EP1523312A1 - Use of a rhein in a therapeutic treatment requiring a rise in the rate of heme oxygenase - Google Patents
Use of a rhein in a therapeutic treatment requiring a rise in the rate of heme oxygenaseInfo
- Publication number
- EP1523312A1 EP1523312A1 EP03750824A EP03750824A EP1523312A1 EP 1523312 A1 EP1523312 A1 EP 1523312A1 EP 03750824 A EP03750824 A EP 03750824A EP 03750824 A EP03750824 A EP 03750824A EP 1523312 A1 EP1523312 A1 EP 1523312A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- rhein
- use according
- diacerein
- derivative
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the treatment in human or animal therapy of conditions requiring an increase in the level of the enzyme heme oxygenase, by administration of an effective dose of rhein or diacerein or one of their salts or esters, as well as the use of rhein or diacerein or a salt or ester thereof for the manufacture of a medicament for the treatment of conditions requiring an elevation of the level of the enzyme heme oxygenase, by acting on the causes of certain conditions acute and chronic, ensuring the prevention and inhibition of the effects of stress on cells and tissues, and ensuring the prevention and treatment of rejection of organ and tissue transplants.
- the reaction of the immune system is a pathophysiological mechanism of response to several types and forms of aggression that target the body ("stress"). This reaction can be responsible for several important pathological forms, referenced for example in Harrison's Principles of Internai Medicine, 14th edition (1998), 749-754.
- Stress a pathophysiological mechanism of response to several types and forms of aggression that target the body
- This reaction can be responsible for several important pathological forms, referenced for example in Harrison's Principles of Internai Medicine, 14th edition (1998), 749-754.
- a large number of studies have been devoted to the mediators responsible for triggering the reaction of the elements of the immune system, and to the pharmacological and therapeutic control of this reaction in its initial phases. These studies have made it possible to produce and market effective drugs, for example in the treatment of acute inflammation.
- the protective mechanisms and the body's response to stress can control the causes that underlie the reaction, and stop the process. Indeed, researchers have often found that the reaction of elements of the immune system, after a first acute phase, could then decrease in a second phase. However, few studies have addressed the question of the spontaneous benign evolution of this reaction, and of its pharmacological and therapeutic control. Because of the persistence of the causes, and / or the ineffectiveness of the treatment, the reaction of the elements of the immune system to stress can become chronic. The transition to chronicity is frequent, can present itself under several important pathological aspects, referenced in particular in Tar owski A. et al. Mol. Med.
- HO-1 represents the level of the heme oxygenase -1
- iNOS the inducible nitric oxide synthetase
- PGE 2 prostaglandin E 2
- HSP heat-shock proteins
- HSP32 heat-shock protein 32K
- HSPs form a family of proteins whose expression is stimulated by stress (heat, hypoxia, oxidation, poisoning by metals, etc.), as verified in experiments carried out by the applicant in vitro on cultures of mouse macrophages , human chondrocytes, and cartilage isolated from the rat femoral head.
- HSPs play a very important role in defense mechanisms and cellular repair in the face of stress.
- HO-1 exerts a very important modulating effect during the inflammatory response: a rise in the level of the enzyme is accompanied by a suppression of the inflammation, while an inhibition results in an increase in the inflammatory response (Nature Medicine (1996) 2: 87-90).
- the discovery of HO-1 and the appreciation of its effects suggested the possibility of pharmacological and therapeutic control of the cellular response to stress; indeed, it would be advantageous to be able to have drugs capable of promoting and / or maintaining the elevation of the level of the HO-1 enzyme, to be used during the treatment of several conditions which induce cellular and tissue stress, such as than observed especially in immunosuppressed patients.
- diacerein In human medicine, diacerein has been administered to patients with osteoarthritis, who have pain and difficulty moving. In addition, treatment with diacerein slows the progression of osteoarthritis disease, with good job security. However, diacerhein as well as rhein have moderate symptomatic anti-inflammatory and analgesic activity in the acute phase of osteoarthritis (Nguyen et al., Arthritis and Rheumatism (1994) 37: 529-536).
- rhein, or diacerein, or their salts or esters also has the effect of protecting the organism against the degradation of organs and tissues, and in particular cartilage, on the part of the cells of the system. immune, and to control the phenomena that occur in response to organ and tissue transplants, which makes it possible to envisage their use in the prevention and treatment of rejection of organ and tissue transplants.
- the present invention therefore relates to the use of diacerein, and more generally rhein and rhein derivatives, in human and veterinary therapy in the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and the inhibition of the effects of stress on cells and tissues, and for the prevention and treatment of organ and tissue transplant rejection.
- Another subject of the invention is the use of rhein and rhein derivatives, in particular diacerein, for the manufacture of a medicament for the treatment of a condition requiring a high level of heme oxygenase.
- R represents a hydrogen atom, or an alkyl group, for example a methyl, ethyl or propyl group, or an alkali or alkaline earth metal atom, for example a sodium, potassium or calcium atom
- Ri and R 2 identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- in which R 'is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl or isopropyl group.
- R preferably represents a hydrogen atom
- R 1 and R 2 preferably represent a hydroxy or acetoxy group.
- the general formula (I) above in which R is a hydrogen atom and Ri and R 2 are an acetoxy group -COOCH 3 is that of diacerein.
- Diacerein and rhein can be prepared by methods known in the art, and for example from extracts of aloe or senna leaf, such as sennosides, or by acetylation of barbaloin followed by oxidation by chromium oxide.
- the diacerein obtained by these processes can be purified if necessary to achieve a product that perfectly meets pharmaceutical standards and offers all the desired guarantees.
- the studies carried out by the applicant to demonstrate the effect of diacerein, rhein and their salts or esters on HO-1 were carried out using validated models, as indicated below.
- the work and experiments in vi tro used the following models: 1.- A validated tissue culture model, and in particular the cartilage of the femoral head of a rat, treated with erythrocytes (in% w / v), erythrocyte lysate (3xl0 6 ), or hemoglobin (in% w / v) , without and after heat stress (lh at 43 ° C). Cartilage integrity was measured by the incorporation of radioactive sulfate ( 35 SO 4 ; in counts per minute, CPM). In this model, erythrocytes, erythrocyte lysate and hemoglobin cause cell destruction, demonstrated by decreased cell viability and the incorporation of radioactive sulfate by cells, as shown in Figures 3 and 4.
- The- A validated cell culture model, and in particular human chondrocytes, treated with erythrocytes (in% w / v), erythrocyte lysate (3xlO ⁇ ), or hemoglobin (in% w / v), without and after thermal stress (lh at 43 ° C).
- Cell integrity was measured by cell viability (living cells versus control), presence of apoptosis (nuclear fragmentation; number and percentage versus control), and incorporation of radioactive sulfate ( 3 S0 4 ; in strokes per minute, CPM).
- Figures 7b and 7c are also "Western blots" of cells (model: mouse macrophages) cultivated without and with diacerein (Figure 7b: columns' ⁇ and columns “D €", respectively) or rhein (Figure 7c) to a concentration of 10 "5 M, and then analyzed at 15, 30 and 60 minutes ( Figure 7b) and 0, 15, 30, 60, 120 minutes as well as 18 hours ( Figure 7c).
- the identity of the protein interest, HO-1 was confirmed with respect to its molecular weight (32 kilodalton; kDa) determined on a reference scale (first column left in Figures).
- FIG. 9 shows that treatment with rhein prevents apoptosis caused by the erythrocyte lysate.
- Diacerheine, rhein, and their salts or esters increase in a dose-dependent manner the levels of the enzyme HO-1 which plays a role in the protection of cellular integrity;
- diacerein, rhein, and their salts or esters preserve the integrity of cells and tissues in the face of deleterious reactions induced by stress; - Diacerheine, rhein, and their salts or esters prevent apoptosis (fragmentation of the nucleus, followed by the destruction and death of cells).
- the Applicant has also carried out work and experiments in vivo, with the use of the model described below.
- the method includes the following steps:
- the isolated tissues istar rat, male
- the subcutaneous implants are stored over a period of 2 weeks;
- Figure 10 shows that the treatment with diacerhein decreases the tissue reaction (formation of the reactive granuloma) depending on the dose (diacerhein: 5, 15 and 50 mg / kg, orally; ** statistically significant difference compared to the control : p ⁇ 0.01).
- Figure 11 shows that the tissue reaction caused by the implantation of rat tissue in mice is reduced by the dose-dependent treatment with diacerein. (left in Figure 11: number of inflammatory cells; right: volume of exudate) (Cont .: control; diacerein: 5, 15 and 50 mg / kg, orally; * statistically significant difference compared to control: p ⁇ 0.05).
- Figure 12 shows that treatment with diacerein preserves the integrity of the transplanted tissue as a function of the dose of diacerein, which is demonstrated by the conservation of the content of collagen (on the left in Figure 12) and of glycosamino. -glycan (GAG; right) in the transplanted tissue (diacerhein: 5, 15 and 50 mg / kg, orally; statistically significant differences versus control: * p ⁇ 0.05: ** p ⁇ 0.01).
- tissue reaction size of the granuloma, number of inflammatory cells, volume of exudate caused by the implantation of rat tissue in the mouse;
- - diacerein, rhein, and their salts or esters preserve the integrity of the transplanted tissues in the face of the tissue reaction; - diacerein, rhein, and their salts or esters prevent the destruction and rejection of the transplanted tissue.
