CN116966184A - Application of itraconazole as analgesic - Google Patents

Application of itraconazole as analgesic Download PDF

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Publication number
CN116966184A
CN116966184A CN202210424298.3A CN202210424298A CN116966184A CN 116966184 A CN116966184 A CN 116966184A CN 202210424298 A CN202210424298 A CN 202210424298A CN 116966184 A CN116966184 A CN 116966184A
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itraconazole
pain
neuropathic pain
pharmaceutically acceptable
treatment
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马超
王涛
孙丰润
张崇敬
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Institute of Basic Medical Sciences of CAMS
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Institute of Basic Medical Sciences of CAMS
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to application of itraconazole as an analgesic. The invention relates to the use of itraconazole for producing a medicament for the treatment of neuropathic pain. The invention proves that itraconazole can effectively relieve mechanical pain and thermal pain caused by chronic neuropathic compression and improve pain threshold. The invention discloses the analgesic effect of itraconazole in neuropathic pain for the first time, and the application expands the application range of itraconazole on one hand and provides a new alternative medicament for the treatment of neuropathic pain on the other hand.

Description

Application of itraconazole as analgesic
Technical Field
The invention relates to the technical field of medicines, in particular to application of itraconazole as an analgesic in neuropathic pain.
Background
Itraconazole, the english name Itraconazole, is triazole. Itraconazole is first applied to clinic as an oral broad-spectrum antifungal agent, and the action mechanism of the itraconazole is that the itraconazole can be combined with isozymes of CYP450 to inhibit the demethylation of 14-a-lanosterol, thereby interfering the synthesis of ergosterol in fungal cell membranes and playing a role in bacteriostasis. The antibacterial spectrum comprises dermatophytes, candida, cryptococcus neoformans, aspergillus, saccharomycetes and other fungi, and is mainly applied to systemic infectious diseases caused by deep fungi. In recent years, researches show that itraconazole can inhibit the Hedehog and mTOR signaling pathways and has remarkable effect on tumor treatment.
Neuropathic pain refers to pain caused by damage or disease to the somatosensory system. Neuropathic pain can be caused by nerve compression, diabetes, neuroma, ion channel-related pathologies, cardiovascular disease, autoimmune disease, and the like. Neuropathic pain has a high incidence, and about 5% of the world's population suffers from neuropathic pain. Neuropathic pain can be classified into peripheral and central neuropathic pain according to the location of the injured neuron. The pathogenesis of neuropathic pain is complex, mainly including peripheral sensitization and central sensitization. Abnormal electrical signal conduction can be detected at both the axons of the damaged nerve and at nociceptors sites on neurons with which it is interacting. Typical characteristics of neuropathic pain are hyperalgesia, pain sensitization, spontaneous pain and allodynia. In the event of neuropathic pain, the associated ion channels located on the cell membrane, such as Na + 、Ca 2+ Channel expression and opening are increased, and the pain-associated marker receptor TRPV1 expression is up-regulated, accompanied by the phenomena of release and spontaneous discharge of some mediators such as substance P.
The common neuropathic pain types mainly refer to peripheral or central neuropathic pain caused by injuries of a sensory nervous system such as nerve/nerve root compression, nerve injury, diabetes, neuroma, ion channel related lesions, cardiovascular diseases or autoimmune diseases, and also are associated with trigger-induced pain, involvement pain, spontaneous pain such as burning sensation, thorn pain, extrusion feeling and the like, and the specific forms mainly include pain caused by chronic compression of the nerve root such as lumbar disc herniation and spine degeneration, primary or secondary trigeminal neuralgia, postherpetic neuralgia pain, neuropathic pain after peripheral nerve injury such as phantom limb pain and residual limb pain after cut-off, pain caused by multiple diseases such as diabetes mellitus and autoimmune diseases and the like, and central nervous pain such as stroke and spinal cord injury and the like.
