and the second single dose is administered about 3 h before the patient is subjected to stress.

[0085] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient as a first single dose between 96 h and 10 h, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, and most preferably between 24 h and 16 h, before the patient is subjected to stress, and a second single dose of the pharmaceutical composition is administered to a patient between 8 h and 0 h, preferably between 5 h and 3 h, before the patient is subjected to stress, preferably the first single dose is administered between 24 h and 16 h, and the second single dose is administered about 3 h before the patient is subjected to stress. In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient as a first single dose between 24 hours and 12 hours, preferably between 24 hours and 16 hours, before the patient is subjected to stress, and as a second single dose between 8 hours and 0 hours, preferably between 5 hours and 3 hours, before the patient is subjected to stress, preferably the first single dose being administered between 24 hours and 16 hours and the second single dose being administered about 3 hours before the patient is subjected to stress.

[0086] In one embodiment, a pharmaceutical composition for use according to the present invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered to a patient as a first single dose between 96 h and 0 h, preferably between 72 h and 1 h, more preferably between 48 h and 2 h, and most preferably between 24 h and 3 h, before the patient is stressed, and a second single dose of the pharmaceutical composition is administered to the patient during the period the patient is stressed. In one embodiment, a pharmaceutical composition for use according to the present invention comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is administered to a patient as a first single dose between 24 h and 0 h, preferably between 20 h and 3 h, before the patient is stressed, and a second single dose is administered to the patient during the period the patient is stressed.

[0087] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient as a first single dose between 96 h and 10 h, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, and most preferably between 24 h and 16 h, before the patient is stressed; a second single dose of the pharmaceutical composition is administered to the patient between 8 h and 0 h, preferably between 5 h and 3 h, before the patient is stressed; and a third single dose of the pharmaceutical composition is administered to the patient during the period the patient is stressed. In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient as a first single dose between 24 hours and 12 hours, preferably between 24 hours and 16 hours, before the patient is stressed, as a second single dose between 8 hours and 0 hours, preferably between 5 hours and 3 hours, before the patient is stressed, and as a third single dose during the period the patient is stressed.

[0088] In one embodiment, pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, for use according to the present invention are provided as aqueous solutions or as solid dosage forms, such as powders, tablets, pills and capsules.

[0089] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is provided such that the dosage of the pharmaceutical composition comprises between about 0.1 mg and 40 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, per kg of patient body weight, preferably between about 0.5 mg and 1 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, per kg of patient body weight.

[0090] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is provided such that the dosage of the pharmaceutical composition comprises between about 0.01 mg and 30 mg, preferably about 5 mg, and more preferably between about 0.5 mg and 2.5 mg of a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, per kg of patient body weight.

[0091] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is provided such that the dosage of the pharmaceutical composition comprises between about 0.001 mg and 30 mg, preferably about 5 mg, and more preferably between about 0.5 mg and 2.5 mg of a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, per kg of patient body weight, and the pharmaceutical composition is provided as an aqueous solution or in solid dosage form, such as a powder, tablet, pill, or capsule. Again, as outlined previously, regardless of the particular vanadium-containing compound or complex and / or route of administration, e.g., oral, IV, IP, SC, etc., dosage levels and administration should preferably result in general plasma exposure levels of between 25 ng / ml and 2500 ng / ml, or more preferably between 100 ng / ml and 1000 ng / ml, of elemental vanadium, although peak plasma levels may exceed these limits. Typically, such plasma exposure levels are achieved in subjects, preferably human subjects, when a physiologically acceptable vanadium compound or vanadium complex, e.g., BMOV, BEOV, etc., is administered orally, subcutaneously, intraperitoneally, or intravenously.

[0092] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention is provided as an aqueous solution or as a solid dosage form, such as a powder, tablet, pill, or capsule, wherein the dosage of the pharmaceutical composition comprises between about 0.01 mg and 30 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, and wherein administration of the pharmaceutical composition to the patient provides a plasma exposure level of elemental vanadium in the patient of between 25 ng / ml and 2500 ng / ml, or preferably between 100 ng / ml and 1000 ng / ml.

