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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P39/02—Antidotes
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• the present invention relates to the use of rosmarinic acid and its derivatives for the manufacture of a medicament for the treatment of fish poisoning by food, in particular ciguatera.
• Ciguatera is a form of ichthyosarcotoxism, that is, food poisoning by the flesh of fish contaminated with ciguatoxins (CTX) of the Gambierdiscus spp. Benthic microalgae found in coral reefs.
• CX ciguatoxins
• Ciguatoxins enter the food chain through coral grazing fish and herbivores grazing algae on which Gambierdiscus toxicus is attached. These fish are then the prey of omnivorous and carnivorous fish; toxins are accumulated along the food chain.
• large predatory fish such as barracuda, moray eels, grouper or jacks are the most likely to cause poisoning.
• Ciguatoxins are liposoluble polyethers, thermostable, low molecular weight, they are among the most powerful marine biotoxins since it is barely a microgram to kill a man.
• the purification and detection techniques by chromatography made it possible to isolate 39 different ciguatoxins. They vary according to their geographical origin (23 Pacific ciguatoxins or P-CTX, 12 Caribbean ciguatoxins or C-CTX and 4 Indian Ocean ciguatoxins or I-CTX), according to the fish species and according to their position in the food chain . Their molecular structures are not all yet elucidated.
• Ciguatoxins are neurotoxins whose action on potential-dependent sodium channels is responsible for the clinical manifestations observed during intoxication.
• CTXs act by keeping the sodium channels open at potential values where normally they should be closed, resulting in spontaneous and repetitive onset of action potentials.
• the opening of the sodium channels is responsible for a massive influx of sodium ions into the cell, causing swelling; this phenomenon is particularly visible at the Ranvier nodes and at the axonal endings.
• Nerve manifestations result from this action of toxins, both on the motor and sensory nerves and on the neuro-motor junctions.
• the Cardiac and digestive manifestations of the disease are also dependent on the action of ciguatoxins on the sympathetic and parasympathetic nervous system.
• ciguatoxins is meant in particular, ciguatoxins of the Pacific or P-CTX-I to 23 of type 1 (Murata et al., 1989. J. Am Chem Soc., 111: 8929-31):
• Mannitol is a compound that has been studied for the treatment of ciguatera; administered 48 to 72 hours after intoxication, mannitol is described as being able to relieve neurological and muscular disorders (Palafox et al, 1988, JAMA 259, 2740-2742, Blythe et al, 1994, Mem. , 465-470).
• blind clinical trials with mannitol and saline could not demonstrate a beneficial effect of mannitol on ciguatera symptoms after 24 hours (Schnorf et al., 2002, Neurol 58, 1155-1163). ); its effectiveness is therefore controversial.
• Tournefortia argentea Lf it was later named Argusia argentea (Lf) Heine and remained under this name until recently when it was renamed Tournefortia before being called Heliotropium in 2003 after molecular studies. It has also been listed under the scientific names Messerschmidia argentea (Lf) Johnston, T. arborea Blanco, T. sarmentosa sensu Non Christian Lam. and T.
• H. foertherianum also inhibits the swelling of human erythrocytes or frogs caused by ciguatoxin (Boydron et al, 2001, Meetings in Toxinology: Exploring, Exploiting Toxins and Controlling Producing Organisms, Scientific and Medical Editions Elsevier, Paris, pp. 63 -6 and Boydron et al, 2002, Meetings in Toxinology: Toxins and Biomedical Research, Elsevier Scientific and Medical Publications, Paris, pp.
• the inventors continued research on H. foertherianum with the aim of identifying the substance capable of combating the symptoms of ciguatoxins.
• Structural analysis of the product is carried out by proton and carbon NMR and mass spectrometry; it allowed us to identify rosmarinic acid.
