WO2002036066A2

WO2002036066A2 - Pharmaceutical compositions comprising organic vanadium complexes for treatment of ischemia

Info

Publication number: WO2002036066A2
Application number: PCT/IL2001/001004
Authority: WO
Inventors: Yoram Shechter; Matityahu Fridkin; Itzhak Goldwaser
Original assignee: Yeda Research and Development Co Ltd
Current assignee: Yeda Research and Development Co Ltd
Priority date: 2000-11-01
Filing date: 2001-10-30
Publication date: 2002-05-10
Anticipated expiration: 2003-05-01
Also published as: AU2002214222A1; WO2002036066A3

Abstract

Organic vanadium complexes can be used for prevention and/or treatment of cerebral ischemia. The vanadium complex may be bis(N-octyl cysteine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium (IV) or a vanadium complex of a hydroxamate, preferably of a monohydroxamate, and is more preferably a vanadium complex of a monohydroxamate of the formula R-CO-NHOH.X, wherein R is a residue selected from: (i) H2N-CH(COY)-(CH2)n-; (ii) H2N-CH(COOH)-CH2-S-CH2; and (iii) pyridyl, piperidyl or tetrahydroisoquinolinyl, wherein n is 1, 2 or 3, and Y is OH or NH2; and X is a vanadium compound selected from a vanadyl (VO2+), metavanadate (VO¿3?-) or vanadate (VO¿4?3-) salt.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ORGANIC VANADIUM COMPLEXES FOR TREATMENT OF ISCHEMIA

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising organic vanadium complexes useful for prevention or treatment of cerebral ischemia.

BACKGROUND OF THE INVENTION

Stroke or cerebral ischemia can be initiated by a state of stress (i.e., by cardiac arrest) and ultimately result in neuronal death and brain damage (Myers and Yamaguchi, 1977). The cellular mechanisms and the sequence of events leading to ischemia are still obscure. An extreme case is a normoxic brain condition in which glucose is consumed by brain tissues at a faster rate and in large quantities. Cellular ATP levels are then depleted, leading to the inability of brain tissues to utilize glucose as a source of energy, thus culminating in ischemia.

Stroke or cerebral ischemia is the third leading cause of death in the U.S. and other Western countries. A large toll on society estimated at hundreds of billions of dollars are spent annually as a result of this pathological syndrome.

Paradoxically, preischemic hyperglycemia has been shown to aggravate (rather than reduce) cerebral ischemic damage. This phenomenon has been initially accounted for by excessive production and accumulation of lactic acid and acidosis in brain tissues (Siesjo, 1981). Studies by Schurr et al. have refuted this hypothesis by demonstrating that high concentrations of lactic acid not only do not damage but rather protect rat hippocampal slices from hypoxia (Schurr et al., 1988a and b). Moreover, it has been demonstrated that hippocampal slices utilize lactate aerobically as an energy source (Schurr et al., 1988b) - an absolute essential event under normoxic conditions when the ATP level is depleted and glucose cannot be utilized as a source of energy. While discrediting the lactoacidosis hypothesis, Schurr et al. have postulated that preischemic hyperglycemia is associated with an increase (or a decrease) in another endogenous substance(s) that is responsible for ischemic damage. In support of this theory, it was further observed that ischemic damage is synergized by short periods of hyperglycemia, but not by prolonged ones, suggesting that the putative substance responsible for the damage is a short-lived species (Schurr et al., 1999). This and other studies pointed toward the hormone corticosterone, the equivalent of human cortisol (Sapolsky, 1986). Corticosterone levels in mice were elevated six-fold within 30 min after glucose loading. The level of this steroid hormone then declined, although elevated levels of circulating glucose still persisted (Sapolsky, 1986a, b). Addition of corticosterone to hippocampal slices aggravated ischemic neuronal damage as described herein.