Current clinical treatment strategies for neuropathic pain rely primarily on drug analgesia. Classical first-line drugs include tricyclic antidepressants such as pregabalin, gabapentin, and 5-hydroxytryptamine norepinephrine reuptake inhibitors such as venlafaxine, duloxetine, and the like. The peripheral neuropathic pain may be treated with an 8% capsaicin patch, a lidocaine patch, or a subcutaneous botulinum toxin type A. There is also evidence that tramadol and opioids such as morphine and the like have analgesic effects, but due to their great side effects, can cause respiratory depression, nausea and vomiting, have severe addiction and withdrawal properties, and are not generally recommended for chronic non-cancerous pain. The bupivacaine, lidocaine and other local anesthetics belong to voltage-gated sodium-controlled ion channel blockers, can stabilize the neural membrane, inhibit ectopic discharge, and can also be used for treating peripheral neuropathic pain, but the effect time is shorter, and the bupivacaine and lidocaine local anesthetics have cardiovascular and central nervous system side effects. In addition, carbamazepine and oxcarbazepine are useful as first line agents for the treatment of trigeminal neuralgia. In summary, although they have analgesic effects, the mechanisms of action of different drugs are different, the therapeutic effects and toxic and side effects are different, and many patients cannot effectively relieve pain under the tolerating doses, so that combination therapy is often adopted.
The analgesic effect of antifungal agents in neuropathic pain has not been reported. The invention discloses the analgesic effect of itraconazole in neuropathic pain for the first time, discovers the new application of itraconazole, and provides a new thought and method for treating neuropathic pain.
Disclosure of Invention
The invention aims to provide a novel therapeutic drug for neuropathic pain.
Accordingly, one aspect of the present invention provides the use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, in the manufacture of a medicament for the treatment of neuropathic pain.
Another aspect of the invention provides the use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, in combination with a non-steroidal anti-inflammatory drug, such as acetaminophen, ibuprofen, piroxicam, meloxicam, in the manufacture of a medicament for the treatment of neuropathic pain.
In another aspect the invention provides the use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, in combination with an amide and an ester local anesthetic, such as bupivacaine, lidocaine, ropivacaine, tetracaine, prilocaine and procaine, for the manufacture of a medicament for the treatment of neuropathic pain.
In another aspect the invention provides the use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, in combination with a tricyclic antidepressant, such as pregabalin, gabapentin, for the preparation of a medicament for the treatment of neuropathic pain.
In another aspect the invention provides the use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, in combination with other medicaments useful for the treatment of neuropathic pain, such as 5-hydroxytryptamine norepinephrine reuptake inhibitors like venlafaxine, duloxetine, or capsaicin, for the manufacture of a medicament for the treatment of neuropathic pain.
In some embodiments, the use according to the invention, wherein the pharmaceutical composition contains itraconazole or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers.
In other embodiments, the use according to the invention, wherein the pharmaceutically acceptable carrier comprises diluents, fillers, binders, disintegrants, granulating agents, lubricants, wetting agents, absorption enhancers, surfactants, adsorption carriers or sustained-release preparation carriers, sweeteners, flavoring agents, colorants and preservatives.
In other embodiments, the use according to the present invention, wherein the medicament is prepared in a desired dosage form, including tablets, troches, lozenges, suspensions, powders, granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal, pills, powders, ointments, pellets, drops, patches, injections, suppositories, sprays, and sustained release formulations.
In a preferred embodiment, the use according to the invention, wherein said neuropathic pain refers to peripheral or central neuropathic pain resulting from injuries to the sensory nervous system such as nerve/nerve root compression, nerve injury, diabetes, neuroma, ion channel-related pathologies, cardiovascular diseases or autoimmune diseases, further it may be accompanied by simultaneous triggering pain, involvement pain and spontaneous pain such as burning, stinging and squeezing.
In another preferred embodiment, the use according to the invention, wherein said neuropathic pain is selected from pain induced after chronic compression of nerve roots, such as lumbar disc herniation and spinal degeneration, primary or secondary trigeminal neuralgia, postherpetic neuralgia pain, neuropathic pain after peripheral nerve injury, such as phantom limb pain and stump pain after cut-off, pain caused by multiple diseases, such as diabetes and autoimmune diseases, and the like, and central neuropathic pain, such as stroke and spinal cord injury.
In another preferred embodiment, the use according to the invention, wherein itraconazole is administered at a daily dose of 1.6-30mg/kg, preferably 2.6-26mg/kg, by weight.
In some embodiments, the use according to the invention, wherein itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, is administered simultaneously, separately or sequentially with a non-steroidal anti-inflammatory drug.
In other embodiments, the use according to the invention, wherein itraconazole or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing same is administered simultaneously, separately or sequentially with an amide and an ester local anesthetic.
In other embodiments, the use according to the invention, wherein itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, is administered simultaneously, separately or sequentially with a tricyclic antidepressant.
