EP1976496A1

EP1976496A1 - Overall therapeutic approach in the treatment of neurodegenerative diseases

Info

Publication number: EP1976496A1
Application number: EP07700501A
Authority: EP
Inventors: Raymond Andrieu; Philippe Le Goff; Max De Reggi
Original assignee: Cerebel SA
Current assignee: Cerebel SA
Priority date: 2006-01-23
Filing date: 2007-01-19
Publication date: 2008-10-08
Also published as: WO2007083228A1

Abstract

The present invention relates to a pharmaceutical product and to its use in the prevention and treatment of neurodegenerative diseases in humans. The method is based on the action of pantethine-derived substances which have demonstrated an up until now unsuspected effectiveness in protecting the integrity of the blood-brain barrier. By virtue of its method that can be generalized to many neurodegenerative diseases, the present invention significantly differentiates from the conventional therapeutic approaches which associate a treatment for each pathogenic origin.

Description

GLOBAL THERAPEUTIC APPROACH IN THE TREATMENT OF NEURODEGENERATIVE DISEASES

With brain tumors and vascular diseases, degenerative diseases are the most common disorders of the central nervous system. Their relative frequency, the severity of their attacks, the disabilities they cause have made them infamous and known to the general public: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, dystonia children, are so many terms belonging to everyday language as they are part of everyday life. Their severity, often related to the absence of therapy, makes it a formidable scourge which, because of their diversity can reach the child as the adult, the marrow as the encephalon, the motor as the higher functions. They can affect neurons such as the constituents of the white matter such as myelin, be limited to very specific structures, or extend to the entire nervous system, affect the child and the young adult or on the contrary make part of what we call aging-related diseases. Their mechanism is also very variable and what finally makes their unit, the common feature that characterizes them, is the existence of a progressive and often unavoidable degeneration of all or part of the nervous system, hence their name of neurodegenerative diseases.

Among the neurodegenerative pathologies, Alzheimer's and Parkinson's diseases currently affect about 22 million people and this population could increase by 40 to 50% in the next 15 to 20 years. In the countries Subtropical Cerebral Malaria, which also belongs to the group of neurodegenerative diseases, kills more than two million people every year, including nearly one million children in Africa alone. The therapeutic approach proposed by the actors of the health professions, and on which continues the current research, consists in wanting to propose a specific remedy for each pathology taken in isolation.

Thus, in a traditional way, the therapeutic approach prevailing in the treatment of Alzheimer's disease relies on the use of specific inhibitors of cholinesterase or acetylcholinesterase which may be supported by modulation if appropriate. allosteric nicotinic receptors.

Regarding Parkinson's disease, there is no cure for the disease. Treatment of Parkinson's disease is therefore intended to correct the patient's symptoms, mainly motor symptoms. The therapeutic choices are essentially guided by the age of onset of Parkinson's disease and the degree of functional impairment. L-Dopa is the reference treatment. The good use of L-Dopa has been accompanied by an increase in life expectancy of at least five years for patients. At the same time, the use of dopamine agonists has been shown to be usually less effective than L-Dopa, but these compounds have less adverse motor effects. Anticholinergics, inhibitors of Mono-Amine-Oxidase B or Catechol-O-Methyl Transferase inhibitors are also mentioned. In the case of Cerebral Malaria, the main current antimalarials can be classified according to their mode of action into two categories:

Elective schizonticides:

This group includes quinoline derivatives and artemisinin derivatives.

Quinoleic derivatives: these are the compounds of the 4-aminoquinoline type (chloroquine, amodiaquine) and the aminoalcohols (lumefantrine, mefloquine, halofantrine, quinine). These molecules interfere with the use of hemoglobin in the nutrient vacuole by inhibiting the formation of hemozoin.

artemisinin derivatives: this new class of antimalarials of the peroxide type also interferes with the use of hemoglobin, by release of free radicals, toxic for the parasite. The artemisinin derivatives have a gametocytocidal action, which reduces the transmission and limits the risks of emerging resistances.

Inhibitors of nucleic acids: or antimetabolites that block the division of the nucleus of the haematozoan.