Vanadium salts were investigated in the last two decades with respect to their insulin-like effects in vitro, and in relation to their antidiabetic actions in diabetic rodents and in human patients (reviewed in Shechter, 1990 and Brichard and Henquin, 1995). Vanadium salts are particularly effective in reversing the deteriorating actions of chronic hyperglycemia in diabetic rodents. For example, in the diabetic liver, vanadium therapy restores the activity of glucokinase, increases the level of 2,6-bisphosphate by elevating the level of the L-pyruvate kinase gene, and suppresses gluconeogenesis by lowering niRNA and protein levels of phosphoenolpyruvate carboxykinase (Gil et al, 1988). In the diabetic muscle, vanadium therapy also restores glycogen synthesis. All of these aberrations are the direct consequence of chronic hyperglycemia in diabetic rodents. In PCT Publication No. WO 99/12875 of the present applicants it was shown that certain amino acid monohydroxamates (HXM), in particular the L- forms of glutamic acid γ-monohydroxamate (Glu(γ)HXM) and aspartic acid β- monohydroxamate (Asp(β)HXM), interact with vanadium (+4) and vanadium (+5). At a 1:1 or 2:1 HXM:vanadium molar stoichiometry, the HXM largely potentiate the insulinomimetic potencies of vanadium (+4) and (+5) in vitro, and normalize the blood glucose level of streptozocin-treated rats in vivo. We have then reported that the 2:1 complex of L-glutamic acid(γ)-monohydroxamate with vanadium (+5) (herein designated LP-100) is 5-7 fold more potent than free vanadium as an insulinomimetic and antidiabetic agent (Goldwaser et al, 1999). A later publication by the inventors (Goldwaser et al, 2000) discloses that these organic vanadium chelators potentiate vanadium-evoked glucose metabolism in vitro and in vivo.

Other organic vanadium complexes such as bis(N-octyl cysteine amide) oxovanadium (IV) (Cam et al., 1993), bis(maltolato)oxo vanadium (IV) (Yuen et al., 1992) and bis(picolinato)oxovanadium (IV) (Sakurai et al., 1995) have been described as presenting antidiabetic action in vivo in animal models.

SUMMARY OF THE INVENTION

It has now been found in accordance with the present invention that organic vanadium complexes, in particular vanadium complexes of monohydroxamates, and more particularly the complex of the L-form of glutamic acid γ- monohydroxamate (Glu(γ)HXM) with vanadium (+5) (2:1, herein designated LP- 100), can antagonize the deteriorating actions of preischemic hyperglycemia and those of corticosterone. Thus, in one aspect, the present invention relates to pharmaceutical compositions for prevention and/or treatment of cerebral ischemia comprising as active ingredient an organic vanadium complex.

Any suitable organic vanadium complex can be used according to the invention such as, but not being limited to, bis(N-octyl cysteine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium

(IV) and a vanadium complex of a hydroxamate, preferably of a monohydroxamate.

In one preferred embodiment, the present invention provides a pharmaceutical composition for prevention and/or treatment of cerebral ischemia comprising as active ingredient an organic vanadium complex of a monohydroxamate of the formula (I):

R-CO-NHOH . X (I) wherein

R is a residue selected from:

(i) H₂N-CH (COY)-(CH₂)_n- (ii) H₂N-CH (COOH)-CH₂-S-CH₂-; and (iii) pyridyl, piperidyl or tetrahydroisoquinolinyl; wherein n is 1, 2 or 3, and Y is OH or NH₂; and X is a vanadium compound selected from a vanadyl (VO²⁺), metavanadate (VO₃ ^") or vanadate (VO₄ ^3") salt.

In a more preferred embodiment, the composition of the invention comprises a vanadium complex of a monohydroxamate of an amino acid as defined in (i) above, most preferably wherein n is 2, namely the γ- monohydroxamate of L-glutamic acid.

Among the monohydroxamates of (iii) above, preferred are the 3-pyridyl radical, namely the nicotinic acid hydroxamate, the 2- or 3-piperidyl radical and the 3-tetrahydroisoquinolrnyl radical.

Examples of vanadium salts used to form the vanadium complexes of hydroxamates used in the compositions of the present invention are, without being limited to, VOCl₂ (+4), VOSO₄ (+4), NaVO₃ (+5) and Na₃VO₄ (+5).