- NSAIDs non-steroidal anti-inflammatory drugs
- COX-1 constitutive isoform
- COX-2 isoform induced in the establishment of inflammation
- COX-2 inhibitors such as celecoxib and rofecoxib, have been developed for the symptomatic treatment of inflammatory diseases.
- Figure 13 shows the comparison of the effects of treatment with a COX-2 inhibitor (rofecoxib) on the one hand, and diacerein on the other hand, on the decrease in tissue reaction (formation of a reactive granuloma) caused by the implantation of rat tissue in mice (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / kg, orally; statistically significant differences from the control: * p ⁇ 0.05 ; ** p ⁇ 0.01).
- Figure 14 compares the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on the decrease in tissue reaction caused by implantation of rat tissue in mice.
- the graph on the left illustrates cell infiltration, and the graph on the right shows the volume of exudate (Cont .: control; DAR: diacerein: 2, 10 and 50 mg / kg, and rofecoxib: 3 mg / Kg, orally; statistically significant difference compared to control: * p ⁇ 0.05).
- Figure 15 compares the differences in the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on preserving the integrity of the transplanted tissue.
- the graph on the left corresponds to the collagen content, that on the right to the glycosaminoglycan (GAG) content in the tissue (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / Kg, by oral route; statistically significant differences versus control: * p ⁇ 0.05: ** p ⁇ 0.01).
- GAG glycosaminoglycan
- diacerhein and rhein have significantly different properties from those of other drugs, such as conventional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors, in particular on the preservation of transplanted tissue and rejection of that tissue.
- NSAIDs non-steroidal anti-inflammatory drugs
- COX-2 inhibitors in particular on the preservation of transplanted tissue and rejection of that tissue.
- diacerhein, or rhein, or their salts and esters with a conventional NSAID or with a COX-2 inhibitor, the actions of which may be complementary, depending on the pathology. treated.
- Diacerein can therefore be combined with an NSAID such as diclofenac at a dose between 25 and 150 mg per day, or with a COX-2 inhibitor like rofecoxib at a dose between 10 and 50 mg per day.
- diacerhein, rhein, as well as their salts and esters can be advantageously used in human and veterinary therapy for the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and inhibition of effects of stress on cells and tissues, and for prevention and treatment of rejection of tissue and organ transplants.
- their use at the doses indicated is very particularly useful for the treatment of the conditions indicated below.
- - inflammations associated with Type I and II diabetes such as peripheral neuropathy and chronic skin ulcer
- connectivities such as lupus erythematosus, scleroderma, sarcoidosis
- Diacerein and rhein have a low solubility in water and in alcohols, and are therefore preferably administered orally.
- the usual oral administration forms in the pharmaceutical field are suitable, and for example, the medicament can be administered in the form of tablets, gelatin capsules or soft gelatin capsules, or any other suitable galenical form.
- a particularly suitable form of administration is that described in patent EP 862423 describing capsules or gelatin capsules in which the diacerein is mixed with a liquid oil and a nonionic surfactant, making it possible to obtain good bioavailability.
- Another form which can be used in the invention, described in US Pat. No. 6,124,358, is prepared by comicronisation of rhein or diacerein with a lauryl sulfate, for example sodium lauryl sulfate.
- the dosage is determined by the practitioner depending on the condition of the patient, but it is generally between 25 mg and 500 mg per day, preferably between 50 mg and 100 mg per day. It is relatively independent of the patient's weight in adults.
- Unit doses, for oral administration are generally between 25 mg and 50 mg.
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Abstract
The invention concerns a novel therapeutic application of rhein and diacerhein. Rhein and diacerhein, as well as the salts and esters thereof, can be used for treating diseases requiring a rise in the rate of the heme oxygenase enzyme, providing prevention and inhibition of stress on cells and tissues, and treatment and prevention of organ and tissue transplant rejections.
Description
ELEVATION DU TAUX D'HEME OXYGYNASE AVEC DES DERIVES DE LA RHEINE ELE V ATIO N U U XD TA 'OXYGYNASE THEME WITH DERIVATIVES RHEINE
La présente invention concerne le traitement en thérapeutique humaine ou animale des affections nécessitant une élévation du taux de l'enzyme hème oxygenase, par administration d'une dose efficace de rhéine ou de diacerhéine ou d'un de leurs sels ou esters, ainsi que l'utilisation de la rhéine ou de la diacerhéine ou d'un de leurs sels ou esters pour la fabrication d'un médicament pour le traitement des affections nécessitant une élévation du taux de l'enzyme hème oxygenase, en agissant sur les causes de certaines conditions aiguës et chroniques, en assurant la prévention et l'inhibition des effets du stress sur les cellules et les tissus, et en assurant la prévention et le traitement du rejet des transplantations d'organes et de tissus.The present invention relates to the treatment in human or animal therapy of conditions requiring an increase in the level of the enzyme heme oxygenase, by administration of an effective dose of rhein or diacerein or one of their salts or esters, as well as the use of rhein or diacerein or a salt or ester thereof for the manufacture of a medicament for the treatment of conditions requiring an elevation of the level of the enzyme heme oxygenase, by acting on the causes of certain conditions acute and chronic, ensuring the prevention and inhibition of the effects of stress on cells and tissues, and ensuring the prevention and treatment of rejection of organ and tissue transplants.
La réaction du système immunitaire est un mécanisme physiopathologique de réponse à plusieurs types et formes d'agression qui ont pour objet l'organisme ("stress"). Cette réaction peut être responsable de plusieurs formes pathologiques importantes, référencées par exemple dans Harrison's Principles of Internai Medicine, 14ème édition (1998), 749-754. Un grand nombre d'études ont été consacrées aux médiateurs responsables du déclenchement de la réaction des éléments du système immunitaire, et au contrôle pharmaco- logique et thérapeutique de cette réaction dans ses phases initiales. Ces études ont permis de produire et mettre sur le marché des médicaments efficaces, par exemple dans le traitement de l'inflammation aiguë.The reaction of the immune system is a pathophysiological mechanism of response to several types and forms of aggression that target the body ("stress"). This reaction can be responsible for several important pathological forms, referenced for example in Harrison's Principles of Internai Medicine, 14th edition (1998), 749-754. A large number of studies have been devoted to the mediators responsible for triggering the reaction of the elements of the immune system, and to the pharmacological and therapeutic control of this reaction in its initial phases. These studies have made it possible to produce and market effective drugs, for example in the treatment of acute inflammation.
Dans des conditions normales, les mécanismes de protection et de réponse de l'organisme au stress (chimique, thermique, mécanique, infectieux, etc.) peuvent maîtriser les causes qui sont à la base de la réaction, et arrêter le processus. En effet, les chercheurs ont souvent constaté que la réaction des éléments du système immunitaire, après une
première phase aiguë, pouvait s'atténuer ensuite dans une deuxième phase. Cependant, peu d'études ont abordé la question de l'évolution bénigne spontanée de cette réaction, et de son contrôle pharmacologique et thérapeutique. En raison de la persistance des causes, et/ou de l'inefficacité du traitement, la réaction des éléments du système immunitaire au stress peut devenir chronique. Le passage à la chronicité est fréquent, peut se présenter sous plusieurs aspects pathologiques importants, référencés notamment dans Tar owski A. et al. Mol. Med. Today (1988) 4:15-18 ; et Levy B.D. et al., Nature Immunol. (2001) 2:612-619. La problématique liée à ce passage à la chronicité a suscité de nombreux travaux de recherche. Cependant, il n'existe aujourd'hui que peu de traitements satisfaisants. De plus, même à faibles doses ces traitements sont souvent mal tolérés par les patients et peuvent provoquer des effets indésirables graves.Under normal conditions, the protective mechanisms and the body's response to stress (chemical, thermal, mechanical, infectious, etc.) can control the causes that underlie the reaction, and stop the process. Indeed, researchers have often found that the reaction of elements of the immune system, after a first acute phase, could then decrease in a second phase. However, few studies have addressed the question of the spontaneous benign evolution of this reaction, and of its pharmacological and therapeutic control. Because of the persistence of the causes, and / or the ineffectiveness of the treatment, the reaction of the elements of the immune system to stress can become chronic. The transition to chronicity is frequent, can present itself under several important pathological aspects, referenced in particular in Tar owski A. et al. Mol. Med. Today (1988) 4: 15-18; and Levy BD et al., Nature Immunol. (2001) 2: 612-619. The problem linked to this transition to chronicity has given rise to numerous research studies. However, there are few satisfactory treatments available today. In addition, even at low doses these treatments are often poorly tolerated by patients and can cause serious adverse effects.
Des travaux ont montré l'influence de certains facteurs endogènes dans 1 ' évolution bénigne spontanée de la réaction des éléments du système immunitaire. Ainsi, D. Willis et al. (Nature Medicine (1996) 2: pp. 87-90) ont montré qu'une enzyme, la hème oxygénase-1 (HO-1) , est exprimée progressivement dans les phases plus avancées de la réaction inflammatoire aiguë, et précède la phase de résolution de cette réaction. Ainsi, un modèle cohérent des événements principaux survenant au cours de cette réaction est illustré sur la Figure 1 (modèle de pleurite induite après injection de carragénine chez le rat), dans laquelle "HO-1", représente le taux de 1 ' hème oxygénase-1, "iNOS", la nitric-oxyde synthétase inductible, et "PGE2", la prostaglandine E2. On observe que le taux de l'hème oxygenase croît progressivement avec le temps, et précède la diminution de la réaction des éléments du système immunitaire.Studies have shown the influence of certain endogenous factors in the spontaneous benign evolution of the reaction of elements of the immune system. Thus, D. Willis et al. (Nature Medicine (1996) 2: pp. 87-90) have shown that an enzyme, heme oxygenase-1 (HO-1), is expressed gradually in the more advanced phases of the acute inflammatory reaction, and precedes the phase resolution of this reaction. Thus, a coherent model of the main events occurring during this reaction is illustrated in FIG. 1 (model of induced pleuritis after injection of carrageenan in rats), in which "HO-1" represents the level of the heme oxygenase -1, "iNOS", the inducible nitric oxide synthetase, and "PGE 2 ", prostaglandin E 2 . It is observed that the level of heme oxygenase gradually increases over time, and precedes the decrease in the reaction of the elements of the immune system.