[0093] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is administered to a patient, and the stress experienced by the patient is trauma, such as trauma caused by surgery, medical trauma caused by a medical procedure, trauma caused by iatrogenic injury, and / or the stress experienced by the patient is caused by any one or more of the following: infection, administration of one or more medication(s), long-term or short-term acute psychological stress due to a life-threatening condition, such as a potentially life-threatening condition, an accident, etc. Indeed, the use of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, of the present invention for the prevention or amelioration of stress-induced hyperglycemia is independent of the cause of the stress; the stress may be any type of trauma to any extent, for example trauma caused by any event, such as surgery-related trauma, or wounds caused by, for example, sports, accidents, etc.

[0094] In one embodiment, pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, for use according to the present invention are used in a dosage regimen such that the increase in glucose content in the patient's blood during the period in which the patient is stressed is less than about 100%, preferably less than about 65%, more preferably less than about 30%, and most preferably less than about 6%, compared to the glucose content in the patient's blood 3 h to 0 min before the patient is stressed, preferably compared to the glucose content in the patient's blood at the time the patient begins to be stressed. An important benefit of the present invention is the provision of a pretreatment modality useful for preventing hyperglycemia in stressed subjects, i.e., pharmaceutical compositions comprising physiologically acceptable organic and / or inorganic vanadium compounds or complexes, such as BMOV, for use according to the present invention prevent the rise in blood glucose levels that would otherwise occur following stress induced in a subject, resulting in health risks, organ damage, and the like. As outlined previously, maintaining normoglycemia, i.e., the presence of normal concentrations of glucose in the blood that do not result in increased risk of health problems or for causing disease or damage to tissues, veins, arteries, etc., is of paramount importance and is highly beneficial to the health of a subject exposed to stress.

[0095] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is used in a dosage regimen such that during the first 1 to 8 hours of a period in which the patient is stressed, preferably during about the first 3 hours of a period in which the patient is stressed, the increase in the glucose content in the patient's blood is less than about 100%, preferably less than about 65%, more preferably less than about 30%, and most preferably less than about 6%, compared to the glucose content in the patient's blood at 3 hours to 0 minutes before the patient is stressed, preferably compared to the glucose content in the patient's blood at the time the patient begins to be stressed, during the first 1 to 8 hours of a period in which the patient is stressed, preferably during about the first 3 hours of a period in which the patient is stressed.

[0096] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is used in a dosage regimen such that, during the first 1 to 8 hours of a period in which the patient is stressed, preferably during about the first 3 hours of a period in which the patient is stressed, the increase in the glucose content in the patient's blood is between about -25% and about 100%, preferably between about 0% and about 75%, more preferably between about 5% and about 65%, and most preferably about 30%, compared to the glucose content in the patient's blood 3 hours to 0 minutes before the patient was stressed, preferably compared to the glucose content in the patient's blood at the time the patient began to be stressed.

[0097] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is used in a pre-treatment regimen before a patient is exposed to stress, or in a treatment regimen including pre-treatment of the patient before the patient is subjected to stress and treatment of the patient during the period of exposure to stress. In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention is used in said (pre-)treatment regimen, wherein the stress exerted on the patient is stress caused by trauma occurring during any one or more of surgery, such as cardiac surgery, amputation surgery, tumor resection surgery, brain surgery, transplant surgery, surgery associated with restoring hemostasis, surgery associated with treating fractures, surgery associated with organ or bone reconstruction, such as hip transplant surgery, vascular surgery, bypass surgery, wound closure, treatment of injury to skin, bone, organ, tissue, artery, vein, medical procedure, iatrogenic injury, infection, administration of one or more medication(s), acute psychological stress, accident, etc.

[0098] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is for use in the manufacture of a medicament.

[0099] In one embodiment, a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is for use in the manufacture of a medicament, wherein the medicament is for use in preventing or alleviating stress-induced metabolic disorders in a stressed patient (stress induces a state of physiological tension in the patient).