With regard to the vanadium complexes of amino acid hydroxamates (HXM), various HXM:vanadium salt stoichiometric molar ratios of the complexes are envisaged by the present invention, but 1:1 and 2:1 HXM:vanadium salt molar ratios are preferred.

In a most preferred embodiment of the present invention, the composition comprises the complex formed between 2 mol of γ-monohydroxamate of L- glutamic acid and 1 mol of NaVO₃ (+5), herein identified as LP-100, of the formula: [H₂N-CH(COOH)-CH₂-CH₂-CO-NHOH]₂ : Na VO₃ The vanadium complexes, in particular the complexes with monohydroxamates of formula I of the compositions of the invention, are prepared by mixing water solutions of the organic compound, e.g. the monohydroxamate, and the vanadium salt, freezing and lyophilizing the solution, thus obtaining a dry powder that can be stored, for example, at room temperature.

The pharmaceutical compositions of the invention are useful for prevention and/or treatment of cerebral ischemia also known as cerebral infarction or stroke.

The dosage to be administered will depend on the conditions of the patient. The allowed amount of vanadium being used in diabetic patients in clinical trials today is about 2-4 mg/kg/day, that corresponds to about 6-12 mg/kg/day of LP- 100. This range could be used for prevention of cerebral ischemia in individuals likely to develop it. However, in case of evolving stroke or acute complete stroke, the dose may be higher since it is an acute treatment.

The compositions of the invention comprising the organic vanadium complex may be presented in soluble form, such as drops, or in the form of capsules or tablets, and are preferably administered orally. They may be administered alone or in combination with another drug for prevention and/or treatment of cerebral ischemia.

In another aspect, the invention relates to the use of an organic vanadium complex, particularly those described above, for the preparation of a pharmaceutical composition for the prevention and/or treatment of cerebral ischemia.

In a further aspect, the invention relates to a method for prevention and/or treatment of cerebral ischemia in order to diminish the deteriorating effects thereof, which comprises administering to an individual in need thereof an effective amount of an organic vanadium complex, particularly those described above.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs. 1A-1B show that corticosterone decreases percentage of rat hippocampal slices with normal neuronal function in an in vitro experimental system, following 30 min hypoxia, in a dose-dependent manner (1 A) and vanadate (200 μM) and LP-100 (20 μM) antagonize corticosterone-evoked ischemic damage in vitro (IB). The indicated concentrations of vanadate and LP-100 were perfused during the 30 min of ischemic period only. Ischemia was induced by depleting glucose for 30 min and oxygen for 4 min.

Fig. 2 shows an in vivo experimental system for analyzing cardiac arrest- evoked cerebral ischemia in hyperglycemic rats and the beneficial effects of vanadate and LP-100. Groups of rats are injected (i.p.) with the indicated concentrations of vanadate or LP-100 administered either 1 h ('early vanadium') or 1 min ('late vanadium') prior to cardiac arrest. Rats are then subjected to glucose- loading and chest compression cardiac arrest. Rats are sacrificed a week later and the extent of neuronal damage in hippocampal slices is evaluated by an electrophysiological procedure. Each group consists of five rats.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to the use of organic vanadium complexes such as vanadium complexes of certain monohydroxamates, more particularly the complex of the L-form of glutamic acid γ-monohydroxamate (Glu(γ)HXM) with vanadium (+5) (2:1, herein designated LP-100), for prevention and/or treatment of cerebral ischemia (also known as cerebral infarction or stroke).

The establishment of both in vitro and in vivo experimental systems for investigating cerebral ischemia led to better understanding of this pathological syndrome. Data from both experimental systems showed that transitory hyperglycemia aggravates cerebral ischemia not because of high circulating glucose levels or lactic acid accumulation and acidosis of brain tissue, but rather due to elevated levels of corticosterone that accompany the early phase of hyperglycemia. Thus, out of the many alterations facilitated by glucose loading in rodents, the 'burst' of corticosterone observed in mice long ago following glucose administration is the event responsible for that aggravation. This point has been confirmed in vitro by demonstrating ischemic damage upon adding corticosterone to hippocampal brain slices. Thus, hyperglycemia, which facilitates deteriorating effects in diabetes, has a damaging role on cerebral ischemia as well.