This group includes antifolates, naphthoquinones and antibiotics. the antifolates: they are divided into two families, antifolics (sulfonamides, including sulfadoxine, sulfones), and antifolinics (proguanil, pyrimethamine). They act at the level of the folate synthesis pathway, which is essential for the biosynthesis of nucleic acids. Antifolics inhibit dihydropteroate synthetase (DHPS) which produces folic acid, antifolinics inhibit dihydrofolate reductase (DHFR) which produces folinic acid.

naphthoquinones: atovaquone is a potent inhibitor of mitochondrial functions by blocking the electron transfer chain at its key enzyme, dihydroorotate dehydrogenase (DHOdase). It has little therapeutic impact when used alone. In combination with an antimetabolite (proguanil), there is an interesting synergy of action through a sequential inhibition of pyrimidine synthesis. An originality of the atovaquone-proguanil combination is its action on the hepatocyte stages of P. falciparum.

Antibiotics: Tetracyclines (doxycycline), macrolides (erythromycin, azythromycin, clindamycin) can inhibit protein synthesis by inhibiting certain functions of the apicoplast.

The new antimalarials: The new antimalarials that have been the subject of recent developments are all associated, in dual therapy at least, and stand out from the most old associations: sulfadoxine-pyrimethamine able to quickly select resistant mutants. Some are fixed: atovaquone-proguanil, arthemeter-lumefantrine, chlorproguanil-dapsone, others free always associating a derivative of artemisinin given the speed of action, the impact on the transmission and the absence of chemoresistance of P. falciparum: artesunate-mefloquine, artesunate-amodiaquine, artesunate. In prophylaxis, chloroquine-proguanil and atovaquone-proguanil combinations are recommended in chloroquine-resistance zones.

The present invention, based on the implementation of an active substance hitherto without indications known in the field concerned, opens a new therapeutic pathway for the global treatment of neurodegenerative diseases by protecting the integrity of the blood-brain barrier. .

WO 2005/023305, WO 95/34811, WO 2004/004774, US 5,373,021, EP 1,532,976, US 6,093,743 and publications "Progress in neuro-psychopharmacology & biological psychiatry" and "Journal of "the fact that pantethine may have an effect on a disease or model of neurodegenerative disease, none of these references mentions or even suggests an effect of pantethine on the protection of the blood-brain barrier.

The approach of the present invention differs significantly from the prior art insofar as the approach is not not discriminating for couples (active substance - therapeutic indication).

The subject of the present invention is a pharmaceutical product comprising, as active ingredient, a substance having a disulfide bridge, more particularly pantethine, which makes it possible to protect the patient's blood-brain barrier and thereby generally treat all or at least several diseases. neurodegenerative.

The subject of the present invention is also a pharmaceutical product according to claim 9 wherein the substance having a disulfide bridge has the general formula: [Z ² HR ⁴ -CR ³ (Z ¹ H) -Y ² -X ² - R ² -Y ¹ -X ¹ -R ¹ -S-] ₂ in which

R ¹ ; R ² , R ³ ; R ⁴ represents a carbon chain, with or without heteroatoms, linear or branched having from 1 to 12 carbon atoms and preferably from 2 to 4 carbon atoms without heteroatoms.

X ¹ ; X ² : represent a secondary amino function -NH- or tertiary amine -NR ⁵ -, in which R ⁵ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom, or still an acyl-C (O) - group.

Y ¹ ; Y ² : represents an acyl group -C (O) - or a secondary amine function -NH- or a tertiary amine function -NR ⁶ -, in which R ⁶ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms carbons and possessing at least 1 acidic hydrogen atom. Z ¹ ; Z ² : represents an oxygen atom or a secondary amine function -NR ⁷ - in which R ⁷ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms.

The present invention further relates to a pharmaceutical according to claim 9 or claim 10 wherein the disulfide bonded material is the compound (R) -N ₁ N ¹ - [dithiobis (ethylene iminocarbonylethylene)] bis (2,4-dihydroxy-3,3-dimethylbutyr-amide) or pantethine according to its trivial name. Finally, the subject of the present invention is also a use of a pharmaceutical product according to one of claims 9 to 11 for the treatment of neurodegenerative diseases, in particular Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, child dystonia, Creutzfeld-Jakob disease, cerebral malaria, West NiIe Virus disease and dengue fever.