L'enzyme hème oxygenase appartient aux "heat-shock proteins" (HSP) : elle est connue également sous le nom de "heat-shock protein 32K" (HSP32) (voir Keyse S.M. et al., Proc.
Natl. Acad. Sci . USA (1991) 86:99-103). Les HSP forment une famille de protéines dont l'expression est stimulée par le stress (chaleur, hypoxie, oxydation, intoxication par des métaux, etc.), comme vérifié dans des expérimentations réalisées par la demanderesse in vitro sur des cultures de macrophages de souris, de chondrocytes humains, et de cartilage isolé de la tête fémorale de rat. La Figure 2 montre les résultats d'un " Western Mot" (une méthode sensible de mesure du taux des protéines d'intérêt) qui analyse l'expression de HSP32 (HO-1) et HSP70 après choc thermique (1 heure à 43°C) dans le modèle du cartilage de tête fémorale de rat (Cont. = contrôle) .The heme oxygenase enzyme belongs to "heat-shock proteins" (HSP): it is also known under the name of "heat-shock protein 32K" (HSP32) (see Keyse SM et al., Proc. Natl. Acad. Sci. USA (1991) 86: 99-103). HSPs form a family of proteins whose expression is stimulated by stress (heat, hypoxia, oxidation, poisoning by metals, etc.), as verified in experiments carried out by the applicant in vitro on cultures of mouse macrophages , human chondrocytes, and cartilage isolated from the rat femoral head. Figure 2 shows the results of a "Western Mot" (a sensitive method for measuring the level of proteins of interest) which analyzes the expression of HSP32 (HO-1) and HSP70 after heat shock (1 hour at 43 ° C) in the rat femoral head cartilage model (Cont. = Control).
Les HSP jouent un rôle très important dans les mécanismes de défense et réparation cellulaire face aux stress. En particulier, la HO-1 exerce un effet modulateur très important au cours de la réponse inflammatoire : une élévation du taux de l'enzyme s'accompagne d'une suppression de l'inflammation, tandis qu'une inhibition entraîne une augmentation de la réponse inflammatoire (Nature Medicine (1996) 2:87-90). La découverte de la HO-1 et l'appréciation de ses effets ont suggéré la possibilité d'un contrôle pharmacologique et thérapeutique de la réponse cellulaire au stress ; en effet, il serait avantageux de pouvoir disposer de médicaments susceptibles de favoriser et/ou de maintenir l'élévation du taux de l'enzyme HO-1, à utiliser au cours du traitement de plusieurs conditions qui induisent un stress cellulaire et tissulaire, telles qu'observé notamment chez les patients immunosupprimés .HSPs play a very important role in defense mechanisms and cellular repair in the face of stress. In particular, HO-1 exerts a very important modulating effect during the inflammatory response: a rise in the level of the enzyme is accompanied by a suppression of the inflammation, while an inhibition results in an increase in the inflammatory response (Nature Medicine (1996) 2: 87-90). The discovery of HO-1 and the appreciation of its effects suggested the possibility of pharmacological and therapeutic control of the cellular response to stress; indeed, it would be advantageous to be able to have drugs capable of promoting and / or maintaining the elevation of the level of the HO-1 enzyme, to be used during the treatment of several conditions which induce cellular and tissue stress, such as than observed especially in immunosuppressed patients.
De plus, les mécanismes cellulaires responsables de la réponse au stress interviennent également lors des phénomènes observés en réponse au transplant d'un tissu ou organe (Harrison's Principles of Internai Medicine, 14ème édition (1998), 1760-68). Donc, il serait aussi avantageux de disposer de médicaments susceptibles de favoriser l'élévation du taux de l'enzyme HO-1 pour protéger l'organisme contre la
dégradation du greffon observée lors de la transplantation de tissus et organes, et utiles pour la prévention et traitement des rejets de transplants.In addition, the cellular mechanisms responsible for the stress response also intervene during the phenomena observed in response to a transplant of a tissue or organ (Harrison's Principles of Internai Medicine, 14th edition (1998), 1760-68). Therefore, it would also be advantageous to have drugs that can promote the elevation of the HO-1 enzyme level to protect the body against graft degradation observed during the transplantation of tissues and organs, and useful for the prevention and treatment of transplant rejection.
Les rhéines et certains de leurs dérivés, y compris la diacerhéine, ont été utilisés en médecine humaine et vétérinaire comme principes actifs de médicaments. Des procédés de préparation ont été mis au point pour obtenir avec un bon rendement de la diacerhéine de pureté compatible avec l'utilisation dans le domaine pharmaceutique, présentant une très faible teneur en aloémodine et autres impuretés indésirables.Rheins and some of their derivatives, including diacerein, have been used in human and veterinary medicine as active ingredients in drugs. Preparation processes have been developed to obtain, with good yield, diacerein of purity compatible with use in the pharmaceutical field, having a very low content of aloemodine and other undesirable impurities.
En médecine humaine, la diacerhéine a été administrée à des patients souffrant d'arthrose, qui présentent des douleurs et des difficultés à se déplacer. Par ailleurs, le traitement par la diacerhéine permet de ralentir la progression de la maladie arthrosique, avec une bonne sécurité d'emploi. Cependant, la diacerhéine ainsi que la rhéine ont une activité symptomatique anti-inflammatoire et antalgique modérée dans la phase aiguë de l'arthrose (Nguyen et al., Arthritis and Rheumatism (1994) 37:529-536). Or, les travaux et expérimentations réalisés par la demanderesse, visant à éclaircir le mécanisme d'action de la diacerhéine et de la rhéine, ont montré de manière tout à fait inattendue que la rhéine, la diacerhéine, et leurs sels ou esters ont pour effet de promouvoir significativement la formation de la HO-1, et de favoriser les mécanismes de contrôle de la réponse cellulaire et tissulaire face au stress. On a ainsi pu démontrer que l'administration de rhéine, ou de diacerhéine, ou de leurs sels ou esters, a pour effet de protéger l'organisme contre les événements délétères liés au stress.In human medicine, diacerein has been administered to patients with osteoarthritis, who have pain and difficulty moving. In addition, treatment with diacerein slows the progression of osteoarthritis disease, with good job security. However, diacerhein as well as rhein have moderate symptomatic anti-inflammatory and analgesic activity in the acute phase of osteoarthritis (Nguyen et al., Arthritis and Rheumatism (1994) 37: 529-536). However, the work and experiments carried out by the applicant, aimed at clarifying the mechanism of action of diacerein and rhein, have shown quite unexpectedly that rhein, diacerein, and their salts or esters have the effect significantly promote the formation of HO-1, and promote the mechanisms of control of the cellular and tissue response to stress. It has thus been demonstrated that the administration of rhein, or diacerein, or their salts or esters, has the effect of protecting the organism from deleterious events linked to stress.
De plus, l'administration de rhéine, ou de diacerhéine, ou de leurs sels ou esters, a aussi pour effet de protéger l'organisme contre la dégradation d'organes et tissus, et notamment le cartilage, de la part des cellules du système immunitaire, et de contrôler les phénomènes qui interviennent
en réponse aux transplantations d'organes et de tissus, ce qui permet d'envisager leur utilisation dans la prévention et le traitement des rejets de greffes d'organes et de tissus.In addition, the administration of rhein, or diacerein, or their salts or esters, also has the effect of protecting the organism against the degradation of organs and tissues, and in particular cartilage, on the part of the cells of the system. immune, and to control the phenomena that occur in response to organ and tissue transplants, which makes it possible to envisage their use in the prevention and treatment of rejection of organ and tissue transplants.
La présente invention a donc pour objet l'utilisation de la diacerhéine, et plus généralement de la rhéine et des dérivés de rhéine, en thérapeutique humaine et vétérinaire dans le traitement des affections nécessitant un taux élevé de l'enzyme hème oxygenase, dans la prévention et l'inhibition des effets du stress sur les cellules et les tissus, et pour la prévention et le traitement des rejets de greffes d'organes et tissus.The present invention therefore relates to the use of diacerein, and more generally rhein and rhein derivatives, in human and veterinary therapy in the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and the inhibition of the effects of stress on cells and tissues, and for the prevention and treatment of organ and tissue transplant rejection.
L'invention a aussi pour objet l'utilisation de la rhéine et des dérivés de la rhéine, en particulier la diacerhéine, pour la fabrication d'un médicament pour le traitement d'une condition nécessitant un taux élevé d'hème oxygenase.Another subject of the invention is the use of rhein and rhein derivatives, in particular diacerein, for the manufacture of a medicament for the treatment of a condition requiring a high level of heme oxygenase.