Vanadium salts and LP-100 antagonize a variety of deteriorating actions originating from hyperglycemia in liver and in muscle tissue of diabetic rodents and, as shown herein, are also effective in reversing corticosterone-evoked cerebral damage in brain slices and in cardiac arrest induced hyperglycemic- ischemic rat model. To date, early diagnosis of stroke episodes in humans is still lacking and it is therefore unknown whether a transitory state of hyperglycemia precedes stroke episodes in nondiabetic human subjects. The level of the 'stress hormone' cortisol (the human analog of rat corticosterone) is, however, elevated under pathological conditions such as ischemia and/or cardiac arrest in an ACTH- dependent fashion.

Vanadium salts mimic the effects of insulin in a post-receptor-mediated fashion and ameliorate diabetic deficiencies originating from hyperglycemia. Hyperglycemia has been implicated in aggravating cerebral ischemia by elevating the levels of corticosterone. It is shown herein that vanadium (+5), and more so L- Glu(γ)HXM- vanadium (+5), (2:1, LP-100), have neuroprotective effects on cerebral ischemia. This is demonstrated in vitro using hippocampal slices, and in vivo in cardiac-arrest-induced transient global cerebral ischemia in hyperglycemic rats. In vitro, application of vanadate (200 μM) or LP-100 (50 μM) prior, or even subsequent to, the addition of 20 μM corticosterone, fully blocked the aggravating effect of corticosterone. In vivo, pretreatment with vanadate (28 μg/kg, i.p.) or LP- 100 (7 μg/kg, i.p.) prior to the ischemic challenge, significantly reduces neuronal damage in brain when measured seven days after the ischemic challenge. Vanadium ameliorates cerebral ischemia by antagonizing the deteriorating effects of corticosterone.

The invention will now be illustrated by the following non-limiting examples. EXAMPLES Material and Methods (a) Materials. LP-100 was prepared as previously described (WO 99/12875).

(b) In vitro system for studying hypoxia: Preparation and maintenance of rat hippocampal slices. Hippocampi were removed from male Sprague-Dawley rats (200-350 g) and slices were prepared using a McLlwain tissue sheer. For each experiment both hippocampi from a single rat were used. About 20-30 slices were prepared, randomized and placed (10-15 per compartment) in a dual incubation/recording (34±0.3°C) chamber (Schurr et al, 1985). Slices were supplied with a humidified gas mixture (95% O /5%CO₂) and perfused with artificial cerebrospinal fluid (aCSF) (1 ml/min) of the following composition (in mM): NaCL 124; KC1, 5; NaH₂PO₄, 3; CaCl₂, 2.5; MgSO₄, 2; NaHCO₃, 23; D- glucose, 10. The pH was 7.3-7.4 (295-300 mOsm). In some experiments, glucose was reduced to 5 mM. Chemicals were of analytical grade and obtained from Sigma Chemical Co. (St. Louis, MO). Corticosterone acetate was dissolved in ethanol for a final CSF concentration of 0.01%.

(c) Hypoxia was obtained by replacement of O₂ in the gas mixture with N₂ over a period of 4 min unless otherwise indicated.

(d) Electrophysiological determination of neuronal damage in hippocampal slices. Neuronal function was estimated by the extracellular recording of electrically-evoked population of spikes in the stratum pyramidal of the CAI region using borosilicate micropipettes of 2-5 mohm. An orthodromic stimulating pattern was applied by placing bipolar-stimulating electrodes in the Schaffer collaterals. A single stimulus pulse of 0.1 ms in duration and of 8-10 V in amplitude was applied each minute. A wave form analysis program was used to determine the amplitude of the evoked population spike (PS). Baseline PS amplitudes (prehypoxia) were consistently found to be 10 mV or greater (Schurr et al., 1995). Following hypoxia, slices that exhibited PSs equal to or larger than 3 mV in amplitude were considered neuronally functional. A slice in which the PS was smaller than 3 mV was considered to be functionally damaged. Nonfunctional slices at 30-min post hypoxia were unresponsive even 6 h later, thus exhibiting irreversible neuronal damage (Schurr and Rigor, 1995). Each data point in the experiments was repeated at least three times. Values are means ±S.D. Each experiment included 10-15 control (aCSF with 20 μM corticosterone) and 10-15 treated (LP-100, or NaVO₃) slices. Paired t-test was applied for the statistical analyses of the electrophysiological data.

