Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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 invention relates to novel pharmaceutical compositions. More particularly it is provided, according to the invention, pharmaceutical compositions comprising as active at least one cytotoxic agent and at least cholest-4-en-3-one oxime or one of these derivatives.
• the main drugs used in cancer chemotherapy can be classified according to their activity. The following are defined: cytotoxic agents;
• hormones and / or agents blocking the secretion of hormones or antagonists
• cytotoxic agents are used to destroy all cancer cells.
• cytotoxic agents interact with cellular Desoxyribonucleic Acid (DNA) or its precursors: they inhibit DNA synthesis or induce irreparable damage to DNA. Some cytotoxic agents act after the transcription phase: they interact with proteins and enzymes involved in proliferation / cell division. Cytotoxic drugs are not specific for cancer cells, they also act on normal cells. It is from this non-specificity that their toxicity results. Furthermore, in the present text, the term "cytotoxic agent” should be understood as a cytotoxic agent, advantageously anticancer, possibly inducing in the patient symptoms of peripheral neuropathies and / or damage to the nervous system.
• DNA Desoxyribonucleic Acid
• cytotoxic agents act after the transcription phase: they interact with proteins and enzymes involved in proliferation / cell division. Cytotoxic drugs are not specific for cancer cells, they also act on normal cells. It is from this non-specificity that their toxicity results. Furthermore, in the present text, the term "cytotoxic agent” should be understood as a cytotoxic agent, advantageously anticancer, possibly induc
• peripheral neuropathies is meant in the sense of the invention the various medical conditions of the peripheral nerve, excluding the attacks of the anterior horn of the spinal cord. Peripheral neuropathies are distinguished into three major groups:
• the clinical signs include amyotrophy, cramps, fasciculations and motor deficit, anesthesia, tactile or proprioceptive hypoesthesia, ataxia, hypoalgesia, painful anesthesia, thermal hypoaesthesia, paresthesia, dysaesthesia, hyperpathia, hyperalgesia, allodynia, isfléxia, hyporeflexia (Stojkovic, Journal of Internal Medicine 27, (2006) 302-312),
• Peripheral neuropathies may be, among other things, caused by the cytotoxic agents used in cancer treatments.
• peripheral neuropathies can disappear sometimes when the taking of said drugs is stopped. However, it may take several weeks or even months to see an improvement.
• cytotoxic agents particularly cytotoxic agents anticancer, whether treatment combination with said anticancer treatment, in the form of a single composition comprising the cytotoxic agent and the agent treating the symptoms of peripheral neuropathies and / or the damage caused to the nervous system by said agents or in the form of different compositions administered in simultaneous or successive ways.
• cytotoxic agents in particular lead to limitation in the main treatment and in the expected benefit (Wickham, Clinical Journal of Oncology Nursing, 11, (3), (2007), 361-376).
• composition according to the invention has been developed for this purpose according to the following criteria: - reduction of the peripheral neuropathies-type side effects generated by the cytotoxic agent;
• the present invention responds to this demand. It offers decisive advantages. Indeed, the new pharmaceutical compositions of the invention have a cytotoxic activity related to the amount of cytotoxic agent present in the composition and delay the occurrence of peripheral neuropathies and / or reduce the pain sensation induced by said cytotoxic agent used.
• cytotoxic agents particularly those used as anticancer agents
• the peripheral neurotoxicity of cytotoxic agents may decrease considerably when said cytotoxic agents are administered to the organism in the form of a composition comprising said cytotoxic agent and at least cholest-4-en-3-one oxime or a the family of choiest-4-en-3-one oxime.
• the invention firstly relates to a composition, particularly a pharmaceutical composition, comprising at least one cytotoxic agent, particularly a cytotoxic anticancer agent and / or inducing in the patient symptoms of peripheral neuropathies and / or damage to the nervous system, preferentially an anticancer cytotoxic agent inducing in the patient symptoms of peripheral neuropathies and / or damage to the nervous system and at least cholest-4-en-3-one oxime or one of these derivatives.
• cytotoxic agent particularly a cytotoxic anticancer agent and / or inducing in the patient symptoms of peripheral neuropathies and / or damage to the nervous system
• an anticancer cytotoxic agent inducing in the patient symptoms of peripheral neuropathies and / or damage to the nervous system and at least cholest-4-en-3-one oxime or one of these derivatives.