La rhéine et la diacerhéine, ainsi que leurs sels et esters, s'avèrent ainsi particulièrement avantageux pour favoriser ou maintenir un taux élevé d'hème oxygenase, dans la prévention et l'inhibition des effets du stress sur les cellules et les tissus, et dans la prévention et le traitement des rejets des greffes d'organes et de tissus chez un sujet nécessitant un tel traitement.Rhein and diacerein, as well as their salts and esters, thus prove to be particularly advantageous for promoting or maintaining a high level of heme oxygenase, in preventing and inhibiting the effects of stress on cells and tissues, and in the prevention and treatment of organ and tissue transplant rejection in a subject in need of such treatment.
La rhéine et ses dérivés utilisables dans l'invention, notamment la diacerhéine, peuvent être représentés par la formule générale (I) suivante :Rhein and its derivatives which can be used in the invention, in particular diacerein, can be represented by the following general formula (I):
dans laquelle R représente un atome d'hydrogène, ou un groupe alkyle, par exemple un groupe méthyle, éthyle ou propyle, ou un atome de métal alcalin ou alcalino-terreux, par exemple un atome de sodium, de potassium ou de calcium, Ri et R2,
identiques ou différents, représentent un groupe hydroxy ou un groupe acyloxy de formule R'-COO- dans laquelle R' est un groupe alkyle de 1 à 4 atomes de carbone, par exemple un groupe méthyle, éthyle ou isopropyle. Dans la formule générale (I) ci-dessus, R représente de préférence un atome d'hydrogène, et Ri et R2 représentent de préférence un groupe hydroxy ou acétoxy. La formule générale (I) ci-dessus dans laquelle R est un atome d'hydrogène et Ri et R2 sont un groupe acétoxy -COOCH3 est celle de la diacerhéine.in which R represents a hydrogen atom, or an alkyl group, for example a methyl, ethyl or propyl group, or an alkali or alkaline earth metal atom, for example a sodium, potassium or calcium atom, Ri and R 2 , identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- in which R 'is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl or isopropyl group. In the general formula (I) above, R preferably represents a hydrogen atom, and R 1 and R 2 preferably represent a hydroxy or acetoxy group. The general formula (I) above in which R is a hydrogen atom and Ri and R 2 are an acetoxy group -COOCH 3 is that of diacerein.
La diacerhéine et la rhéine peuvent être préparées par les méthodes connues de la technique, et par exemple à partir de produits d'extraction d'aloès ou de feuille de séné, tels que des sennosides, ou par acétylation de barbaloïne suivie d'une oxydation par l'oxyde de chrome. On peut aussi utiliser les procédés de synthèse décrits dans les brevets EP 801639 et EP 909268. Ces procédés consistent, par exemple, à effectuer une réaction de Diels-Alder sur une naphtoquinone telle que la juglone au moyen d'un diène acyclique pour obtenir une tétrahydroanthraquinone qui peut être aisément transformée en rhéine et diacerhéine après déprotection oxydante.Diacerein and rhein can be prepared by methods known in the art, and for example from extracts of aloe or senna leaf, such as sennosides, or by acetylation of barbaloin followed by oxidation by chromium oxide. One can also use the synthetic methods described in patents EP 801639 and EP 909268. These methods consist, for example, in carrying out a Diels-Alder reaction on a naphthoquinone such as juglone by means of an acyclic diene to obtain a tetrahydroanthraquinone which can be easily transformed into rhein and diacerein after oxidative deprotection.
La diacerhéine obtenue par ces procédés peut être purifiée si nécessaire pour parvenir à un produit répondant parfaitement aux normes pharmaceutiques et offrant toutes les garanties voulues. Par exemple, on peut utiliser le procédé de purification décrit dans le brevet EP 754173, suivant lequel on prépare un sel soluble de diacerhéine par action de triéthylamine et d'acétate de potassium, puis on effectue une hydrolyse en milieu faiblement acide. Les études effectuées par la demanderesse pour mettre en évidence l'effet de la diacerhéine, de la rhéine et de leurs sels ou esters sur la HO-1 ont été réalisées en utilisant des modèles validés, comme indiqué ci-après.The diacerein obtained by these processes can be purified if necessary to achieve a product that perfectly meets pharmaceutical standards and offers all the desired guarantees. For example, one can use the purification process described in patent EP 754173, according to which a soluble salt of diacerein is prepared by the action of triethylamine and potassium acetate, then hydrolysis is carried out in a weakly acid medium. The studies carried out by the applicant to demonstrate the effect of diacerein, rhein and their salts or esters on HO-1 were carried out using validated models, as indicated below.
Les travaux et expérimentations in vi tro ont utilisé les modèles suivants:
1.- Un modèle validé de culture de tissu, et notamment le cartilage de tête fémorale de rat, traité avec érythrocytes (en % w/v) , lysat d' érythrocytes (3xl06) , ou hémoglobine (en % w/v), sans et après stress thermique (lh à 43°C). L'inté- grité du cartilage a été mesurée par l'incorporation de sulfate radioactif (35S04; en coups per minutes, CPM) . Dans ce modèle, les érythrocytes, le lysat d' érythrocytes et l'hémoglobine provoquent la destruction cellulaire, démontrée par une diminution de la viabilité cellulaire et de 1 ' incor- poration de sulfate radioactif par les cellules, comme le montrent les Figures 3 et 4.The work and experiments in vi tro used the following models: 1.- A validated tissue culture model, and in particular the cartilage of the femoral head of a rat, treated with erythrocytes (in% w / v), erythrocyte lysate (3xl0 6 ), or hemoglobin (in% w / v) , without and after heat stress (lh at 43 ° C). Cartilage integrity was measured by the incorporation of radioactive sulfate ( 35 SO 4 ; in counts per minute, CPM). In this model, erythrocytes, erythrocyte lysate and hemoglobin cause cell destruction, demonstrated by decreased cell viability and the incorporation of radioactive sulfate by cells, as shown in Figures 3 and 4.
La Figure 3 montre que les érythrocytes provoquent une destruction cellulaire en fonction de leur dose, mise en évidence par la diminution de l'incorporation cellulaire de sulfate radioactif (modèle: cartilage de tête fémorale de rat avec érythrocytes en %v/v; Cont. = contrôle: solution sans érythrocytes; 35S04 = sulfate radioactif; sem = erreur standard) .Figure 3 shows that the erythrocytes cause cell destruction according to their dose, highlighted by the decrease in cellular incorporation of radioactive sulfate (model: rat femoral head cartilage with erythrocytes in% v / v; Cont. = control: solution without erythrocytes; 35 S0 4 = radioactive sulfate; wk = standard error).
De la même manière, la Figure 4 montre que l'hémoglobine provoque une destruction cellulaire en fonction de sa dose, mise en évidence par la diminution de l'incorporation cellulaire de sulfate radioactif (modèle: cartilage de tête fémorale de rat avec hémoglobine en %v/v; Cont. = contrôle: solution sans hémoglobine; 35S04 = sulfate radioactif; sem = erreur standard) .Similarly, Figure 4 shows that hemoglobin causes cell destruction depending on its dose, highlighted by the decrease in cellular incorporation of radioactive sulphate (model: rat femoral head cartilage with hemoglobin in% v / v; Cont. = control: hemoglobin-free solution; 35 S0 4 = radioactive sulfate; wk = standard error).
Dans ce modèle de culture de tissu, les HSP préalablement induites par le stress préviennent la destruction cellulaire, comme démontré sur la Figure 5 par une augmentation de l'incorporation de sulfate radioactif par les cellules (modèle: cartilage de tête fémorale de rat soumis à stress thermique (lh à 43°C) et ensuite traité avec hémoglobine (l%w/v); 35S04 = sulfate radioactif; sem = erreur standard). 2.- Un modèle validé de culture de cellules, et notamment les chondrocytes humains, traités avec érythrocytes (en % w/v) , lysat d' érythrocytes (3xlOβ) , ou hémoglobine (en % w/v), sans
et après stress thermique (lh à 43°C) . L'intégrité cellulaire a été mesurée par la viabilité cellulaire (cellules vivantes par rapport au contrôle), la présence d'apoptose (fragmentation nucléaire; en nombre et pourcentage par rapport au contrôle), et l'incorporation de sulfate radioactif (3 S04; en coups per minutes, CPM) .In this tissue culture model, the stress-induced HSPs prevent cell destruction, as shown in FIG. 5 by an increase in the incorporation of radioactive sulphate by the cells (model: rat femoral head cartilage subjected to heat stress (lh at 43 ° C) and then treated with hemoglobin (l% w / v); 35 S0 4 = radioactive sulfate; wk = standard error). 2.- A validated cell culture model, and in particular human chondrocytes, treated with erythrocytes (in% w / v), erythrocyte lysate (3xlO β ), or hemoglobin (in% w / v), without and after thermal stress (lh at 43 ° C). Cell integrity was measured by cell viability (living cells versus control), presence of apoptosis (nuclear fragmentation; number and percentage versus control), and incorporation of radioactive sulfate ( 3 S0 4 ; in strokes per minute, CPM).