(e) Procedure for determining stroke-brain damage in vivo: Cardiac arrest induces transient global cerebral ischemia (TGI) that is more intensive in hyperglycemic rats. In all experiments, 24 h fasted Sprague Dawley male rats (250-350 g) are used. The procedures for chest compression-induced cardiac arrest, blood pressure monitoring, resuscitation and preparation of hippocampal slices for electrophysiological and histological analyses are performed as previously described (Schurr et al., 1996; Reid et al, 1996; Li et al., 1999) with no modifications. Briefly, rats are anesthetized with ketamine + xylazine [(75 mg + 9 mg)kg, i.p.]. The anesthetized rat is placed supine and a 14-gauge angiocath tube is placed in the trachea for the respiratory assistance during resuscitation following chest compression-induced cardiac arrest. A catheter is placed in the abdominal aorta via the femoral artery for continuous monitoring of blood pressure before and during chest compression, and during cardiopulmonary resuscitation (CPR). Temperature is controlled at 35.5 + 0.5° C during the chest compression- resuscitation period and during 1 h post-TGI. Chest compression is maintained for 5 min by placing a 3-kg weight on a chest bar (Reid et al., 1996). The speed of the weight descent is regulated manually to allow deflation of the lungs as they are compressed. The end point of compression is the complete loss of pulse pressure. Post-compression CPR is initiated at the end of 5-min compression after removing the weight and chest bar. Chest massage is applied to reestablish cardiac circulation. Reoxygenation of the rat is enhanced by ventilation with a humidified mixture of 95%O₂/5%CO₂ at intervals of 5 s. Systemic circulation usually returns within 1-3 min after compression is terminated. All rats are loaded with glucose (2 g/kg, i.p.) 15 min prior to chest compression. LP-100 is administered 60 min prior to chest compression (several doses, i.p.) while controls are injected with the vehicle.

Example 1. Vanadate and LP-100 reverse corticosterone-enhanced ischemic damage in hippocampal slices. Rat hippocampal slices were maintained under an atmosphere of carbogen

(95% O₂, 5% CO₂) and perfused with aCSF containing 10 mM D-glucose as described in section (b) above. In the experiments summarized in Figure 1, slices were perfused for 30 min with aCSF containing no glucose, and then exposed to a 4 min period of hypoxia obtained by changing the composition of the gas mixture to 95% N₂, 5% CO₂. These experimental conditions were previously shown to bring about a significant degree of neuronal damage in general, particularly in corticosterone-augmented ischemic neuronal damage. In this case, damage is intensified when hippocampal slices are maintained at low concentrations of glucose (Schurr et al., 1987; Sapolsky, 1986; Elliot et al, 1993). As shown in Fig. 1 A, increasing concentrations of corticosterone, prior to induction of hypoxia, reduced the extent of normal neuronal function in a dose- dependent fashion. Thus, at 0, 5, 10, 15 and 20 μM corticosterone, the percentage of slices showing normal neuronal function amounted to 57+3, 41+8, 18+2 and 10+1%, respectively (Fig. 1A). When vanadate (200 μM) or LP-100 (50 μM) were included in the incubation medium, along with corticosterone, prior to the induction of hypoxia, the aggravating effect of the steroid (10+1% neuronal function, Fig. IB) was fully antagonized (59+2% neuronal function). Moreover, addition of vanadate and LP-100 even after the induction of ischemia (i.e. 1 or 2 min after changing the composition of the gas mixture to 95% N₂, 5% CO₂) decreased significantly the corticosterone-evoked ischemic damage (42+7% neuronal function, Fig. IB). The latter finding suggests that vanadium and LP-100 might have a neuroprotective effect also on a post-ischemic event, namely, after a stroke has occurred.