In other embodiments, the use according to the invention, wherein itraconazole or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing same is administered simultaneously, separately or sequentially with other drugs useful in the treatment of neuropathic pain.
The Itraconazole of the invention has the English name of Itraconazole and is triazole compound, and the molecular formula of Itraconazole is C 35 H 38 C 12 N 8 O 4 The structural formula is as follows:
the free itraconazole is basic and can form an acid addition salt with any pharmaceutically acceptable acid. The acids include inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like.
The term "pharmaceutically acceptable salt" as used herein refers to salts of itraconazole, particularly acid addition salts as described above, which are safe and effective when used in mammals, and which possess the biological activity of itraconazole itself. Thus, the pharmaceutically acceptable salt may be the hydrochloride, hydrobromide, sulfate, phosphate, mesylate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, acetate, propionate, lactate, trifluoroacetate, maleate, citrate, fumarate, oxalate, tartrate, benzoate, and the like of itraconazole.
The "pharmaceutical composition" of the present invention means a mixture containing itraconazole or a pharmaceutically acceptable salt thereof as an active ingredient with other chemical components, which may be another or more drugs having physiological activities such as non-steroidal anti-inflammatory drugs, amides and ester local anesthetics, etc., and may be physiologically or pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Pharmaceutical compositions containing itraconazole or a pharmaceutically acceptable salt thereof as an active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring phospholipids such as lecithin, or synthetic products such as polyoxyethylene stearate, heptadecaethyleneoxycetyl alcohol, polyethylene oxide sorbitol monooleate and the like. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspending agent may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
The pharmaceutical composition may also be in the form of an emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, such as soy lecithin, or synthetic products such as sorbitan monooleate, polyethylene oxide sorbitol monooleate, and the like. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Sweeteners such as glycerin, propylene glycol, sorbitol or sucrose may be used. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical composition may also be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention.
The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
The "neuropathic pain" as used herein refers to a disease caused by injury to the sensory nervous system, and includes various pains caused by damage to the somatosensory system or diseases. It generally includes, but is not limited to, chronic compression pain such as lumbar disc herniation, trigeminal neuralgia, herpetic-induced neuralgia, and central nerve pain after stroke.
The "daily dose of itraconazole to be administered" according to the present invention is calculated as the amount of itraconazole free base, and may be 1.6-30mg/kg, preferably 2.6-26mg/kg, based on the weight of the body. However, it is well known to those skilled in the art that the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention is proved by specific experiments: in a chronic neuropathic compression pain model of a rat, after itraconazole is injected into the abdominal cavity, the mechanical and thermal pain threshold values of the affected side of the rat are obviously improved, which suggests that itraconazole can effectively relieve neuropathic pain of the affected side of the rat and has the potential of treating neuropathic pain.
For a better understanding of the present invention, reference will now be made to the following examples, which are illustrated in the accompanying drawings and are to be construed as being limiting.
Drawings
Fig. 1 shows threshold changes in pain caused by plantar mechanical stimulation after intraperitoneal injection of itraconazole in rats, p <0.01.
Fig. 2 shows the change of thermal stimulation threshold of the sole to thermal stimulation after intraperitoneal injection of itraconazole in rats, p <0.01.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Itraconazole adopted in the embodiment of the invention is purchased from Shanghai microphone Biochemical technology Co., ltd, and the purity is more than 98%;
DMSO used in the examples of the present invention was purchased from Sigma-Aldrich.
SD rats used in the examples of the present invention were purchased from Beijing Wallkukan Co.
The preparation method of the itraconazole solution used in the embodiment of the invention comprises the following steps: accurately weighing 7.1mg of itraconazole powder, adding 1ml of DMSO, and mixing by ultrasound for 30s to obtain the itraconazole powder with the concentration of 10mM/L, and diluting 1000 times when in use, wherein the final concentration is 10 mu M/L.
The preparation method of the 10% chloral hydrate solution used in the embodiment of the invention comprises the following steps: precisely weighing 10.0g of chloral hydrate solid, adding 100mL of double distilled water, and magnetically stirring to dissolve the chloral hydrate solid with the mass fraction of 10%.
Example 1 effect of itraconazole on the behavioural behaviour of a chronic neuropathic compression model in rats
1. Construction of rat chronic neuropathic compression model (the chronic constriction injury, CCI)
1) Female SD rats, weighing 150-200 g, were anesthetized with 10% chloral hydrate solution (0.3 ml/100 g) after weighing.