The invention further relates to a use according to claims 15 to 20.

The present invention is applicable to the therapeutic effect and the use of a range of active substances derived from pantethine (or (R) -N, N '- [dithiobis- (ethylene-iminocarbonylethylene)] bis (2 , 4-dihydroxy-3,3-dimethylbutyr-amide)) on neurodegenerative diseases independently of the pathogen due to a regulatory action at the cell membrane allowing intrinsic protection of the blood-brain barrier. In autumn 2000, the team led by Max de Reggi surveyed a series of genetically modified mice, created by the team led by Philippe Naquet. In these mice the Vanin-1 gene had been inactivated. The latter is part of a family of genes that Philippe Naquet and his collaborators had identified a short time ago. The family consists of three human members, VNN-1, VNN-2, and VNN-3. In mice, only two genes, Vanin-1 and Vanin-3, are present.

These genes code for the same enzyme pantethinase, which hydrolyzes pantethine to vitamin B5 and cystamine. These different genes are unequally expressed from one organ to another, and even today their respective properties are not fully understood. Moreover, in 2000 their physiological impact was totally unknown. To clarify this point, the Vanin-1 ^"/" mice were constructed. The inactivation of the second gene, Vanin-3, proved impossible because it was lethal at the embryonic stage.

The inactivation of the Vanin-1 gene has the effect of reducing the physiological concentration of cystamine which, by its thiol function, is likely to intervene in cellular antioxidant defense mechanisms. In the minds of the project's promoters, the inactivation of the Vanin-1 gene and thus the lowering of the cystamine level should have led to an increased sensitivity to oxidative stress. Because of his experience in the field of oxidative stress, Max de Reggi's team was interested in verifying this hypothesis. For this purpose, it has been chosen to implement two models of intestinal inflammation. This choice was justified by the strong expression of the Vanin-1 gene in the intestine. The first model uses a natural agent that induces chronic inflammation (the parasitic worm Schistosoma mansoni) and the other a chemical agent, causing acute inflammation (indomethacin). But to the researchers' surprise, the results of this study were the opposite of the original hypothesis. Indeed, Vanin-1 ^{v ~} mice were found to be remarkably protected from oxidative stress, in both models implemented.

These findings led Max's team at Reggi to hypothesize that the role of cystamine was independent of its antioxidant properties.

In fact, consecutively, it has been shown that cystamine-deficient mice produce more glutathione, which is at the center of antioxidant defenses and detoxification processes by the body. This is because cystamine is an inhibitor of γ-glutamylcysteine synthase, the key enzyme in glutathione synthesis. This mechanism was verified by the reverse experiment: the administration of cystamine to Vanin-1 ^{~ A} mice reduces glutathione production and restores normal sensitivity to oxidative stress (Martin F et al J Clin Invest 113: 591-597 , 2004).

Going up the process of bio-synthesis of cystamine by the action of Vanin genes, partially inactivated in Vanin-

1 ^" '^" , and by coupling the observations with independently published results, Max de Reggi's team was interested on the molecules of the family of symmetrical or non-symmetrical dimers having a disulfide bridge of:

General Formula (A): [Z ² HR ⁴ -CR ³ (Z ¹ H) -Y ² -X ² -R ² -Y ¹ -X ¹ -R ¹ -S-] ₂

in which :

R ¹ ; R ² ; R ³ ; R ⁴ : represent a carbon chain, with or without heteroatoms, linear or branched having from 1 to 12 carbon atoms and preferably from 2 to 4 carbon atoms without hetero atoms

X ¹ ; X ² : represent a secondary amino function -NH- or tertiary amine -NR ⁵ -, in which R ⁵ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom, or still an acyl group -C (O) -.

Y ¹ ; Y ² : represents an acyl group -C (O) - or a secondary amine function -NH- or a tertiary amine function -NR ⁶ -, in which R ⁶ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms carbons and possessing at least 1 acidic hydrogen atom.