[0100] A further aspect of the present invention relates to a method for preventing or ameliorating stress-induced metabolic disorders in a stressed patient, wherein the stress induces a state of physiological tension in the patient, and a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex of the present invention, such as BMOV, is administered to the patient in need thereof.

[0101] One aspect of the present invention relates to the use of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex of the present invention, such as BMOV, for the prevention or amelioration of stress-induced metabolic disorders in a stressed patient (stress induces a state of physiological tension in the patient).

[0102] One aspect of the present invention relates to a method for preventing or ameliorating stress-induced metabolic disorders (stress induces a state of physiological tension in a patient) in a stressed patient, comprising the step of administering to the patient a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex of the present invention, such as BMOV.

[0103] One aspect of the present invention relates to the administration of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex of the present invention, such as BMOV, for the prevention or amelioration of stress-induced metabolic disorders in a stressed patient (stress induces a state of physiological tension in the patient).

[0104] One aspect of the present invention is a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex of the present invention, such as BMOV, for the prevention or amelioration of stress-induced metabolic disorders in a stressed patient (stress induces a state of physiological tension in the patient).

[0105] A second aspect of the present invention relates to a kit of parts comprising a container containing at least two doses of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the present invention, the kit further comprising instructions for use of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, provided in said container in the prevention or alleviation of stress-induced metabolic disorders (stress induces a state of physiological tension in a patient) in a patient who becomes stressed.

[0106] In one embodiment, a kit of parts according to the invention comprises a first container containing a single dose of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention, and a second container containing a single dose of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention. For example, the kit may comprise a screw-cap container containing a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention as bulk tablets or pills for oral administration. Alternatively, the kit may comprise at least two vials, each containing a single dose of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention, wherein the pharmaceutical composition is provided as an aqueous solution for intravenous administration, or the pharmaceutical composition is provided as a powder, granules, etc. for dissolution in an aqueous solution, such that an aqueous solution comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, is provided, for example, for intravenous administration. Those skilled in the art will, of course, appreciate that many alternative formulations of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, such as BMOV, for use according to the invention can be provided, each formulation being tailored according to the intended route of administration, the intended dosage regimen, the intended dosage amount, etc.

[0107] An additional aspect of the present invention is a drug delivery device or kit, comprising an insulin-mimetic vanadium compound of the present invention and a pharmaceutically acceptable carrier, the device or kit being adapted for local administration of the vanadium compound to a patient in need thereof. Local delivery of vanadium-based insulin mimics significantly enhanced biomechanical properties over a 4-week period, with outcomes being dose-dependent and superior results obtained with low doses of the vanadium compound.

[0108] This invention is further illustrated by the following examples, which should not be construed as limiting in any way. [Example]

[0109] Example 1 Effect of BMOV on stress-induced hyperglycemia in normal healthy rats - In vivo evaluation of the ability of BMOV to prevent or attenuate hyperglycemia

[0110] Stress-induced hyperglycemia models have been developed that do not involve any surgical procedures to induce hyperglycemia in subjects, and do not require the administration of any composition by injection to induce hyperglycemia in subjects. Stress is induced by injection of adrenaline into subjects, such that subjects are stressed in a time-controlled manner.

[0111] Objective: The objective of the demonstration study was to demonstrate the beneficial effect of BMOV on stress- and / or trauma-induced hyperglycemia in healthy subjects.

[0112] Methods: Male Wistar rats (weight 300-400 g) were included in the study. 1) Series 1: Rats (n = 13; 4-5 rats / group) were infused with adrenaline via the jugular vein at rates of 0.1, 0.3, or 1 μg / kg / min for 180 min to determine the optimal blood glucose-increasing dose of adrenaline. Blood glucose levels were measured from samples taken from the femoral artery before the start of the adrenaline infusion and 15, 30, 45, 60, 90, 120, 150, and 180 min after the start of the adrenaline infusion. 2) Series 2: Animals (n = 4; 1-2 animals per group) were infused with adrenaline (1 μg / kg / min) or saline (1 ml / kg) for 200 min, starting 120 min after the initiation of adrenaline or saline, through the right and left jugular veins, respectively, followed by BMOV (0.2, 0.6, 1.7, and 5 ml / kg) or vehicle for 20-20 min. Glucose levels were measured at t = 0, 120, 140, 160, 180, and 200 min.