• a surprising aspect of the invention is that the decrease in peripheral neurotoxicity has been shown with different anticancer agents, which are known to have a different mechanism of action against cancer, as well as their driving mechanism. at the onset of peripheral neuropathies (Wickham, Clinical Journal of Oncology Nursing, 11, (3), (2007), 361-376).
• An advantageous aspect of the invention lies in the fact that said pharmaceutical composition makes it possible to prevent and / or treat peripheral neuropathies without modifying the effectiveness of the cytotoxic agent.
• the composition may comprise as cytotoxic agent at least one anti-cancer cytotoxic agent, possibly having as an undesirable side effect peripheral neuropathies. It is understood that the composition according to the invention may comprise as cytotoxic agent, several cytotoxic agents, particularly anticancer agents and / or having as undesirable side effect peripheral neuropathies, and very particularly anti-cancer cytotoxic agents having as an undesirable side effect peripheral neuropathies, or still the mixture of at least one such agent with at least one other cytotoxic agent, possibly anticancer but not having as undesirable side effect peripheral neuropathies.
• the cytotoxic agent included in the composition according to the invention may be an anticancer cytotoxic agent and / or having as an undesirable side effect peripheral neuropathies, and very advantageously an anticancer cytotoxic agent having as an undesirable side effect peripheral neuropathies.
• composition particularly the pharmaceutical composition, according to the invention may comprise one or more compounds of the family of cholest-4-en-3-one oxime.
• cytotoxic agent particularly a cytotoxic anticancer agent known to cause peripheral neuropathies
• platinum derivatives in particular cisplatin and its derivatives, such as carboplatin and oxaliplatin
• the alkaloids of the periwinkle vinca alkaloids
• vinblastine vincristine
• vindesine vinorelbine
• taxanes such as paclitaxel or docetaxel.
• these agents are used in a preferred manner according to the invention. As indicated above, these agents can be used according to the invention, alone or together with each other or associated with another cytotoxic agent, particularly a cytotoxic anticancer agent, very particularly with at least one other cytotoxic agent, particularly another cytotoxic anti-cancer agent. not presenting as peripheral effect of peripheral neuropathies.
• composition according to the invention comprises, as active principle in addition to the cytotoxic agent (s), at least one compound corresponding to formula I 1, in particular the oxime of cholest-4-en-3 -one.
• cytotoxic agent s
• compounds of formula I particularly cholest-4-en-3-one oxime and their derivatives which diminish or treat peripheral neuropathies, are described in international applications WO 2004/082581 and WO 2007/080270.
• the invention relates to a composition, particularly a pharmaceutical composition, characterized in that it comprises at least: a compound of formula I in which
• R represents a group chosen from
• A represents a hydrogen atom or together with B a carbon-carbon bond
• B represents a hydrogen atom, a hydroxyl group or together with a carbon-carbon bond
• D represents a hydrogen atom or together with C a carbon-carbon bond
• E represents a hydrogen atom or together with F a carbon-carbon bond
• F represents a hydrogen atom or together with E a carbon-carbon bond, or one of its addition salts with pharmaceutically acceptable acids, or one of its esters or one of the addition salts with the pharmaceutically acceptable acids of said esters, and at least one cytotoxic agent, particularly a cytotoxic anticancer agent.
• the addition salts with pharmaceutically acceptable acids may be for example salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic or glyoxylic acids.
• aspartic, alkane sulfonic acids such as methane or ethanesulphonic, arylsulphonic acids, such as benzene or para-toluene sulfonic acids, or carboxylic acids.
• esters is meant according to the invention the oxime esters which can be prepared by techniques known to those skilled in the art, for example by an esterification reaction between an acid and hydroxy-imine (or oxime).
• oxime esters there may be mentioned acetates, propionates, oxalates, succinates, tartrates, fumarates, malonates, or methanesulphonates, ethanesulphonates or phosphates.
• oxime esters may also represent hydrolysable esters in vivo for example metabolically.
• the oxime group represents the two isomers syn and anti in mixture or one or the other isolated.
• R has the meaning R2 or R3 or R4,
• E represents together with F a double bond
• C, D, A, B represent a hydrogen atom and R has the meaning R1, or one of its addition salts with acceptable acids, or one of its esters or one of the addition salts with the acceptable acids of said esters.