Z ¹ ; Z ² : represents an oxygen atom or a secondary amine function -NR ⁷ - in which R ⁷ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms. Among the molecules described by the general formula given above, the compound of formula (R) -N, N '- [α] ithiobis- (ethylene-iminocarbonylethylene)] bis (2,4-dihydroxy-3,3-dimethylbutyramide) or pantethine according to its trivial name has shown a particular effectiveness.

These original findings aroused the interest of Max de Reggi's team, who investigated whether the compounds mentioned above could not play a role in other pathologies with an inflammatory component. The research axes of the team to be deployed in the direction of cerebral malaria, it is this field which was first the object of the experimental exploration. Cerebral malaria is caused in humans by the parasite Plasmodium falciparum. In the mouse, it is the parasite P. berghei strain ANKA which, in some strains of mice, causes a brain syndrome quite comparable to that observed in humans: convulsions and ataxia, followed by death. This is experimental cerebral malaria (ECM).

This second series of experiments consisted in injecting the parasite into CBA / J mice, a very sensitive strain. Pantethine was then administered to a portion of these animals; the latter constitute the so-called "treaty" group. Other infested animals that do not receive pantethine are referred to as "controls".

At first, the product was administered orally (it was introduced into the animal drinking water). Of a total of 17 treated animals and as many controls, the treatment delayed the onset of the brain syndrome, and 3 mice survived, while no controls reached 8 days.

The next step was to administer the product by intraperitoneal injections. The experiment presented below shows that under these conditions, only one treated mouse (in a group of 20) present (late) the brain syndrome, contrary to witnesses who all succumb.

It should be noted that the cerebral syndrome is manifested only in the short period indicated above; beyond that, deaths are the consequence of the rapid proliferation of the parasite, which is not impeded by this treatment. It follows in particular a severe anemia, without cerebral involvement.

The results presented here have been supported by numerous complementary tests aimed at clarifying the mechanism of protection provided by pantethine injections.

These pioneering results led to the conclusion that the increase in the physiological levels of pantethine could bring about a clear improvement vis-à-vis a cerebral pathology of infectious origin, such as cerebral malaria.

In addition, an element that would have been unpredictable has increased interest in the potential of pantethine. The analysis of mouse brains included in the tests demonstrates the surprising characteristic of pantethine administered to induce protection of the blood-brain barrier.

Treated with Evans Blue, the brain of the model having received no pantethine is colored intensely.

Brain of a mouse This reflects an alteration of the not having received blood-brain barrier. pantethine in an ECM study

In contrast, the brain of the model who received pantethine remains protected of the action of Evans Blue.

Brain of a mouse This testifies to a preservation of having received the quality of the haematopaithetin barrier during encephalics. ECM study

The work was then continued by demonstrating the protective effects of pantethine on the blood-brain barrier in the context of cerebral pathologies of non-infectious etiology, Parkinson's disease and multiple sclerosis.

The murine model of Parkinson's disease uses a neurotoxic specific to dopaminergic neurons, MPTP. The evaluation is performed by assaying dopamine levels in the striatum and by tests of motor skills. The diagrams presented below show the preservation of striatal dopamine (Scheme 1) and the maintenance of normal motricity (Scheme 2) by administering pantethine. The motricity is evaluated by the time of return of the mouse placed, head up, at the top of a rod (test pole).

Witness: group that did not receive neurotoxic

MPTP: group that received the neurotoxic

MPTP / THP22: Neurotoxic group, combined with pantethine administration.

MPTP / THP22 MPTP indicator

Diagram 1

Figure 2 It was then shown that pantethine administration provides flagrant protection in the murine model of multiple sclerosis (EAE). In this case, the pathology is induced experimentally by immunizing mice with a derivative of the myelin sheath of neurons.

Two models have been implemented, the "relapsing-remitting" model and the chronic model, which correspond respectively to the early and more advanced form of the disease. The red zone indicates the period of administration of pantethine.

In the first case, the pathological symptoms gradually disappear, even after the interruption of treatment (diagram 3). In the second case, the pathology is attenuated during the duration of the treatment, then returns to a normal level of gravity after the stop of this one (diagram 4). This demonstrates that the improvement observed initially is directly related to the treatment.

cfays posHmmurHzation

Figure 3

1 5 9 13 17 21 2β 33 3? 41 45 49 days poβHmmunizatioii

Figure 4

The protection observed in these different pathologies is due to the multiple mechanisms of action of pantethine. These are not yet fully understood.