[0113] Results: Adrenaline infusion induced a dose-dependent sustained increase in blood glucose levels after 45 minutes. The highest dose (1 μg / kg / min) produced the most significant increase with peak levels at approximately 120 minutes, which remained nearly constant until 180 minutes after the start of the infusion. BMOV significantly reduced hyperglycemia between 160 and 180 minutes compared with the adrenalin + vehicle control group, and a decrease in glucose levels was observed in both groups after 160 minutes.

[0114] The conclusion drawn from these demonstrative in vivo experiments is that BMOV significantly reduced hyperglycemia induced by a high dose (1 μg / kg / min) of adrenaline at 160-180 minutes in subjects compared to the group of subjects receiving vehicle. The adrenaline infusion reflects the subject's exposure to stress, e.g., stress experienced by the subject's body during trauma, such as trauma inflicted during surgical procedures.

[0115] General test system parameters

[0116] experimental animals In total, 31 healthy male Wistar rats weighing 300-400 g were purchased from Toxicoop Hungary Zrt. and included in the study.

[0117] livestock Housing: Animals were housed in cages conforming to the size recommendations in the latest Guide for the Care and Use of Laboratory Animals DHEW (NIH) and EU Guidelines 63 / 2010. Litter placed under the cages was changed at least three times per week. Animal rooms were temperature-controlled, had a 12-hour light / dark cycle with lights on from 7 AM to 7 PM, and were kept clean and parasite-free. Acclimatization: Animals were acclimatized to the housing facility for at least 3 days prior to testing. Food: Any standard rodent chow, fasting started 12 hours before the experiment. Water: Any filtered tap water. Contaminants: There are no known contaminants that would reasonably be expected to be found in food or water at levels that would interfere with the results of this test. Identification: Each animal was given a sequential ID number.

[0118] Experimental group Series 1 - Determining Adrenaline Dosage, Optimizing the Paradigm Experimental model (4-5 rats / group)

[0119] [Table 1]

[0120] Series 2 - Control points (1-2 rats / group)

[0121] [Table 2]

[0122] method The term "saline" has its ordinary scientific meaning and refers throughout this application to an aqueous sodium chloride (NaCl) solution containing 9.0 grams of NaCl per liter of water. Saline is also referred to as "table salt solution," "normal saline solution" (NSS, NS, or N / S), "physiological saline," and "isotonic saline."

[0123] An experimental model for determining optimal adrenaline infusion rates. In the first part of this study (Table 1, Table 3, Series 1), thirteen (13) healthy male Wistar rats were anesthetized by intraperitoneal (i.p.) injection of thiopental (Tiobarbital 0.5 g, Braun Medical SA) after 12 hours of fasting. After onset of anesthesia, the right jugular vein was cannulated for the administration of adrenaline (Tonogen 1 mg / ml injection, Gedeon Richter Plc., Budapest, Hungary; epinephrine) as a slow, continuous infusion for 180 minutes at a rate of 0.1, 0.3, or 1 μg / kg / min (after 50×, 16.6×, and 5× Tonogen dilutions, the infusion volume is calculated based on the animal's body weight: approximately 100 μl / h). Blood samples were collected by femoral artery cannulation 15, 30, 45, 60, 90, 120, 150, and 180 min before and 15, 30, 45, 60, 90, 120, 150, and 180 min after the start of adrenaline infusion via an 8- to 10-cm-long PE50 (ID = 0.4 mm; dead space 10-13 μL) cannula for determination of blood glucose levels by direct dropping onto DCont TREND test strips (77 Elektronika).