Comme déjà observé pour le cartilage de tête fémorale, dans ce modèle aussi les érythrocytes, le lysat d' érythrocytes ou l'hémoglobine provoquent la destruction cellulaire. Par contre, les HSP induites par un stress préviennent cette destruction cellulaire et préservent les cellules, comme le montre la Figure 6 qui dénombre les cellules vivantes (modèle: chondrocytes humains soumis à stress thermique (lh à 43°C) et ensuite traité avec lysat d' érythrocytes (3xlOβ) ; sem = erreur standard) .As already observed for the femoral head cartilage, in this model also erythrocytes, erythrocyte lysate or hemoglobin cause cell destruction. On the other hand, stress-induced HSPs prevent this cell destruction and preserve the cells, as shown in Figure 6 which counts living cells (model: human chondrocytes subjected to thermal stress (lh at 43 ° C) and then treated with lysate erythrocytes (3x10 β ); sem = standard error).
Sur la base de ces expériences, les études effectuées par la demanderesse ont mis en évidence les effets de la diacerhéine, de la rhéine et de leurs sels ou esters sur l'expression de la HO-1, comme illustré en détail ci-après en référence aux Figures 7a, 7b et 7c.On the basis of these experiences, the studies carried out by the applicant have demonstrated the effects of diacerein, rhein and their salts or esters on the expression of HO-1, as illustrated in detail below in reference to Figures 7a, 7b and 7c.
La Figure 7a est un " Western blot" (modèle: cartilage de tête fémorale de rat; Cont. = contrôle; Veh. = solution témoin; diacerhéine: lOμM et lOOμM) qui montre que la diacerhéine, par comparaison avec le contrôle et la solution témoin, entraîne une augmentation de l'expression de la HO-1 en fonction de la dose.Figure 7a is a "Western blot" (model: cartilage of the femoral head of a rat; Cont. = Control; Vehicle. Control solution; diacerein: 10 μM and 100 μM) which shows that diacerein, in comparison with the control and the solution control, increases the expression of HO-1 depending on the dose.
Les Figures 7b et 7c sont également des " Western blot" de cellules (modèle: macrophages de souris) cultivées sans et avec diacerhéine (Figure 7b: colonnes '<ε et colonnes "D€", respectivement) ou rhéine (Figure 7c) à une concentration de 10"5 M, et ensuite analysées à 15, 30 et 60 minutes (Figure 7b) et 0, 15, 30, 60, 120 minutes ainsi que 18 heures (Figure 7c). L'identité de la protéine d'intérêt, la HO-1, a été confirmée par rapport à son poids moléculaire (32 kilodalton; kDa) déterminé sur une échelle de référence (première colonne
à gauche dans les Figures) . Ces résultats démontrent que la diacerhéine et la rhéine entraînent une augmentation de l'expression de la HO-1 en fonction du temps.Figures 7b and 7c are also "Western blots" of cells (model: mouse macrophages) cultivated without and with diacerein (Figure 7b: columns'<ε and columns "D €", respectively) or rhein (Figure 7c) to a concentration of 10 "5 M, and then analyzed at 15, 30 and 60 minutes (Figure 7b) and 0, 15, 30, 60, 120 minutes as well as 18 hours (Figure 7c). The identity of the protein interest, HO-1, was confirmed with respect to its molecular weight (32 kilodalton; kDa) determined on a reference scale (first column left in Figures). These results demonstrate that diacerhein and rhein cause an increase in the expression of HO-1 as a function of time.
En utilisant les modèles in vi tro décrits ci-dessus, les études effectuées par la demanderesse ont aussi démontré que la diacerhéine, la rhéine et leurs sels ou esters, en raison de leur effet sur la HO-1, préservent l'intégrité cellulaire, comme illustré en détail sur les Figures 8 et 9.By using the in vi tro models described above, the studies carried out by the applicant have also demonstrated that diacerein, rhein and their salts or esters, due to their effect on HO-1, preserve cellular integrity, as shown in detail in Figures 8 and 9.
La Figure 8 (modèle: chondrocytes humains; lysat = produit de la lyse de 3xl06 érythrocytes; diacerhéine: lOOμM; sem = erreur standard) montre que le traitement par la diacerhéine prévient la destruction cellulaire provoquée par le lysat d' érythrocytes .FIG. 8 (model: human chondrocytes; lysate = product of the lysis of 3 × 10 6 erythrocytes; diacerein: 100 μM; sem = standard error) shows that treatment with diacerein prevents cell destruction caused by the erythrocyte lysate.
La Figure 9 (modèle: chondrocytes humains; lysat = produit de la lyse de 3xl06 érythrocytes; rhéine: lOOμM; sem = erreur standard) montre que le traitement par la rhéine prévient l'apoptose provoquée par le lysat d' érythrocytes .FIG. 9 (model: human chondrocytes; lysate = product of the lysis of 3 × 10 6 erythrocytes; rhein: 100 μM; wk = standard error) shows that treatment with rhein prevents apoptosis caused by the erythrocyte lysate.
Les conclusions principales des travaux et expérimentations réalisés par la demanderesse in vitro avec les modèles décrits ci-dessus, sur les effets de la diacerhéine, de la rhéine et de leurs sels ou esters, sont les suivantes:The main conclusions of the work and experiments carried out by the applicant in vitro with the models described above, on the effects of diacerein, rhein and their salts or esters, are the following:
- La diacerhéine, la rhéine, et leurs sels ou esters augmentent de façon dose - dépendante les niveaux de 1 ' enzyme HO-1 qui joue un rôle dans la protection de l'intégrité cellulaire;- Diacerheine, rhein, and their salts or esters increase in a dose-dependent manner the levels of the enzyme HO-1 which plays a role in the protection of cellular integrity;
- Grâce à cette augmentation de la HO-1, la diacerhéine, la rhéine, et leurs sels ou esters préservent l'intégrité des cellules et des tissus face aux réactions délétères induites par le stress; - La diacerhéine, la rhéine, et leurs sels ou esters préviennent l'apoptose (fragmentation du noyau, suivi par la destruction et la mort des cellules) .- Thanks to this increase in HO-1, diacerein, rhein, and their salts or esters preserve the integrity of cells and tissues in the face of deleterious reactions induced by stress; - Diacerheine, rhein, and their salts or esters prevent apoptosis (fragmentation of the nucleus, followed by the destruction and death of cells).
La demanderesse a également réalisés des travaux et expérimentations in vivo, avec l'utilisation du modèle décrit ci-après.
On a mesuré l'effet de la diacerhéine, de la rhéine et de leurs sels ou esters sur l'intensité de la réaction tissulaire et des phénomènes de destruction et rejet à la suite de l'implantation d'un tissu, en utilisant le modèle du granulome et dégradation de tissu de rat induites chez la souris (Bottomley KM et al., Osteoarthritis and Cartilage (1998) 6: 19-23.).The Applicant has also carried out work and experiments in vivo, with the use of the model described below. We measured the effect of diacerein, rhein and their salts or esters on the intensity of tissue reaction and destruction and rejection phenomena following implantation of tissue, using the model of granuloma and induced degradation of rat tissue in mice (Bottomley KM et al., Osteoarthritis and Cartilage (1998) 6: 19-23.).
La méthode comprend les étapes suivantes :The method includes the following steps:
- les tissus isolés (rat istar, mâle) sont placés dans du coton stérile et implantés en sous-cutané chez des souris TO; - les implants sous-cutanés sont conservés sur une période de 2 semaines;- the isolated tissues (istar rat, male) are placed in sterile cotton and implanted subcutaneously in TO mice; - the subcutaneous implants are stored over a period of 2 weeks;
- traitement quotidien des animaux avec diacerhéine, rhéine et leurs sels ou esters, ainsi qu'avec les contrôles et comparateurs, aux doses optimales indiquées; - récupération du tissu implanté et du granulome réactif;- daily treatment of animals with diacerein, rhein and their salts or esters, as well as with controls and comparators, at the optimal doses indicated; - recovery of implanted tissue and reactive granuloma;
- mesure du degré de la réponse inflammatoire tissulaire (évaluation des dimensions du granulome, du nombre de cellules inflammatoires dans l' exsudât, et du volume de l' exsudât), et du rejet (évaluation de la dégradation du tissu implanté) . En utilisant le modèle décrit ci-dessus, les études effectuées par la demanderesse ont démontré que la diacerhéine, la rhéine, et leurs sels ou esters diminuent la réaction tissulaire (formation du granulome, recrutement de cellules inflammatoires, formation d'un exsudât) provoquée par la transplantation de tissu de rat chez la souris, et préservent l'intégrité du tissu transplanté, comme illustré en détail sur les Figures 10, 11 et 12 ci-après.- measurement of the degree of the inflammatory tissue response (evaluation of the dimensions of the granuloma, of the number of inflammatory cells in the exudate, and of the volume of the exudate), and of the rejection (evaluation of the degradation of the implanted tissue). Using the model described above, the studies carried out by the applicant have demonstrated that diacerhein, rhein, and their salts or esters decrease the tissue reaction (granuloma formation, recruitment of inflammatory cells, formation of exudate) caused by rat tissue transplantation in mice, and preserve the integrity of the transplanted tissue, as illustrated in detail in Figures 10, 11 and 12 below.
La Figure 10 montre que le traitement avec la diacerhéine diminue la réaction tissulaire (formation du granulome réactif) en fonction de la dose (diacerhéine: 5, 15 et 50 mg/kg, par voie orale; ** différence statistiquement significative par rapport au contrôle : p<0,01).Figure 10 shows that the treatment with diacerhein decreases the tissue reaction (formation of the reactive granuloma) depending on the dose (diacerhein: 5, 15 and 50 mg / kg, orally; ** statistically significant difference compared to the control : p <0.01).