The protection of the blood-brain barrier by the administration of pantethine, or of one of its derivatives corresponding to the general formula (A), the assembly forming the generic term "pantethine-derivative", would proceed from the same logic than that which was formulated on the mode of action of the molecule on the phospholipid layer of cells. Indeed, in case of encephalitis, the degradation of the blood-brain barrier by the action of infectious agents, or by other mechanisms, such as an autoimmune reaction, we observe the formation of vesicles on the surface of endothelial cells . These vesicles can then fragment and disperse into microparticles.

This phenomenon of vesiculation results from the modification of the distribution of membrane phospholipids between the two layers of the cytoplasmic membrane.

Robert Zwaal (Maastπcht)

The administration of "pantethine-derivative" makes it possible to regulate this phenomenon by acting directly on the phospholipids.

The lipid bilayer of the cell membrane has an asymmetric structure, with phosphatidylserine (PS) and phosphatidylethanolamine (PE) exclusively limited to the inner leaflet. However, under certain physiopathological conditions, PS migrates to the outer leaflet. This occurs when programmed cell death (apoptosis) or under the influence of inflammatory factors, infectious origin or not. This movement is controlled by the combined effect of several enzymes, translocase, flippase and scramblase. The translocation of PS profoundly alters the physiology of the cell, resulting in particular:

-> Activation of the cells involved in the inflammatory response

(monocytes, granulocytes, platelets, endothelial cells, etc.); -> the expression of adhesion molecules, allowing these cells to associate to trigger inflammation;

-> assembly and activation of coagulation factors, thrombosis generators;

-> budding cells, with release of microparticles that amplify the inflammatory response.

This property resulting from the administration of "pantethine-derivative" would extend the field of indication to other neurological diseases operating by analogous mechanisms.

The subject of the present invention is therefore a pharmaceutical product and its use, as well as a treatment method for the prevention and treatment of neurodegenerative diseases in humans, based on the action of the substances derived from pantethine for the reinforcement and the protection of the integrity of the blood-brain barrier. The originality of the invention lies in the fact that we do not seek to treat each neurodegenerative disease individually, but that we can treat several or all neurodegenerative diseases by acting on a strengthening of the blood-brain barrier. This method stands out significantly from conventional therapeutic approaches that combine a particular treatment for each pathogenic origin.

Claims

1. Therapeutic method based on the use of a substance having a disulfide bridge for treating in general human neurodegenerative diseases, inducing protection of the blood-brain barrier.

2. Therapeutic method according to claim 1, in which the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, child's dystonia, Creutzfeld-Jakob, cerebral malaria, the original disease "West NiIe Virus" and dengue fever.

3. Therapeutic method according to one of claims 1 to 2 wherein the neurodegenerative diseases preferentially include Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral malaria.

4. Therapeutic method according to one of claims 1 to 3 wherein the cerebral malaria is the main pathological target.

5. Therapeutic method according to claim 1 wherein the substance having a disulfide bridge has the general formula [Z ² HR ⁴ -CR ³ (Z ¹ H) -Y ² -X ² -R ² -Y ¹ -X ¹ -R ¹ -S-] ₂ in which: R ¹ ; R ² ; R ³ ; R ⁴ : represent a carbon chain, with or without heteroatoms, linear or branched having from 1 to 12 carbon atoms and preferably from 2 to 4 carbon atoms without heteroatoms X ¹ ; X ² : represent a secondary amino function -NH- or tertiary amine -NR ⁵ -, in which R ⁵ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom, or still an acyl group -C (O) -. Y ¹ ; Y ² : represents an acyl group -C (O) - or a secondary amine function -NH- or a tertiary amine function -NR ⁶ -, in which R ⁶ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms carbons and possessing at least 1 acidic hydrogen atom.

Z ¹ ; Z ² : represents an oxygen atom or a secondary amine function -NR ⁷ - in which R ⁷ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms.