• the compound of formula I may be chosen from cholestan-3-one oxime, cholest-4-en-3-one oxime and cholest-1 oxime.
• 4-dien-3-one most preferably the oxime of cholest-4-en-3-one, or the oxime of cholest-1,4-dien-3-one or one of their addition salts with pharmaceutically acceptable acids, or an ester thereof, or an ester of the addition salts.
• the compound of formula I used according to the invention is the oxime of cholest-4-en-3-one. It is understood according to the invention that the oxime group represents the two isomers syn and anti in mixture or isolated.
• the cytotoxic agent, particularly the anticancer cytotoxic agent, very particularly the agent having as undesirable side effect of peripheral neuropathies may be an agent chosen from all the known cytotoxic agents, particularly cytotoxic anticancer agents, more particularly the agents with undesirable side effect of peripheral neuropathies.
• cytotoxic agents particularly cytotoxic anticancer agents, more particularly the agents with undesirable side effect of peripheral neuropathies.
• cytotoxic agents particularly cytotoxic anticancer agents, more particularly the agents with undesirable side effect of peripheral neuropathies.
• cisplatin and its derivatives such as carboplatin and oxaliplatin
• vinca alkaloids such as vinblastine, vincristine, vindesine and vinorelbine
• taxanes such as docetaxel and paclitaxel.
• oxaliplatin carboplatin, cisplatin, vinblastine, vincristine or paclitaxel may be used according to the invention.
• oxaliplatin In a very preferred manner, according to the invention, oxaliplatin, vincristine or paclitaxel.
• cytotoxic agent having the adverse effect of peripheral neuropathies means any cytotoxic agent, particularly any cytotoxic anticancer agent which, during treatment, causes peripheral neuropathies in the patient.
• composition according to the invention may be in various forms, for example a single composition comprising the various compounds used according to the invention, but also in the form of two or more compositions each comprising at least one of the different compounds used according to the invention. invention, that said compositions are administered simultaneously or successively.
• the composition will be understood as a single composition comprising at least the two compounds used according to the invention.
• pharmaceutical composition is meant in the present invention, a composition whose components are pharmaceutically acceptable.
• the components are suitable or acceptable for oral administration.
• the compounds can be advantageously present at physiologically effective doses.
• the cytotoxic agent and / or the cholest-4-en-3-one oxime or one of these derivatives may each be in the composition in a quantity between 0.1 and 2000 mg / ml.
• the cytotoxic agent and / or the oxime of cholest-4-en-3-one or one of these derivatives may be in the composition in a ratio cytotoxic agent / cholest-4-en-3-one oxime or derivatives, ranging from 0.1 to 300.
• the cytotoxic agent and / or the oxime of cholest-4-en-3-one or one of these derivatives can each be in the composition in an amount of between 0.degree. , 1 and 2000 mg / ml and in a cytotoxic agent / oxime ratio of cholest-4-en-3-one or derivatives, between 0.1 and 300.
• a composition comprising cholest-4-en-3-one oxime and oxaliplatin a composition comprising cholestoxime. 4-en-3-one and vincristine or a composition comprising oxime of cholest-4-en-3-one and paclitaxel.
• composition according to the present invention can be used in mammals, more specifically in humans.
• the compounds of the composition may be in a common galenic form.
• each of the compounds of the composition may be in a galenical form identical to that of the other compound or different.
• the compounds of the composition when according to the invention, they are in a common galenic form, they will be administered simultaneously and according to the same route of administration.
• each of the compounds of the composition when, according to the invention, each of the compounds of the composition is in a galenical form identical to that of the other compound, or different, they can be administered either simultaneously or successively, in accordance with identical or different administration.
• the cytotoxic agent can be administered daily or with a lapse of time less than or greater than one day between two doses, this time being able to vary during the treatment.
• the compound of formula I may be taken daily, before, during or after taking anticancer drugs, or before, during and after, or before and during, before and after, or during and after taking the cytotoxic agent. It can also be envisaged that the cytotoxic agent is changed during the treatment of the same patient, in order to obtain an optimized anti-cancer effect.
• the oxime of cholest-4-en-3-one or one of these derivatives, particularly the compounds corresponding to formula I, their esters, their addition salts with pharmaceutically acceptable acids as well as that the addition salts with the pharmaceutically acceptable acids of said esters can be formulated for the digestive or parenteral route.