La Figure 11 montre que la réaction tissulaire provoquée par l'implantation de tissu de rat chez la souris est diminuée par le traitement avec la diacerhéine en fonction de la dose
(à gauche sur la Figure 11: nombre de cellules inflammatoires ; à droite : volume de l'exsudat) (Cont.: contrôle; diacerhéine : 5, 15 et 50 mg/kg, par voie orale; * différence statistiquement significative par rapport au contrôle : p<0, 05) .Figure 11 shows that the tissue reaction caused by the implantation of rat tissue in mice is reduced by the dose-dependent treatment with diacerein. (left in Figure 11: number of inflammatory cells; right: volume of exudate) (Cont .: control; diacerein: 5, 15 and 50 mg / kg, orally; * statistically significant difference compared to control: p <0.05).
La Figure 12 montre que le traitement avec la diacerhéine préserve l'intégrité du tissu transplanté en fonction de la dose de diacerhéine, ce qui est mis en évidence par la conservation de la teneur en collagène (à gauche sur la Figure 12) et en glycosamino-glycane (GAG; à droite) dans le tissu transplanté (diacerhéine: 5, 15 et 50 mg/kg, par voie orale; différences statistiquement significatives versus contrôle : * p<0,05: ** p<0,01) .Figure 12 shows that treatment with diacerein preserves the integrity of the transplanted tissue as a function of the dose of diacerein, which is demonstrated by the conservation of the content of collagen (on the left in Figure 12) and of glycosamino. -glycan (GAG; right) in the transplanted tissue (diacerhein: 5, 15 and 50 mg / kg, orally; statistically significant differences versus control: * p <0.05: ** p <0.01).
Les conclusions principales des travaux et expéri- mentations sur les effets de la diacerhéine, de la rhéine, et de leurs sels ou esters réalisés in vivo par la demanderesse avec le modèle décrit ci-dessus sont les suivantes:The main conclusions of the work and experiments on the effects of diacerein, rhein, and their salts or esters carried out in vivo by the applicant with the model described above are as follows:
- la diacerhéine, la rhéine, et leurs sels ou esters diminuent la réaction tissulaire (dimensions du granulome, nombre de cellules inflammatoires, volume de l'exsudat) provoquée par l'implantation du tissu de rat dans la souris ;- diacerein, rhein, and their salts or esters decrease the tissue reaction (size of the granuloma, number of inflammatory cells, volume of exudate) caused by the implantation of rat tissue in the mouse;
- la diacerhéine, la rhéine, et leurs sels ou esters préservent l'intégrité des tissus transplantés face à la réaction tissulaire ; - la diacerhéine, la rhéine, et leurs sels ou esters préviennent la destruction et le rejet du tissu transplanté.- diacerein, rhein, and their salts or esters preserve the integrity of the transplanted tissues in the face of the tissue reaction; - diacerein, rhein, and their salts or esters prevent the destruction and rejection of the transplanted tissue.
Pour le traitement des phénomènes inflammatoires aigus, les médicaments le plus largement utilisés sont les antiinflammatoires non stéroïdiens (AINS) , même s'ils présentent certains effets indésirables, et en particulier une tendance à induire des ulcérations gastriques ou intestinales (Goodman and Gilman, The Pharnαacological Basis of Therapeutics; 9ème édition, McGraw Hill) . Ces effets indésirables sont liés à l'inhibition de l'enzyme cyclo-oxygénase-1 (COX-1; isoforme constitutive) .
La découverte de l'existence d'une autre isoforme de l'enzyme cyclo-oxygénase, la cyclo-oxygénase-2 (COX-2; isoforme induite dans l'établissement de l'inflammation), a ouvert de nouvelles perspectives vers la mise au point de médicaments potentiellement plus spécifiques et plus sûrs. Les AINS disponibles aujourd'hui ont pour effet d'inhiber sélectivement l'action de la COX-2, et donc d'agir sur l'inflammation avec une incidence plus faible d'effets secondaires indésirables sur le tractus gastro-intestinal supérieur. Ainsi, une nouvelle classe de médicaments, les inhibiteurs de la COX-2 tels que le celecoxib et le rofecoxib, a été développée pour le traitement symptomatique des maladies inflammatoires.For the treatment of acute inflammatory phenomena, the most widely used drugs are non-steroidal anti-inflammatory drugs (NSAIDs), even if they have certain undesirable effects, and in particular a tendency to induce gastric or intestinal ulcerations (Goodman and Gilman, The Pharnαacological Basis of Therapeutics; 9th edition, McGraw Hill). These side effects are related to the inhibition of the enzyme cyclooxygenase-1 (COX-1; constitutive isoform). The discovery of the existence of another isoform of the enzyme cyclooxygenase, cyclooxygenase-2 (COX-2; isoform induced in the establishment of inflammation), opened new perspectives towards the setting developing potentially more specific and safer drugs. The NSAIDs available today have the effect of selectively inhibiting the action of COX-2, and therefore of acting on inflammation with a lower incidence of undesirable side effects on the upper gastrointestinal tract. Thus, a new class of drugs, COX-2 inhibitors such as celecoxib and rofecoxib, have been developed for the symptomatic treatment of inflammatory diseases.
Cependant, à ce jour aucun effet favorable sur l'enzyme hème oxygenase n'a été observé ni pour les AINS "classiques" ni pour les inhibiteurs de la COX-2.However, to date no favorable effect on the enzyme heme oxygenase has been observed either for "conventional" NSAIDs or for COX-2 inhibitors.
Les études réalisées par la demanderesse ont confirmé que les AINS classiques ainsi que les inhibiteurs de la COX-2 diminuent la réaction tissulaire (granulome, infiltration de cellules inflammatoires, exsudât) provoquée par la trans- plantation de tissu de rat chez la souris. Par contre, ni les AINS classiques, ni les inhibiteurs de la COX-2, ne préservent l'intégrité du tissu transplanté, contrairement à la rhéine et la diacerhéine, comme les montrent les Figures 13, 14 et 15 ci-jointes . La Figure 13 montre la comparaison des effets du traitement avec un inhibiteur de la COX-2 (le rofecoxib) d'une part, et la diacerhéine d'autre part, sur la diminution de la réaction tissulaire (formation d'un granulome réactif) provoquée par l'implantation de tissu de rat chez la souris (diacerhéine: 5, 15 et 50 mg/Kg, et rofecoxib: 3 mg/kg, par voie orale; différences statistiquement significatives par rapport au contrôle: * p<0,05; ** p<0,01).The studies carried out by the applicant have confirmed that conventional NSAIDs as well as COX-2 inhibitors decrease the tissue reaction (granuloma, infiltration of inflammatory cells, exudate) caused by the transplantation of rat tissue in mice. In contrast, neither conventional NSAIDs nor COX-2 inhibitors preserve the integrity of the transplanted tissue, unlike rhein and diacerein, as shown in Figures 13, 14 and 15 attached. Figure 13 shows the comparison of the effects of treatment with a COX-2 inhibitor (rofecoxib) on the one hand, and diacerein on the other hand, on the decrease in tissue reaction (formation of a reactive granuloma) caused by the implantation of rat tissue in mice (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / kg, orally; statistically significant differences from the control: * p <0.05 ; ** p <0.01).
La Figure 14 permet de comparer les effets du traitement avec le rofecoxib d'une part, la diacerhéine d'autre part, sur la diminution de la réaction tissulaire provoquée par
l'implantation de tissu de rat chez la souris. Le graphique de gauche illustrel ' infiltration cellulaire, et celui de droite le volume de l'exsudat (Cont.: contrôle; DAR : diacerhéine: 2, 10 et 50 mg/kg, et rofecoxib: 3 mg/Kg, par voie orale; différence statistiquement significative par rapport au contrôle: * p<0, 05) .Figure 14 compares the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on the decrease in tissue reaction caused by implantation of rat tissue in mice. The graph on the left illustrates cell infiltration, and the graph on the right shows the volume of exudate (Cont .: control; DAR: diacerein: 2, 10 and 50 mg / kg, and rofecoxib: 3 mg / Kg, orally; statistically significant difference compared to control: * p <0.05).
La Figure 15 permet de comparer les différences des effets du traitement avec le rofecoxib d'une part, la diacerhéine d'autre part, sur la préservation de l'intégrité du tissu transplanté. Le graphique de gauche correspond à la teneur en collagène, celui de droit à la teneur en glycosa- mino-glycane (GAG) dans le tissu (diacerhéine: 5, 15 et 50 mg/Kg, et rofecoxib: 3 mg/Kg, par voie orale; différences statistiquement significatives versus contrôle: *p<0,05: **p<0,01) .Figure 15 compares the differences in the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on preserving the integrity of the transplanted tissue. The graph on the left corresponds to the collagen content, that on the right to the glycosaminoglycan (GAG) content in the tissue (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / Kg, by oral route; statistically significant differences versus control: * p <0.05: ** p <0.01).
Les résultats obtenus montrent que la diacerhéine et la rhéine ont des propriétés significativement différentes de celles d'autres médicaments, tels que les anti-inflammatoires non stéroïdiens (AINS) classiques et les inhibiteurs de la COX-2, notamment sur la préservation d'un tissu transplanté et le rejet de ce tissu.The results obtained show that diacerhein and rhein have significantly different properties from those of other drugs, such as conventional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors, in particular on the preservation of transplanted tissue and rejection of that tissue.