6. Therapeutic method according to claims 1 and 5 wherein the substance having a disulfide bridge is the compound (R) - N, N '- [dithiobis- (ethylene-iminocarbonylethylene)] bis (2,4-dihydroxy-3) , 3-dimethylbutyr-amide), or pantethine according to its trivial name.

7. Therapeutic method according to one of claims 1 and 5 to 6 wherein the substance having a disulfide bridge is administered to the patient mixed with pharmaceutical excipients to adjust the dosage.

8. Therapeutic method according to one of claims 1 to 7 wherein the active substance is panthein and the therapeutic indication is cerebral malaria.

9. Pharmaceutical product comprising as active ingredient a substance having a disulfide bridge, enhancing the protection of the blood-brain barrier.

The pharmaceutical product according to claim 9, wherein the disulfide bonded material has the general formula [Z ² HR ⁴ -CR ³ (Z ¹ H) -Y ² -X ² -R ² -Y ¹ -X ¹ -R ¹ -S-] ₂ in which

R ¹ ; R ² , R ³ ; R ⁴ represents a carbon chain, with or without heteroatoms, linear or branched having from 1 to 12 carbon atoms and preferably from 2 to 4 carbon atoms without heteroatoms. X ¹ ; X ² : represent a secondary amino function -NH- or tertiary amine -NR ⁵ -, in which R ⁵ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom, or still an acyl-C (O) - group. Y ¹ ; Y ² : represents an acyl group -C (O) - or a secondary amine function -NH- or a tertiary amine function -NR ⁶ -, in which R ⁶ represents a linear carbon chain or branched having from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom.

The pharmaceutical product according to claim 9 or claim 10 wherein the disulfide bonded material is the compound (R) -N, N '- [dithiobis- (ethylene-iminocarbonylethylene)] bis (2,4-dihydroxy) -3,3-dimethylbutyramide) or pantethine according to its trivial name.

12. Use of a pharmaceutical according to one of claims 9 to 11 for the overall treatment of neurodegenerative diseases by strengthening the blood brain barrier of patients.

13. Use according to claim 12 for the treatment of Alzheimer's disease, Parkinson's disease, chorea of

Huntington, amyotrophic lateral sclerosis, multiple sclerosis, child dystonia, Creutzfeld-Jakob disease, cerebral malaria, West NiIe Virus disease and dengue fever

14. Use according to claim 12 for the treatment of Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral malaria.

15. Use of a disulfide-bonded substance for the manufacture of a medicament for the global treatment of neurodegenerative diseases in humans by strengthening the blood-brain barrier.

The use of claim 15 wherein the neurodegenerative diseases to be considered include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, child's dystonia, disease. Creutzfeld-Jakob, cerebral malaria, West NiIe Virus disease and dengue fever.

17. Use according to one of claims 15 or 16 wherein the substance having a disulfide bridge meets the general formula

[Z ² HR ⁴ -CR ³ (Z ¹ H) -Y ² -X ² -R ² -Y ¹ -X ¹ -R ¹ -S-] ₂ in which:

X ¹ ; X ² : represent a secondary amino function -NH- or tertiary amine -NR ⁵ -, in which R ⁵ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms and having at least 1 acidic hydrogen atom, or still an acyl group -C (O) -. Y ¹ ; Y ² : represents an acyl group -C (O) - or a secondary amine function -NH- or a tertiary amine function -NR ⁶ -, in which R ⁶ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms carbons and possessing at least 1 acidic hydrogen atom.

Z ¹ ; Z ² : represents an oxygen atom or a secondary amine function -NR ⁷ - in which R ⁷ represents a linear or branched carbon chain containing from 1 to 9 carbon atoms

18. Use according to one of claims 15 to 17 wherein the substance having a disulfide bridge is the compound (R) -N ₁ N'- [dithiobis- (ethylene-iminocarbonylethylene)] bis (2,4-dihydroxy - 3,3-dimethylbutyr-amide), or pantethine according to its trivial name.

19. Use according to claim 18 wherein the therapeutic indication is cerebral malaria.

20. Use of a formulation comprising a substance having a disulfide bridge according to one of claims 15 to 18 disulfide and at least one pharmaceutical excipient.