• the present invention thus relates to compounds of general formula
• R 1 to R 10 represent, independently of one another:
• Ci-C 6 acyl C 2 -C 6 alkyl or an aryl radical of C 3 -C 10;
• Z 1 selected from the group consisting of hydrogen, alkyl Ci-C 6 acyl, C 2 -C 6 alkyl, aryl C 3 - Ci 0 and a glycosyl radical;
• o a radical -COOZ 5 or a radical with Z 5 and Z 6 selected, independently of one another, from a hydrogen atom and a C 1 -C 6 alkyl radical; o a -CN function;
• two adjacent radicals selected from R 1 to R 5 or from R 6 to R 10 may together form a ring selected from the group consisting of phenyl, naphthyl, furanyl, thiophenyl, pyrrolyl and triazolyl;
• Xi to Xi 2 represent, independently of one another, a carbon atom or a nitrogen atom
• Z'i selected from the group consisting of hydrogen, alkyl CpC 6, a C 2 -C 6 acyl radical and an aryl radical C 3 -CiO ;
• a radical with Z ' 2 and Z' 3 selected, independently of each other, from the group consisting of a hydrogen atom, an oxygen atom, a nitrogen atom, a C 1 -C 6 alkyl radical a C 2 -C 6 acyl radical and a C 3 -C 10 aryl radical;
• radical -COOZ ' 4 or a radical with Z ' 4 selected from the group consisting of a hydrogen atom and a C 2 -C 6 acyl radical and Z' 5 selected from the group consisting of a hydrogen atom, a C 2 -C 6 acyl radical; and a C 3 -C 10 aryl radical;
• Z represents an oxygen atom or a chain -NZ 7 -, with Z 7 selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl radical and an aryl radical;
• W 1 and W 2 represent, independently of one another:
• the present invention also relates to the use of the compounds as defined above for the preparation of a pharmaceutical composition intended for the prevention and / or treatment of disorders caused by poisoning with ciguatoxins.
• the compounds of general formula (I) that are the subject of the present invention are especially used after having been isolated, for example, from plant extracts; they can also be obtained isolated after a chemical synthesis.
• Halogen atom means the chemical elements of group VII of the Periodic Table of Elements, in particular fluorine, chlorine, bromine and iodine.
• C1-C alkyl-alkyl radical means a linear or branched hydrogen-carbon radical of 1 to 6 carbon atoms.
• C 2 -C 6 acyl radical is meant a radical R JL R ', comprising 2 to 6 carbon atoms, R being an alkyl chain with m carbon atoms, m between 0 and 4, and R' a radical alkyl with n carbon atoms, n between 1 and 5, and such that m + n is between 1 and 5.
• chain or alkyl radical is meant respectively a linear or branched chain or a hydrogenocarbon radical.
• C 3 -C 10 aryl radical is meant a mono- or bicyclic aromatic radical of 3 to 10 carbon atoms.
• the aryl radicals in C 3 -C O are selected from the group consisting of pyrrole, thiophene, furan, oxazole, isoxazole, thiazole, imidazole, pyrazole pyridinyl, pyrimidinyl, guanyl, naphthyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl.
• glycosyl radical is meant a monomer or dimer of residues glycosyl, mannosyl, glucuronyl, glucosamine and mannosamine.
• the compounds of general formula (I) are such that:
• - Xi to Xj 2 represent a carbon atom
• Y 1 and Y 2 represent a hydrogen atom.
• a compound of general formula (I) which is preferred according to the invention is rosmarinic acid.
• Rosmarinic acid ((R) -a - [[3- (3,4-Dihydroxyphenyl) -1-oxo-2E-propenyl] oxy] -3,4-dihydroxybenzenepropanoic acid, molecular weight 360 and crude chemical formula Ci S Hi 6 O 8 ) is a polyphenolic compound of structure:
• Rosmarinic acid can also be produced by a biotechnological plant cell culture method (Hippolyte et al., 1992, 1. Plant Cell Rep.11, 109-112) or be isolated from plants (Lu et al., 1999 Phytochemistry 51, 91-94, Zgorka et al., J. J. Pharmaceut, Biomed 26, 79-87.).
• This compound is known to present biological activities of interest: antiviral, antibacterial, anti-inflammatory and antioxidant (Petersen et al, 2003,
• the compounds of general formula (I) can be synthesized by peptide coupling (obtaining ester and amide analogues) between carboxylic acid units and alcohol / amine units as described by See-Hyoung Park et al. (Bioorganic and Medicinal Chemistry Letters 2003, 12 (20), 3455-3459). Disorders caused by poisoning with ciguatoxins are of several types:
• Neurological signs that specifically target the central nervous system include cerebellar syndromes (cerebellar ataxia may be observed with disturbances of coordination and balance), central nervous system involvement, chronic fatigue (asthenia, lethargy, sleep disturbances with nightmares, early awakenings, intolerance to exercise, lack of motivation, various pains, etc.), headaches, dizziness, dizziness, visual or auditory hallucinations
• Those targeting the peripheral nervous system most commonly include paresthesia (tingling, numbness, tingling) that are observed mainly in the extremities, the face (perioral, labial, lingual, pharyngeal); dysaesthesia, which are also frequent and considered as one of the most suggestive signs of ciguatera: the patient complains of burning sensations or electric shocks when in contact with cold objects; Ataxia can also be mentioned.