Conformément à la présente invention, il peut être utile d'associer la diacerhéine, ou la rhéine, ou leurs sels et esters, à un AINS classique ou à un inhibiteur de la COX-2, dont les actions peuvent être complémentaires, selon la pathologie traitée. Ainsi la diacerhéine peur être associée à un AINS tel que le diclofenac à une dose comprise entre 25 et 150 mg par jour, ou à un inhibiteur de la COX-2 comme le rofecoxib à une dose comprise entre 10 et 50 mg par jour. Comme indiqué précédemment, la diacerhéine, la rhéine, ainsi que leurs sels et esters, peuvent être avantageusement utilisés en thérapeutique humaine et vétérinaire pour le traitement des affections nécessitant un taux élevé de l'enzyme hème oxygenase, dans la prévention et l'inhibition des effets du stress sur les cellules et les tissus, et pour
la prévention et le traitement du rejet des transplantations de tissus et d'organes. A titre d'exemple, leur utilisation aux doses indiquées est tout particulièrement utile pour le traitement des affections indiquées ci-après. - les inflammations associées au diabète Type I et II, telles que neuropathie périphérique et ulcère chronique cutanéIn accordance with the present invention, it may be useful to combine diacerhein, or rhein, or their salts and esters, with a conventional NSAID or with a COX-2 inhibitor, the actions of which may be complementary, depending on the pathology. treated. Diacerein can therefore be combined with an NSAID such as diclofenac at a dose between 25 and 150 mg per day, or with a COX-2 inhibitor like rofecoxib at a dose between 10 and 50 mg per day. As previously indicated, diacerhein, rhein, as well as their salts and esters, can be advantageously used in human and veterinary therapy for the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and inhibition of effects of stress on cells and tissues, and for prevention and treatment of rejection of tissue and organ transplants. By way of example, their use at the doses indicated is very particularly useful for the treatment of the conditions indicated below. - inflammations associated with Type I and II diabetes, such as peripheral neuropathy and chronic skin ulcer
- la dégénérescence maculaire- macular degeneration
- la rétinite,- retinitis,
- l'uvéite intermédiaire ou postérieure non infectieuse - le glaucome- non-infectious intermediate or posterior uveitis - glaucoma
- les "connectivités" (comme le lupus érythémateux, la sclérodermie, la sarcoïdose)- "connectivities" (such as lupus erythematosus, scleroderma, sarcoidosis)
- l'érythème noueux et la dermite atopique de l'adulte, en cas d'inefficacité, intolérance ou contre-indication des traitements classiques (photothérapie et/ou photochimiothérapie)- knotty erythema and atopic dermatitis in adults, in the event of ineffectiveness, intolerance or contraindication of conventional treatments (phototherapy and / or photochemotherapy)
- la myasténie et la mucoviscidose- myastenia and cystic fibrosis
- la sinusite chronique, la bronchite chronique obstruc- tive, les bronchiéctasies - la tuberculose (avec ses localisations pulmonaire, rénale, osseuse) et la prévention de la formation du granulome (comme dans les parasitoses, la leishmaniose, la pneumo- coniose)- chronic sinusitis, chronic obstructive bronchitis, bronchiectasis - tuberculosis (with its pulmonary, renal, bone localizations) and the prevention of granuloma formation (as in parasitoses, leishmaniasis, pneumoconiosis)
- l'hépatite chronique (d'origine virale, alcoolique), la pancréatite chronique- chronic hepatitis (of viral, alcoholic origin), chronic pancreatitis
- la glomérulonéphrite, le syndrome néphrotique et la toxémie ("urémie") du patient en dialyse rénale- glomerulonephritis, nephrotic syndrome and toxemia ("uremia") of the patient on renal dialysis
- les infections opportunistes de patients immuno- supprimés et "grands brûlés", l'ostéomyélite - les anémies hémolytiques, la drépanocytose, 1 ' hémar- throse- opportunistic infections of immunosuppressed and "severely burned" patients, osteomyelitis - hemolytic anemias, sickle cell anemia, hemarthrosis
- le développement de la plaque athéromateuse, l'ictus hémorragique, la thrombophlébite- development of atheromatous plaque, hemorrhagic stroke, thrombophlebitis
- l'aplasie médullaire acquise (même si bénéficiant d'une greffe de moelle osseuse allogénique)
- la prévention du rejet d'un tissu (cartilage, peau, moelle osseuse) ou organe (foie, rein, cœur) transplanté- acquired spinal cord aplasia (even if benefiting from an allogeneic bone marrow transplant) - prevention of rejection of a transplanted tissue (cartilage, skin, bone marrow) or organ (liver, kidney, heart)
- la prévention du rejet du greffon, et du rejet après greffe, y compris à la phase initiale de transplantation hépatique, ainsi que le traitement préventif ou curatif de la maladie du greffon contre l'hôte- prevention of graft rejection, and rejection after transplant, including at the initial stage of liver transplantation, as well as preventive or curative treatment of graft versus host disease
- le traitement du rejet, notamment chez des patients initialement traités par des protocoles immunosuppresseurs .- the treatment of rejection, especially in patients initially treated with immunosuppressive protocols.
La diacerhéine et la rhéine possèdent une faible solu- bilité dans l'eau et dans les alcools, et sont donc de préférence administrées par voie orale. Les formes d'administration par voie orale usuelles dans le domaine pharmaceutiques sont adéquates, et par exemple, on peut administrer le médicament sous forme de comprimés, de gélules ou de capsules molles de gélatine, ou toute autre forme galenique appropriée.Diacerein and rhein have a low solubility in water and in alcohols, and are therefore preferably administered orally. The usual oral administration forms in the pharmaceutical field are suitable, and for example, the medicament can be administered in the form of tablets, gelatin capsules or soft gelatin capsules, or any other suitable galenical form.
Une forme d'administration particulièrement appropriée est celle décrite dans le brevet EP 862423 décrivant des capsules ou gélules dans lesquelles la diacerhéine est mélangée à une huile liquide et un surfactif non ionique, permettant d'obtenir une bonne biodisponibilité. Une autre forme utilisable dans l'invention, décrite dans le brevet US 6124358, est préparée par comicronisation de la rhéine ou de la diacerhéine avec un lauryl sulfate, par exemple le lauryl sulfate de sodium. La posologie est déterminée par le praticien en fonction de l'état du patient, mais elle est généralement comprise entre 25 mg et 500 mg par jour, de préférence entre 50 mg et 100 mg par jour. Elle est relativement indépendante du poids du patient, chez l'adulte. Les doses unitaires, pour adminis- tration par voie orale, sont généralement comprises entre 25 mg et 50 mg.
A particularly suitable form of administration is that described in patent EP 862423 describing capsules or gelatin capsules in which the diacerein is mixed with a liquid oil and a nonionic surfactant, making it possible to obtain good bioavailability. Another form which can be used in the invention, described in US Pat. No. 6,124,358, is prepared by comicronisation of rhein or diacerein with a lauryl sulfate, for example sodium lauryl sulfate. The dosage is determined by the practitioner depending on the condition of the patient, but it is generally between 25 mg and 500 mg per day, preferably between 50 mg and 100 mg per day. It is relatively independent of the patient's weight in adults. Unit doses, for oral administration, are generally between 25 mg and 50 mg.
Claims
1. Utilisation de la rhéine et de dérivés de rhéine en thérapeutique humaine ou vétérinaire pour le traitement d'une affection nécessitant une élévation du taux de l'enzyme hème oxygenase .1. Use of rhein and rhein derivatives in human or veterinary therapy for the treatment of a condition requiring an increase in the level of the enzyme heme oxygenase.
2. Utilisation selon la revendication 1, caractérisée en ce que la rhéine et le dérivé de rhéine sont représentés par la formule générale (I) :2. Use according to claim 1, characterized in that the rhein and the rhein derivative are represented by the general formula (I):
dans laquelle R représente un atome d'hydrogène, ou un groupe alkyle, ou un atome de métal alcalin ou alcalino-terreux, Ri et R2, identiques ou différents, représentent un groupe hydroxy ou un groupe acyloxy de formule R'-COO- dans laquelle R' est un groupe alkyle de 1 à 4 atomes de carbone. in which R represents a hydrogen atom, or an alkyl group, or an alkali or alkaline earth metal atom, Ri and R 2 , identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- wherein R 'is an alkyl group of 1 to 4 carbon atoms.
3. Utilisation selon la revendication 2, caractérisée en ce que le dérivé est la rhéine ou la diacerhéine.3. Use according to claim 2, characterized in that the derivative is rhein or diacerein.
4. Utilisation selon l'une quelconque des revendications précédentes, caractérisée en ce que le dérivé de rhéine est administré à raison de 25 à 500 mg par jour.4. Use according to any one of the preceding claims, characterized in that the rhein derivative is administered in an amount of 25 to 500 mg per day.
5. Utilisation selon l'une quelconque des revendications précédentes, caractérisée en ce que le dérivé de rhéine est sous forme ad inistrable par voie orale.5. Use according to any one of the preceding claims, characterized in that the rhein derivative is in ad form without oral administration.
6. Utilisation de la rhéine et de dérivés de rhéine pour la fabrication d'un médicament pour le traitement d'une affection nécessitant une élévation du taux de l'enzyme hème oxygenase.6. Use of rhein and rhein derivatives for the manufacture of a medicament for the treatment of a condition requiring an increase in the level of the enzyme heme oxygenase.