[0124] Experimental model for investigating the effect of BMOV treatment on blood glucose levels Based on the results of the blood glucose-increasing effect of adrenaline infusion, in Series 2 (see Table 2), four healthy male Wistar rats were anesthetized as described above, and the right jugular vein was cannulated for a 200-minute infusion of adrenaline (1 μg / kg / min at a 5x dilution) or saline (1 ml / kg). The left jugular vein was cannulated for the infusion of the test compound BMOV (1.7 mg / ml stock solution; 0.2, 0.6, 1.7, or 5 ml / kg for 20-20 minutes in each animal, starting 120 minutes after the start of the adrenaline or saline infusion) or vehicle. Blood glucose levels were measured twice at each time point by directly depositing blood onto DCont TREND test strips (77 Elektronika, Budapest, Hungary). Blood samples (500 μl per hour) were collected every 20 minutes (Figures 1 and 3) via the right femoral artery before the start of the adrenaline infusion, and before and after administration of each dose of BMOV. Blood samples were centrifuged at 4,000 rpm for 15 minutes at 4°C. Prepared and separated samples from the centrifuged plasma (total volume 200 μl) were kept at -70°C until transport.

[0125] [Table 3]

[0126] result In Figure 2, these results are shown for the experiments outlined above, designated "Series 1." It is clear that the intravenous introduction of adrenaline into subjects produces a hyperglycemic state in an adrenaline dose-dependent manner, with the magnitude of the induced increase in glucose levels in the subjects' blood increasing over the time course that adrenaline is administered. In Figure 3, the results show that treatment of subjects in experimental "Series 2" with BMOV, i.e., intraperitoneal injection of adrenaline, during the course of stress administration, with administration of BMOV initiated with a delay relative to the onset of stress induction in the subjects. By administering BMOV after the onset of stress induction and during the ongoing progression of stress, the magnitude of the increase in glucose levels in the subjects is reduced.

[0127] Conclusions of Experiments "Series 1 and Series 2"

[0128] Series 1 Adrenaline infusion induced a dose-dependent sustained increase in blood glucose levels 45 minutes after the start of the infusion (Figures 1, 2, Tables 4, 5). The high dose (1 μg / kg / min of a 5x dilution of epinephrine) produced the most significant increase with glucose levels peaking approximately 120 minutes after the start of the infusion with adrenaline, which remained nearly constant until the end of the infusion (180 minutes). Based on these results, the effects of the test compound BMOV on blood glucose levels were best investigated 120 minutes after the start of the infusion of adrenaline in subjects.

[0129] Series 2 Blood glucose levels began to decline 160 minutes after the start of adrenaline infusion in subjects in the [tonogen epinephrine + vehicle] test group and the [tonogen + BMOV] group, which, without wishing to be bound by any theory, is due to the dilution effect of the relatively high infusion volume administered from this point onwards. Therefore, the experimental protocol was modified according to Series 3. See Figure 3 and Tables 6 and 7.

[0130] Blood glucose levels in Series 1

[0131] [Table 4]

[0132] [Table 5]

[0133] Blood glucose levels in Series 2

[0134] [Table 6]

[0135] [Table 7]

[0136] Example 2 Experiments demonstrating this have shown that pre-treating a subject with BMOV prior to the occurrence of stress to which the subject is subjected reduces and / or prevents hyperglycemia during the subject's exposure to stress.

[0137] Test substance Name: Bis(maltolato)oxovanadium (BMOV) BMOVs were dissolved in phosphate-buffered saline.

[0138] General test system parameters

[0139] Animal Requirements Twelve healthy male Wistar rats weighing 300-400 g were purchased from the Animal House of the University of Pecs (Hungary) and included in the validation study.

[0140] livestock Housing: Animals were housed in cages following size recommendations in the current Guide for the Care and Use of Laboratory Animals DHEW (NIH) and EU Guidelines 63 / 2010. Litter placed under the cages was changed at least three times per week. Animal rooms were temperature-controlled, lit from 7 AM to 7 PM on a 12-hour light / dark cycle, kept clean, and parasite-free. Acclimatization: Animals were acclimatized to the housing facility for at least 3 days prior to testing. Food: Any standard rodent chow, fasting started 3 hours before adrenaline injection. Water: Any filtered tap water. Contaminants: There were no known contaminants that could reasonably be expected to be found in food or water at levels that would interfere with the results of this study. Identification: Each animal was given a sequential ID number.