• paresthesia tingling, numbness, tingling
• dysaesthesia which are also frequent and considered as one of the most suggestive signs of ciguatera: the patient complains of burning sensations or electric shocks when in contact with cold objects; Ataxia can also be mentioned.
• myalgia myalgia
• arthralgia especially large joints, especially the knees, ankles, shoulders and elbows.
• Pruritus is one of the main symptoms of ciguatera, so much so that it gave its name to the disease in New Caledonia: "the guitar". It is the palms of the hands and the soles of the feet that are most often affected. Pruritus can sometimes be generalized, especially after ingestion of alcohol or following a significant physical exercise, ie when the cutaneous blood flow is increased. The itching can be very severe and cause scratching lesions with their lot of complications: excoriations, abscesses, cellulitis, scars, lichenification.
• the compounds and / or the pharmaceutical compositions according to the invention are more particularly intended to treat diffuse abdominal pain and / or nausea and vomiting and / or diarrhea and / or cerebellar syndrome and / or chronic fatigue and / or headache and / or vertigo and / or dizziness and / or visual or auditory hallucinations and / or paresthesia and / or dysesthesia and / or disorders of swallowing and / or convulsions and / or disturbances of consciousness and / or coma and / or respiratory function paralysis and / or sinus bradycardia less than 60 / min and / or arterial hypotension and / or orthostatic hypotension and / or myalgia and / or arthralgia and / or pruritus and / or rash.
• the amount of compound of general formula (I) and in particular rosmarinic acid to be administered to the mammal depends in particular on the severity of the pathology and symptoms to be treated, resulting in particular from the amount of ciguatoxin absorbed and the route by which it has been, it finally depends on the age and weight of the individual to be treated.
• rosmarinic acid is not very toxic, it can be administered in high concentration.
• the daily dose of rosmarinic acid or its derivative is between 0.1 mg and 1 g, preferably between 5 and 500 mg, taken in 1 to 3 times.
• composition comprising a compound of general formula (I) may be suitable for oral, parenteral, pulmonary, ocular, nasal administration.
• the present invention will be better understood using the additional description which follows, which refers to examples of isolation and characterization of rosmarinic acid as the active ingredient of H. foertherianum and the evaluation of its activity against the effects of ciguatoxins; and the appended figures in which:
• FIG. 1 is a graph showing the cellular viability of neuroblastomas in the presence of ciguatoxins contained in samples of toxic giant clam (GPS59) at 100 ⁇ g / ml with or without rosmarinic acid (in a range of 10 to 1000 ⁇ g / ml).
• Figure 2 is the competition curve between radioligand ([ 3 H] -PbTx-
• the active ingredient of / f. foertherianum was isolated by bioguided chemical fractionation.
• Yellified leaves to H. foertherianum were harvested at the foot of a tree in the coastal region of New Caledonia (Anse Vata, Nouméa).
• the remedy is prepared according to the method usually used (Laurent et al, 1993). Briefly, 200 g of yellowing leaves are boiled in 1 liter of water for 30 minutes. The solution (about 750 ml) is then filtered and lyophilized to give 7.934 g of crude extract. 7.8 g are then redissolved in water and partitioned with n-butanol. 500 mg of the butanol phase are chromatographed on a silica column and eluted with 6 mixtures of dichloromethane and methanol of increasing polarity. The active principle (approximately 360 mg) is eluted mainly (90%) at CH 2 Cl 2 MeOH.
• the structural analysis of the product is carried out by proton and carbon NMR using a Brucker ARX400 spectrometer.
• the mass spectrum is obtained on a Perkin Elmer API Sciex triple quadrupole spectrophotometer equipped with electrospray.
• the compound was identified as rosmarinic acid by comparison of mass spectral and NMR data with those of a control compound and those of the literature.
• LD50 of rosmarinic acid was determined after injection of intravenous (iv) solution at 531 mg / kg in mice (Sigma-Aldrich record, derived from Petersen, 2003. Reference: Parnham, MJ, Kesselring, K., 1985. Rosmarinic Acid Drugs of the Future 10, 756-757.
• the salmon lamb sample (Refl5) supplied by the Louis Malardé Institute, was collected at Mururoa (Tuamotu Archipelago, French Polynesia).