7. Utilisation selon la revendication 6, caractérisée en ce que la rhéine et le dérivé de rhéine sont représentés par la formule générale (I) : 7. Use according to claim 6, characterized in that the rhein and the rhein derivative are represented by the general formula (I):
dans laquelle R représente un atome d'hydrogène, ou un groupe alkyle, ou un atome de métal alcalin ou alcalino-terreux, Ri et R2, identiques ou différents, représentent un groupe hydroxy ou un groupe acyloxy de formule R'-COO- dans laquelle R' est un groupe alkyle de 1 à 4 atomes de carbone. in which R represents a hydrogen atom, or an alkyl group, or an alkali or alkaline earth metal atom, Ri and R 2 , identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- wherein R 'is an alkyl group of 1 to 4 carbon atoms.
8. Utilisation selon la revendication 7, caractérisée en ce que le dérivé est la rhéine ou la diacerhéine.8. Use according to claim 7, characterized in that the derivative is rhein or diacerein.
9. Utilisation selon l'une quelconque des revendications 6 à 8, caractérisée en ce que le dérivé de rhéine est administré à raison de 25 à 500 mg par jour. 9. Use according to any one of claims 6 to 8, characterized in that the rhein derivative is administered in an amount of 25 to 500 mg per day.
10. Utilisation selon l'une quelconque des revendications 6 à 9, caractérisée en ce que le dérivé de rhéine est sous forme administrable par voie orale.10. Use according to any one of claims 6 to 9, characterized in that the rhein derivative is in form which can be administered orally.
11. Utilisation selon la revendication 10, caractérisée en ce que la dose unitaire est comprise entre 25 mg et 50 mg. 11. Use according to claim 10, characterized in that the unit dose is between 25 mg and 50 mg.
12. Utilisation selon l'une quelconque des revendications 6 à 11, caractérisée en ce que le dérivé de rhéine est associé à un anti-inflammatoire non stéroïdien (AINS) ou à un inhibiteur de COX-2.12. Use according to any one of claims 6 to 11, characterized in that the rhein derivative is associated with a non-steroidal anti-inflammatory drug (NSAID) or with a COX-2 inhibitor.
13. Utilisation selon l'une quelconque des revendica- tions 6 à 12, caractérisée en ce que le traitement est destiné à soigner ou prévenir les rejets de transplants.13. Use according to any one of claims 6 to 12, characterized in that the treatment is intended to treat or prevent rejection of transplants.
14. Utilisation selon l'une quelconque des revendications 6 à 12, caractérisée en ce que le traitement est destiné à la prévention et à l'inhibition des effets du stress sur les cellules et les tissus. 14. Use according to any one of claims 6 to 12, characterized in that the treatment is intended for the prevention and inhibition of the effects of stress on cells and tissues.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0209340A FR2842738B1 (en) | 2002-07-23 | 2002-07-23 | USE OF A RHEINE FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OF CHRONIC INFLAMMATION, THE PREVENTION AND TREATMENT OF REJECTION OF ORGAN AND TISSUE TRANSPLANTATION |
| FR0209340 | 2002-07-23 | ||
| PCT/FR2003/002286 WO2004010990A1 (en) | 2002-07-23 | 2003-07-18 | Use of a rhein in a therapeutic treatment requiring a rise in the rate of heme oxygenase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1523312A1 true EP1523312A1 (en) | 2005-04-20 |
Family
ID=30011416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03750824A Withdrawn EP1523312A1 (en) | 2002-07-23 | 2003-07-18 | Use of a rhein in a therapeutic treatment requiring a rise in the rate of heme oxygenase |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20060058392A1 (en) |
| EP (1) | EP1523312A1 (en) |
| JP (1) | JP2005538098A (en) |
| AU (1) | AU2003269037A1 (en) |
| CA (1) | CA2493074A1 (en) |
| FR (1) | FR2842738B1 (en) |
| IL (1) | IL166434A0 (en) |
| MX (1) | MXPA05000904A (en) |
| WO (1) | WO2004010990A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI473610B (en) * | 2008-10-28 | 2015-02-21 | Twi Biotechnology Inc | Pharmaceutical compositions containing diacerein |
| AR078101A1 (en) * | 2009-08-20 | 2011-10-12 | Anchen Lab Inc | METHODS FOR DIAGNOSING THE DIABETES AND DETERMINING THE EFFECTIVENESS OF TREATMENTS |
| US8652540B2 (en) * | 2012-06-04 | 2014-02-18 | Hong Kong Baptist University | Method of using rhein for treating fibrotic conditions and tumors |
| JP6887987B2 (en) * | 2015-08-17 | 2021-06-16 | ティダブリューアイ・バイオテクノロジー・インコーポレイテッドＴＷＩ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ， Ｉｎｃ． | Diaselein or an analog thereof for inhibiting ASC expression, NLRP3 expression, and / or the formation of the NLRP3 inflammasome complex. |
| TW201739448A (en) * | 2016-05-06 | 2017-11-16 | 安成生物科技股份有限公司 | Methods and formulations for treatment and/or prevention of blood-associated disorders |
| EP3570835B1 (en) * | 2017-01-19 | 2023-08-09 | TWI Biotechnology, Inc. | Diacerein for preventing or treating immunoinflammatory dermal disorders |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA761627B (en) * | 1976-03-16 | 1978-01-25 | C Friedmann | Improvements in or relating to the treatment of arthritis |
| JPH0374326A (en) * | 1989-08-17 | 1991-03-28 | Tsumura & Co | Chemiluminescence inhibitor |
| CA2132690A1 (en) * | 1994-09-22 | 1996-03-23 | Dean Willis | Control and modulation of inflammatory response in humans in need of such control and modulation |
| US5652265A (en) * | 1995-03-29 | 1997-07-29 | Wisconsin Alumni Research Foundation | Production of rhein and rhein derivatives |
| IT1283771B1 (en) * | 1996-07-31 | 1998-04-30 | Medidom Lab | PROCEDURE FOR THE PREPARATION OF REINA DERIVATIVES |
| JP4049406B2 (en) * | 1996-10-15 | 2008-02-20 | 正規 小菅 | Tsu fluid improving agent and composition for oral administration containing the same |
| NZ500287A (en) * | 1997-04-11 | 2002-10-25 | Sangstat Medical Corp | Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation |
| CN1086289C (en) * | 1997-09-30 | 2002-06-19 | 中国人民解放军肾脏病研究所 | Medicine for treating diabetes and nephrosis containing rheinic acid |
| PT1917966E (en) * | 1998-02-13 | 2010-03-17 | Nutramax Lab Inc | Agents and methods for protection, treatment and repair of connective tissue |
| WO2000012118A2 (en) * | 1998-08-28 | 2000-03-09 | President And Fellows Of Harvard College | Inhibiting cardiomyocyte death |
| JP2000119182A (en) * | 1998-10-09 | 2000-04-25 | Nippon Chemiphar Co Ltd | Hemoxygenase induction promoter |
| CA2355066A1 (en) * | 1998-12-17 | 2000-06-22 | Sangstat Medical Corporation | Extending graft survival by heme oxygenase-i expression induced immunomodulation |
| JP3860752B2 (en) * | 2000-03-17 | 2006-12-20 | 利男 田中 | Heme oxygenase-1 induction or induction enhancer |
| US6610750B1 (en) * | 2000-09-15 | 2003-08-26 | Laboratoires Negma | Treatment of osteoarthritis |
| US20020128317A1 (en) * | 2001-01-23 | 2002-09-12 | Laboratories Negma | Treatment of pathological conditions characterized by an increased IL-1 level |
-
2002
- 2002-07-23 FR FR0209340A patent/FR2842738B1/en not_active Expired - Fee Related
-
2003
- 2003-07-18 MX MXPA05000904A patent/MXPA05000904A/en not_active Application Discontinuation
- 2003-07-18 US US10/522,035 patent/US20060058392A1/en not_active Abandoned
- 2003-07-18 AU AU2003269037A patent/AU2003269037A1/en not_active Abandoned
- 2003-07-18 EP EP03750824A patent/EP1523312A1/en not_active Withdrawn
- 2003-07-18 WO PCT/FR2003/002286 patent/WO2004010990A1/en active Application Filing
- 2003-07-18 JP JP2004523858A patent/JP2005538098A/en active Pending
- 2003-07-18 CA CA002493074A patent/CA2493074A1/en not_active Abandoned
-
2005
- 2005-01-20 IL IL16643405A patent/IL166434A0/en unknown
Non-Patent Citations (5)
| Title |
|---|
| DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Database accession no. 1989:624957 * |
| DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1989, LU M ET AL: "Biochemical study of Chinese rhubarb. xxx. Immunosuppressive effects of anthraquinone derivatives", Database accession no. EMB-1989263837 * |
| JOURNAL OF CHINA PHARMACEUTICAL UNIVERSITY 1989 CN, vol. 20, no. 4, 1989, pages 223 - 226, ISSN: 1000-5048 * |
| LU MING ET AL.: "Biochemical study of Chinese rhubarb XXX.", ZHONGGUO YAOKE DAYUE XUEBAO, 1989, Ohio * |
| See also references of WO2004010990A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IL166434A0 (en) | 2006-01-15 |
| JP2005538098A (en) | 2005-12-15 |
| AU2003269037A1 (en) | 2004-02-16 |
| FR2842738A1 (en) | 2004-01-30 |
| FR2842738B1 (en) | 2006-02-10 |
| MXPA05000904A (en) | 2005-03-23 |
| WO2004010990A1 (en) | 2004-02-05 |
| CA2493074A1 (en) | 2004-02-05 |
| US20060058392A1 (en) | 2006-03-16 |
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