5 Example 2. Vanadium and LP-100: Beneficial effects on glucose-enhanced ischemic neuronal damage in rats in vivo.

In the set of experiments summarized in Fig. 2, Sprague-Dowley male rats are first brought to a hyperglycemic state by injecting glucose 15 min prior to the cardiac arrest procedure. This specific time point of glucose administration, rather l o than earlier ones, is chosen to obtain maximal elevation of corticosterone (Schurr et al., 1999). Cardiac arrest induces a transient global cerebral ischemia which, if massive enough, by and large extends the duration of the neuronal damage. Treated rats are sacrificed one week after the insult, hippocampal slices are prepared and the degree of neuronal damage is evaluated both by

15 electrophysiological and histological procedures (see Materials and Methods). As shown in Fig. 2, in the absence of glucose-loading at normoglycemic conditions (5.5 mM glucose), the percentage of slices showing neuronal damage seven days after the insult amounts to 40+6% (leftmost column). When glucose is injected 15 min prior to the insult, the circulating glucose level is 19.0+5 mM and the extent of

20 neuronal damage reaches a value of 58+5%. Intraperitoneal (i.p.) administration of vanadate (28 μg/kg) to normoglycemic rats 60 min prior to chest compression (cardiac arrest) has some neuroprotective effect (a decrease from 40+6 to 26+15%). Within the group of the hyperglycemic rats, the neuroprotective effect of vanadium and of LP-100 is clearly impressive: The extent of slices showing

25 neuronal damage in the vanadium-treated group is 30+12%, as compared to 58±5% in the non-vanadium treated group. Vanadium therapy does not decrease appreciably the circulating glucose level, further suggesting that the neuroprotective action of vanadium takes place by antagonizing the deteriorating effects of corticosterone on cerebral ischemia. Finally, low concentrations of insulin (1.2 U/kg) are coadministered subcutaneously (s.c.) along with LP-100 (Fig. 2, right column). We have previously found that this combination (but not each compound individually) largely decreases glucose levels in diabetic-hyperglycemic rats. As shown in Fig. 2, this combination reduces both circulating glucose levels and the extent of corticosterone-evoked cerebral ischemia.

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Claims

CLAIMS:

1. A pharmaceutical composition for prevention and/or treatment of cerebral ischemia comprising an organic vanadium complex, optionally with a

5 pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein said organic vanadium complex is bis(N-octyl cysteine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium (IV) or a vanadium l o complex of a hydroxamate.

3. The pharmaceutical composition according to claim 2, wherein said hydroxamate is a monohydroxamate.

15 4. The pharmaceutical composition according to claim 3, comprising a vanadium complex of a monohydroxamate having the formula (I):

R-CO-NHOH.X (I) wherein 20 R is a residue selected from:

(i) H₂N-CH(COY)-(CH₂)_n-

(ii) H₂N-CH(COOH)-CH₂-S-CH₂-; and

(iii) pyridyl, piperidyl or tetrahydroisoquinolinyl; wherein n is 1, 2 or 3, and Y is OH or NH₂; and X is a vanadium compound 25 selected from a vanadyl (VO²⁺), metavanadate (VO ^") or vanadate (VO₄ ^3") salt.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein said vanadium compound is VOCl₂, VOSO₄ , NaVO and Na₃VO₄.

30 6. The pharmaceutical composition according to claim 4 or 5, comprising a vanadium complex of an amino acid monohydroxamate of the formula:

H₂N-CH(COY)-(CH₂)_n-CO-NHOH.X (I) wherein n is 1, 2 or 3, Y is OH or NH₂, and X is a vanadium compound selected from a vanadyl (VO²⁺), metavanadate (VO₃ ^" ) or vanadate (VO₄ ^3") salt.

7. The pharmaceutical composition according to claim 6, wherein the active ingredient is a 1:1 or 2:1 vanadyl or vanadate complex of L-glutamic acid γ- monohydroxamate.