• the medicaments according to the invention may also comprise at least one other therapeutically active ingredient, whether it is active on the same pathology or on a different pathology, for simultaneous, separate or spreading use over time, in particular during a treatment in a subject with cancer.
• the composition may further comprise one or more excipient (s) or vehicle (s) physiologically acceptable, inert (s), that is to say pharmaceutically inactive and non-toxic.
• excipient s
• vehicle s
• physiologically acceptable, inert s
• the compositions according to the invention may contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc.
• compositions according to the invention can be formulated in the form of an injectable suspension, gels, oils, tablets, suppositories, powders, capsules, capsules, etc., possibly by means of galenic forms or devices providing sustained and / or delayed release.
• an agent such as cellulose, carbonates or starches is advantageously used.
• one of the active compounds of the composition according to the invention is formulated in an injectable solution, while the other (s) is (are) in a form, for example, of capsule for oral administration.
• the administration may be carried out by any method known to those skilled in the art, preferably orally or by injection, typically intraperitoneal, intracerebral, intrathecal, intravenous, intra-arterial, intravenous. -muscle or subcutaneous.
• the anticancer agent will be administered intravenously and the compound of formula I will be administered orally.
• the compounds are generally packaged as liquid suspensions, which can be injected by means of syringes or infusions, for example. It is understood that the flow rate and / or the injected dose, or in general the dose to be administered, may be adapted by those skilled in the art depending on the patient, the pathology, the mode of administration, etc. It is understood that repeated administrations can be performed, optionally in combination with other active ingredients and / or any pharmaceutically acceptable carrier (buffers, saline, isotonic, in the presence of stabilizing agents, etc.).
• the invention is usable in mammals, especially in humans.
• the daily doses of the compounds will be the minimum doses to obtain the desired therapeutic effect.
• the doses will depend on multiple factors, in particular the route of administration, the duration of administration, the timing of administration, the rate of removal of the compound, the or various products used in combination with the compound the patient's age, weight, physical condition, medical history, and other information known in medicine.
• Doses of anticancer compounds and compounds of formula I and for example cholest-4-en-3-one oxime will generally be in the range of 0.001 to 100 mg per kilogram per day for humans.
• the daily dose may be administered in two, three, four, five, six or more doses taken daily or in multiple sub-doses administered at appropriate intervals during the day. It is also understood that the anticancer treatment may correspond to a non-daily intake, as is usually done with the anticancer compounds of the invention.
• the subject of the invention is also the use of the composition according to the invention for the manufacture of a cytotoxic drug intended to treat cancer while preventing and / or treating the peripheral neuropathies-type peripheral effects caused by the anticancer treatment.
• the subject of the invention is also the use of the composition according to the invention for the manufacture of a cytotoxic drug intended to prevent and / or treat the peripheral neuropathy-type side effects caused by the anticancer treatment.
• Another object is a method for preventing the occurrence of peripheral neuropathies-type side effects during anticancer treatments, by applying a composition according to the invention.
• the subject of the invention is also the use of at least the oxime of cholestasis.
• the invention further relates to a pharmaceutical kit for the treatment of cancer, including at least one cytotoxic anticancer compound and at least one compound of formula I.
• Example 1 Effect of cholest-4-en-3-one oxime on vincristine sulfate-induced neuropathies.
• Methods Wistar adult male rats of approximately 250 g were used.
• the vincristine sulphate was injected intravenously at 200 ⁇ g / kg on days 1, 4 and 6 (cumulative total dose of 600 ⁇ g / kg).
• the thresholds of elongation of the animal's paw to non-harmful mechanical stimulation were measured in the rats on days 0, 3, 5, 7 and then every day from day 10 to day 14.
• the cholest 4-en-3-one (10, 30 and 100 mg / kg once daily) was administered orally from day 10 to day 14 and the tabulation thresholds of the paw were measured 4h after administration of cholest-4-en-3-one oxime. 8 rats were used per dose tested.
• a stock solution of cholest-4-en-3-one oxime in corn oil was prepared on the first day of the experiment and administered once daily by oral gavage (5 ml / kg).