[0141] method

[0142] Experimental model Pretreatment Group 1, three healthy male Wistar rats were treated twice with BMOV 15 mg / kg by intraperitoneal injection (i.p.) 16-24 h and 3 h before the start of the adrenaline infusion. Group 2, three healthy male Wistar rats were treated with BMOV 15 mg / kg by intraperitoneal injection (i.p.) 3 h before the start of the adrenaline infusion. Group 3, three healthy male Wistar rats were treated with PBS vehicle 3 h before the start of the adrenaline infusion, see Figure 4.

[0143] Investigating the effects of BMOV treatment on blood glucose levels induced by acute adrenergic stress After 3 h of fasting, rats were anesthetized by intraperitoneal (i.p.) injection of thiopental (thiobarbital 0.5 g, Braun Medical SA). After onset of anesthesia, the right jugular vein was cannulated for administration of adrenaline (Tonogen 1 mg / ml injection, Gedeon Richter Plc., Budapest, Hungary; Tonogen contains epinephrine) as a slow continuous infusion at a rate of 0.3 micrograms / kg / min (approximately 100 microliters / h) of Tonogen for 180 min each. See Tables 8 and 9 for further details. Blood samples were collected from the femoral artery (or via carotid artery cannulation, as this was more suitable for higher volumes) via an 8-10 cm long PE50 (ID = 0.4 mm; dead space 10-13 microliters) cannula 30, 60, 90, 120, 150, and 180 min before and 30, 60, 90, 120, 150, and 180 min after the start of the adrenaline infusion by direct dropping onto point-of-care strips twice only at 180 min for measurement of glucose levels.

[0144] [Table 8]

[0145] Measurement of blood glucose levels in subjects in groups 1 to 3 Measurement of glucose levels was performed with a DCont TREND blood glucose meter. Two DCont TREND test strips (77 Elektronika, http: / / www.regolymedical.hu / en / measuring-tools-and-surgicalinstruments / vercukormero-d-cont-trend.html) were used to measure blood glucose levels. See Table 9 for the blood sampling regimen during the course of the study.

[0146] [Table 9]

[0147] Study endpoints Blood sugar levels Aliquot plasma samples were prepared and stored at −70° C. until shipment.

[0148] result Administration of a single dose of BMOV to a subject 3 h before stress significantly reduced the degree of hyperglycemia during the stress period (Figure 5; Tables 10 and 11). Furthermore, administration of a first dose of BMOV to a subject 16-24 h before stress, followed by administration of a second dose of BMOV 3 h before stress, significantly reduced the incidence of hyperglycemia and significantly reduced the degree of increase in blood glucose levels during the stress period (Figure 5; Tables 10 and 11). Compared with a control group administered vehicle (phosphate-buffered saline) instead of BMOV, administration of two doses of a pharmaceutical composition containing BMOV reduced the increase in blood glucose levels in subjects undergoing 180-minute adrenaline-induced stress. Subjects treated twice with BMOV before stress induction experienced increases in blood glucose levels of between about -75% and about +84% over the 180-minute course of stress induction following administration of BMOV 3 h prior to stress induction. Conversely, in the control group pretreated with vehicle before stress induction, blood glucose levels in subjects increased, for example, from 5.7 mM / L to 13.4 mM / L at t=180 min and from 5.7 mM / L at t=0 to 14.9 mM / L at t=180 min. See Table 10, Table 11, Figures 5 and 6. Thus, pretreatment of subjects with BMOV (either 3 h before the onset of stress or 16-24 hours thereafter 3 h before the onset of stress) prior to the onset of a stressful insult (herein, an infusion of adrenaline beginning at t=0 min) surprisingly significantly reduces the occurrence of hyperglycemia in stressed subjects. In Figure 6, glucose levels in the blood of subjects exposed to stress are shown at 180 min after the start of the adrenaline infusion.