• the giant clam sample (GPS59) was collected at Raivavae (Austral Islands, French Polynesia). The toxicity of these two samples was previously confirmed on mouse, by a cytotoxicity test on neuroblastomas and radioligand tests with P-CTX-3.
• 96-well plates are prepared with a number of 50,000 cells in 100 ⁇ l of medium per well. Outer wells are not used, to avoid variations in response due to edge effects. The cells are incubated for 24 hours at 37 ° C. with 5% CO 2 to give them time to adhere.
• Ouabain is an inhibitor of Na / K ATPase, and veratridine, an activator of sodium channels.
• the joint action of these two products induces a high intracellular level of sodium and causes an alteration of the morphology of the cells which significantly reduces their viability.
• the induction by these two compounds of sensitization to the toxins acting on the sodium channels makes it possible to visualize the cytotoxicity of the toxins.
• LST loach
• GSP clam
• the acid rosmarinique is added at different concentrations (final concentration per well between 10 and 1000 ⁇ g / ml).
• Each well is supplemented with the culture medium in order to obtain a final volume of 200 ⁇ l.
• the cells are thus incubated at 37 ° C. and 5% CO 2 for 18 h.
• the wells are emptied of their medium and the plate is allowed to dry on absorbent paper in order to carry out the MethylThiazolyldiphenyl-Tetrazolium (MTT) bromide test.
• MTT MethylThiazolyldiphenyl-Tetrazolium
• the MTT assay is based on the ability of viable cells (mitochondrial succinate dehydrogenase) enzymes to convert the yellow tetrazolium salt to PBS insoluble formazan crystals.
• the formed formazan crystals are dissolved by means of 150 ⁇ l of DMSO (dimethylsulfoxide) for each well. After homogenization, the plates are read with a UV plate reader at 490 nm. Then data is transferred and processed in Excel® and analyzed with GraphPad software
• the graph of FIG. 1 shows the cytotoxicity measured by the cellular viability of a toxic fatty clam extract (GPS59) at 100 ⁇ g / ml in the presence or absence of rosmarinic acid at different concentrations (10 to 1000 ⁇ g / ml).
• This graph clearly shows the protective effect of rosmarinic acid, the effect of this compound significantly increases cell viability from 50 ⁇ g / ml. Similar results were observed with toxic salmoneal loach extract. On the basis of these results, it can be estimated that the IC50 of rosmarinic acid (concentration of rosmarinic acid to reduce by 50% the cell mortality caused by ciguatoxins and associated toxins) is between 0.5 and 1 mg / ml. IV.2. Displacement of the 3 H "
• Rat brain synaptosomes are prepared as previously described by Dechraoui et al. (1999, Toxicon 37 (1): 125-43). The protein concentration of the synaptosomal preparations is determined in duplicate by the Bradford method with bovine serum albumin as standard (Bradford, M.M., 1976, Anal Biochem 72: 248-254).
• the final concentration of protein is of the order of 120 ⁇ g / ml.
• the ligand-receptor interaction detection test is carried out in a tube with a final concentration of 1,1 nM tritiated [ 3 H] PbTx-3, according to the protocol of Darius et al. (Darius et al, 2007 Toxicon 50 (5), 612-626). Radioactivity is determined using a Perkin Elmer Microbeta Trilux 1450 scintillation counter in 2 ml counting vials of a Betaplate scintillation liquid (Perkin Elmer).
• the non-specific interaction is evaluated by measuring the radioactivity in the presence of a saturating [ 3 H] PbTx-3 (0.67 mM) concentration and subtracted from the total interaction to lead to the specific interaction.
• Ciguatoxin P-CTX-3C obtained from a clonal culture of Gambierdiscus polynesiensis is known to have a better affinity to the site of action than Brevetoxins; it has been used as an internal standard for sample calibration (Chinain et al, 1999, Darius et al, 2007).
• Two quality control tubes of radioligand experiments are used at each experiment; they are composed of a toxic extract of Gambierdiscus polynesiensis with a known concentration of P-CTX-3C ciguatoxin equivalent to 3.1 ⁇ g.
• L 5 IC 50 is defined as the concentration of extract capable to induce 50% inhibition of the interaction with [ 3 H] PbTx-3 and is expressed in equivalent mg / ml of extract.
• Figure 2 shows the competition curve between the radioligand ([ 3 H] -
• the level of rosmarinic acid is estimated at 1.2 mg / g of fresh leaves of Heliotropium foertherianum; for leaves of about 10 grams, a dozen mg of rosmarinic acid and for a remedy based on a decoction of 4 to 5 leaves, about fifty mg of this product.

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