• the oxime of cholest-4-en-3-one was reduced to a fine powder and mixed with the necessary amount of vehicle to obtain concentrations of 0.2, 6 and 20 mg / ml, the whole is then homogenized by magnetic stirring for at least 10 minutes. Inventory solutions were stored at 4 ° C between administrations.
• Statistical analysis was performed using a two-way ANOVA followed by a Tukey test to compare the effect of the test compound with the vehicle.
• Example 2 Effect of cholest-4-en-3-one oxime on hypersensitivity painful in a rat model with paclitaxel-induced neuropathies.
• Paclitaxel (6 mg / ml in a 50:50 mixture of Cremophor and ethanol) was diluted just before use with 0.9% sodium chloride solution at a concentration of 2 mg / ml and injected intraperitoneally into the plasma. a volume of 1 ml / kg on days 0, 2, 4 and 6.
• Fresh solutions of cholest-4-en-3-one oxime (Sigma) in corn oil were prepared weekly at a concentration of 0.6 or 6.0 mg / ml. This solution was provided to the animal by oral gavage in a volume of 5ml / kg.
• Group 1 cholest-4-en-3-one oxime at 3 mg / kg orally, daily for 17 days (day -1) (day 15), starting the day before the first paclitaxel injection and continuing for 9 days after the last paclitaxel injection). On days when cholest-4-en-3-one oxime and paclitaxel had to be administered, cholest-4-en-3-one oxime was given at 9 o'clock, and paclitaxel at 1 o'clock; group 2: the same as above except that the cholest-4-en-3-one oxime is brought to 30 mg / kg;
• the animals were positioned in cages containing a metal wire floor giving access to the underside of the legs of the animals. Every stimulus mechanical was applied to the middle of the heel of the left hind paw. The presence or absence of removal of the paw was noted. This was repeated 5 times on each hind foot and the animal responses were summarized as a percentage of response (5 paw retractions at 15gVFH stimulation corresponded to a score of 50%).
• Rats were used to the test environment for 3 days. Sensitivity reference level tests at 4g and 15gVFH were performed for 3 consecutive days; the mean of the last two corresponded to the sensitivity level before paclitaxel treatment. Behavioral tests to test the effects of paclitaxel began on day 16 and were repeated on days 19, 22, 25, 28, 31, 35 and 40 by an experimenter who did not know the treatments applied to each animal.
• the paclitaxel-treated animals that received the vehicle developed mechanical pallodynia and significant mechanical hyperalgesia that became apparent on day 16 and persisted for 40 days of observation.
• Oxaliplatin was injected intraperitoneally at 3 mg / kg three times weekly and for three weeks (cumulative total dose 27 mg / kg). Paw elongation times as well as the amplitude of the animal's response to non-harmful thermal stimulation with acetone taste were measured in rats before and after treatment with oxaliplatin days 1 and 18, respectively, and then each day of treatment with cholest-4-en-3-one oxime, from day 22 to day 25.
• Cholest-4-en-3-one oxime ( 1, 10 and 100 mg / kg once daily) was administered orally from day 22 to day 25 and the tabulation thresholds of the paw were measured 4 hours after the administration of cholest-4 oxime. en-3-one. 7 to 9 rats were used per dose tested.
• the reaction time at which the animals withdraw their hind paw following the deposition of the drop of acetone was calculated as the average of six consecutive tests carried out at 5-minute intervals by an experimenter ignoring the treatments applied to each animal. animals. A limit of 20 seconds has been imposed.
• the amplitude of the acetone drop response was scored on a scale of 0 to 3: 0 (no response); 1 (rapid withdrawal of the paw); 2 (prolonged withdrawal of the paw); 3 (repeated withdrawal of the paw with licking and / or bite). The score of each of the six tests was cumulated.
• a stock solution of cholest-4-en-3-one oxime in corn oil was prepared on the first day of the experiment and administered once daily by oral gavage (5 ml / kg).
• the oxime of cholest-4-en-3-one was reduced to a fine powder and mixed with the necessary amount of vehicle to obtain concentrations of 0.2, 2 and 20 mg / ml, the whole is then homogenized by stirring. magnetic for at least 10 minutes. Inventory solutions were stored at 4 ° C between administrations.
• a statistical analysis was performed using a two-way ANOVA followed by a Bonferroni test to compare the effect of the test compound with the vehicle.

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