[0149] [Table 10] TIFF0007757035000011.tif143149 TIFF0007757035000012.tif142149

[0150]

Table 11

Claims

1. A pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex and further comprising a pharmaceutically acceptable excipient for use in preventing stress-induced hyperglycemia in a stressed patient, wherein the stress is trauma, for example trauma caused by surgery, trauma caused by a medical procedure, trauma caused by iatrogenic injury, and / or the stress experienced by the patient is acute psychological stress of long or short duration due to an infection, a life-threatening condition, for example potentially life-threatening conditions and incidents. and the like, wherein the pharmaceutical composition is administered to the patient before the patient is subjected to stress, the physiologically acceptable organic and / or inorganic vanadium compound or complex is bis(maltolato)oxide vanadium (BMOV) or bis(ethylmaltolato)oxovanadium(IV) (BEOV), preferably BMOV, and the increase in glucose content in the patient's blood during the period in which the patient is subjected to stress is less than about 65% compared to the glucose content in the patient's blood at the time the patient begins to be subjected to stress.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition comprises BMOV or BEOV as the sole active pharmaceutical ingredient, or the pharmaceutical composition comprises a combination of BMOV and BEOV as the active pharmaceutical ingredients.

3. 3. The pharmaceutical composition for use according to claim 1 or 2, which is administered to a patient at least once between 96 h and 0 h before the patient is subjected to stress, preferably between 72 h and 1 h, more preferably between 48 h and 2 h, and most preferably between 24 h and 3 h before the patient is subjected to stress.

4. 4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex is administered orally to a patient, or administered intravenously, or administered intraperitoneally, or administered intramuscularly, or administered intradermally to a patient, preferably administered intravenously, or administered intradermally, or administered intraperitoneally to a patient.

5. 5. The pharmaceutical composition for use according to claim 4, which is an aqueous solution, preferably comprising between about 0.001 mg and 10 mg of physiologically acceptable organic and / or inorganic vanadium compounds or complexes per ml of pharmaceutical composition, preferably between about 0.5 mg / ml and 5 mg / ml, more preferably about 2 mg of physiologically acceptable organic and / or inorganic vanadium compounds or complexes per ml.

6. The at least one pharmaceutically acceptable excipient comprises phosphate buffered saline, the phosphate buffered saline containing NaH ２ P.O. ４ .H ２ O1.86g / l, Na ２ HPO ４ . 2H ２ 9.50 g / l of HCl and 4.40 g / l of NaCl, preferably the pharmaceutically acceptable additive is NaH ２ P.O. ４ .H ２ O about 1.86 g / l, Na ２ HPO ４ . 2H ２ 6. The pharmaceutical composition for use according to claim 5, comprising phosphate buffered saline consisting of about 9.50 g / L of O and about 4.40 g / L of NaCl.

7. 5. The pharmaceutical composition for use according to claim 4, wherein the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex is orally administered to a patient, said pharmaceutical composition being provided as a capsule, tablet, pill, or water-soluble powder for oral administration.

8. 8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein a single dose of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex is administered to the patient or the dosage regimen is the administration of at least two doses of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex to the patient per 12h to 48h, preferably two doses between 16h to 24h.

9. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the dosage of the pharmaceutical composition comprising the physiologically acceptable organic and / or inorganic vanadium compound or complex administered to the patient comprises between 0.01 mg and 30 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of the patient's body weight, preferably between 0.1 mg and 15 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of the patient's body weight, more preferably between about 0.15 mg and 10 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of the patient's body weight, and most preferably between about 0.5 mg and 2.5 mg of the physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of the patient's body weight.

10. 10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein a first single dose of the pharmaceutical composition is administered to the patient at a time point between 96 h and 10 h, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, and most preferably between 24 h and 16 h, before the patient is subjected to stress, and a second single dose of the pharmaceutical composition is administered to the patient at a time point between 8 h and 0 h, preferably between 5 h and 3 h, before the patient is subjected to stress, preferably wherein the first single dose is administered between 24 h and 16 h, and the second single dose is administered about 3 h before the patient is subjected to stress.