8. The pharmaceutical composition according to claim 7, wherein the active ingredient is the 2:1 vanadate complex of L-glutamic acid γ-monohydroxamate of the formula:

[H₂N-CH(COOH)-CH₂-CH₂-CO-NHOH]₂ : Na VO₃

9. Use of an organic vanadium complex, optionally with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for prevention and/or treatment of cerebral ischemia.

10. Use according to claim 9, wherein said organic vanadium complex is bis(N- octyl cysteine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium (IN) or a vanadium complex of a hydroxamate.

11. Use according to claim 10, wherein said hydroxamate is a monohydroxamate.

12. Use according to claim 11, wherein said vanadium complex of a monohydroxamate has the formula (I):

R-CO-ΝHOH.X (I) wherein

R is a residue selected from: (i) H₂N-CH(COY)-(CH₂)_n - (ii) H₂N-CH(COOH)-CH₂-S-CH₂-; and (iii) pyridyl, piperidyl or tetrahydroisoquinolinyl; wherein n is 1, 2 or 3, and Y is OH or NH₂; and X is a vanadium compound selected from a vanadyl (NO²⁺), metavanadate (NO₃~) or vanadate (NO ^3~) salt.

13. Use according to any one of claims 9 to 12, wherein said vanadium compound is NOCI₂, NOSO₄ , ΝaNO₃ and Νa₃NO₄.

14. Use according to claim 12 or 13, wherein said vanadium complex of an amino acid monohydroxamate has the formula:

H₂Ν-CH(COY)-(CH₂)_n -CO-ΝHOH.X (I) wherein n is 1, 2 or 3, Y is OH or NH₂, and X is a vanadium compound selected from a vanadyl (NO²⁺), metavanadate (NO₃ ^" ) or vanadate (NO₄ ^3") salt.

15. Use according to claim 14, wherein said vanadium complex of an amino acid monohydroxamate is a 1:1 or 2:1 vanadyl or vanadate complex of L-glutamic acid γ-monohydroxamate.

16. Use according to claim 15, wherein vanadium complex is the 2:1 vanadate complex of L-glutamic acid γ-monohydroxamate of the formula:

[H₂Ν-CH(COOH)-CH₂-CH₂-CO-ΝHOH]₂ : Na VO₃

17. A method for prevention and/or treatment of cerebral ischemia which comprises administering to an individual in need thereof an effective amount of an organic vanadium complex.

18. The method according to claim 17, wherein said organic vanadium complex is bis(N-octyl cysteine amide) oxovanadium (IN), bis(maltolato)oxovanadium (IN), bis(picolinato) oxovanadium (IN) or a vanadium complex of a hydroxamate.

19. The method according to claim 18, wherein said hydroxamate is a monohydroxamate.

20. The method according to claim 19, wherein said vanadium complex of a monohydroxamate has the formula (I):

R-CO-NHOH.X (I) wherein

R is a residue selected from: (i) H₂N-CH(COY)-(CH₂)„ -

(ii) H₂N-CH(COOH)-CH₂-S-CH₂-; and (iii) pyridyl, piperidyl or tetrahydroisoquinolinyl; wherein n is 1, 2 or 3, and Y is OH or NH₂; and X is a vanadium compound selected from a vanadyl (NO²⁺), metavanadate (VO{ ) or vanadate (NO₄ ^3") salt.

21. The method according to any one of claims 17 to 20, wherein said vanadium compound is NOCl₂, NOSO₄ , ΝaNO₃ and Νa₃VO₄.

22. The method according to claim 20 or 21, wherein said vanadium complex of an amino acid monohydroxamate has the formula:

23. The method according to claim 22, wherein said vanadium complex is a 1:1 or 2:1 vanadyl or vanadate complex of L-glutamic acid γ-monohydroxamate.

24. The method according to claim 7, wherein said complex is the 2:1 vanadate complex of L-glutamic acid γ-monohydroxamate of the formula:

[H₂N-CH(COOH)-CH₂-CH₂-CO-NHOH]₂ : Na VO₃