11. 10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein a first single dose of the pharmaceutical composition is administered to the patient at a time between 96 h and 1 h, preferably between 72 h and 1 h, more preferably between 48 h and 2 h, and most preferably between 24 h and 3 h before the patient is subjected to stress, and a second single dose of the pharmaceutical composition is administered to the patient during the period in which the patient is subjected to stress.

12. 10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein a first single dose of the pharmaceutical composition is administered to the patient between 96 h and 10 h, preferably between 72 h and 12 h, more preferably between 48 h and 14 h, and most preferably between 24 h and 16 h, before the patient is subjected to stress; a second single dose of the pharmaceutical composition is administered to the patient between 8 h and 0 h, preferably between 5 h and 3 h, before the patient is subjected to stress; and a third single dose of the pharmaceutical composition is administered to the patient during the period in which the patient is subjected to stress.

13. 13. The pharmaceutical composition for use according to any one of claims 10 to 12, provided as an aqueous solution or as a solid dosage form, such as, for example, powders, tablets, pills, and capsules, wherein the dosage of the pharmaceutical composition comprises between about 0.01 mg and 30 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, preferably about 0.5 mg to 2.5 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight.

14. 14. The pharmaceutical composition for use according to any one of claims 9 to 13, provided as an aqueous solution or as a solid dosage form such as, for example, powders, tablets, pills, capsules and the like, wherein a dosage of the pharmaceutical composition comprises between about 0.01 mg and 30 mg of physiologically acceptable organic and / or inorganic vanadium compound or complex per kg of patient body weight, and wherein administration of the dosage of the pharmaceutical composition to said patient provides a plasma exposure level of between 25 ng / ml and 2500 ng / ml of elemental vanadium in said patient, or preferably between 100 ng / ml and 1000 ng / ml.

15. 15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein the increase in glucose content in the patient's blood during the period in which the patient is under stress is less than about 30%, preferably less than about 6%, compared to the glucose content in the patient's blood at the time the patient begins to be under stress.

16. 15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein during the first 1 to 8 hours of a period in which the patient is under stress, preferably during about the first 3 hours of a period in which the patient is under stress, the increase in the glucose content in the patient's blood is less than about 65%, preferably less than about 30%, more preferably less than about 6%, compared to the glucose content in the patient's blood at the time the patient begins to be under stress.

17. 15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein during the first 1 to 8 hours of a period in which the patient is under stress, preferably during about the first 3 hours of a period in which the patient is under stress, the increase in the glucose content in the patient's blood is between about 5% to about 65%, preferably about 30%, compared to the glucose content in the patient's blood at the time the patient begins to be under stress.

18. 18. The pharmaceutical composition for use according to any one of claims 1 to 17, wherein the stress inflicted on a patient is stress caused by trauma occurring during any one or more of surgical procedures, such as cardiac surgery, amputation surgery, tumor resection surgery, brain surgery, transplant surgery, surgery associated with restoring hemostasis, surgery associated with treating fractures, surgery associated with organ or bone reconstruction, such as hip graft surgery, vascular surgery, bypass surgery, wound closure, treatment of injuries to skin, bone, organs, tissues, arteries, veins, medical procedures, iatrogenic injury, infection, acute psychological stress, accidents, etc.

19. 20. A kit of parts comprising a container containing at least two doses of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex for use according to any one of claims 1 to 18, further comprising instructions for use of the pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex provided in said container in the prevention of stress-induced hyperglycemia in a patient who becomes stressed, the stress inducing a state of physiological tension in the patient.

20. 20. The kit of parts according to claim 19, comprising a first container containing a single dose of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, preferably BMOV, and a second container containing a single dose of a pharmaceutical composition comprising a physiologically acceptable organic and / or inorganic vanadium compound or complex, preferably BMOV.

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