2) The right sciatic nerve of the rat was exposed and 3 knots (central to peripheral) were ligated on the sciatic nerve with a chrome catgut. The ligation degree should be that the leg of the rat is slightly dithered, and the generated chronic compression pain can last for more than 21 days, and the muscle and skin are sutured, and the iodophor is disinfected.
2. Rat behavioural test
1) Von-Frey test
Von-Frey was performed on day 7 of the molding operation. Itraconazole was administered in a single dose by intraperitoneal injection at a dose of 2.6mg/kg before the test, and the test was performed at 0h, 1h and 1.5h after the administration. The right hindpaw of the rat, namely the ischial nerve ligation side during CCI modeling, is used as the operation side; while the left hind paw, which was not treated, served as the control side. Experiment 6 SD rats per group, each rat was placed in a separate glass separator, placed on an iron mesh, and subjected to environmental adaptation for 30 minutes. At the beginning of the test, a hand-held pressure sensor (IITC electronic Von Frey pain tester, 2390, 90 g) was used to slowly contact the rat's bilateral hind paw ankle position with the tipped iron wire until the hind paw was lifted, and the maximum value indicated by the sensor was recorded as the foot contraction threshold at this time. Each mouse was tested 3 times per side, averaged, and each test was performed at 3 minute intervals. The experimental data obtained by the test are subjected to statistical analysis by non-paired t test through Graphpad Prism8 software, so that the statistical significance is achieved; and drawing a cylindrical statistical chart by taking the test time after administration as an abscissa and the foot shrinkage threshold value as an ordinate.
2) Hargreaves test
Hargreaves test was performed on day 7 of the molding operation. Itraconazole was administered in a single dose by intraperitoneal injection at a dose of 2.6mg/kg before the test, and the test was performed at 0h, 1h and 1.5h after the administration. The right hindpaw of the rat, namely the ischial nerve ligation side during CCI modeling, is used as the operation side; while the left hind paw, which was not treated, served as the control side. Experiment 6 SD rats per group, each rat was placed in a separate glass partition, placed on a clean glass plate, and subjected to environmental adaptation for 30 minutes. At the beginning of the test, a hand-held thermal pain-sensitive tester (BME-410C, a product of institute of biological engineering, academy of sciences of China) was placed at the bottom of the rear feet of the rat on both sides under the glass plate, heating was started until the rear feet were lifted, and the irradiation time on the display screen was recorded as a thermal stimulation threshold. Each mouse was tested 3 times per side, averaged, and the time interval for each test was 3 minutes. The experimental data obtained by the test are subjected to statistical analysis by non-paired t test through Graphpad Prism8 software, so that the statistical significance is achieved; and drawing a cylindrical statistical chart by taking the test time after administration as an abscissa and the thermal stimulation threshold as an ordinate.
3. Results
Fig. 1 is a Von-Frey mechanical stimulus pain threshold and fig. 2 is a thermal stimulus pain threshold. According to the experimental results, compared with 0h after administration (regarded as non-administration control), the pain threshold of mechanical stimulation and thermal stimulation at the operation side of the rat is obviously increased in 1h and 1.5h after the itraconazole is injected into the abdominal cavity, which indicates that the itraconazole has an analgesic effect.
In conclusion, the invention simulates neuropathic pain by constructing a chronic neuropathic compression model of a rat, adopts an intraperitoneal injection mode to administer itraconazole, and combines the behavioral test result to prove that the itraconazole has an analgesic effect in neuropathic pain for the first time, thereby providing a new application for itraconazole on one hand and providing a new thought for the treatment of neuropathic pain on the other hand.

Claims (12)

1. Use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the preparation of a medicament for the treatment of neuropathic pain.
2. Use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, in combination with a non-steroidal anti-inflammatory drug, such as acetaminophen, ibuprofen, piroxicam, meloxicam, for the manufacture of a medicament for the treatment of neuropathic pain.
3. Use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in combination with an amide and an ester local anesthetic, such as bupivacaine, lidocaine, ropivacaine, tetracaine, prilocaine and procaine, for the preparation of a medicament for the treatment of neuropathic pain.
4. Use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, in combination with a tricyclic antidepressant, such as pregabalin, gabapentin, for the preparation of a medicament for the treatment of neuropathic pain.
5. Use of itraconazole or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, in combination with other drugs useful for the treatment of neuropathic pain, such as 5-hydroxytryptamine norepinephrine reuptake inhibitors like venlafaxine, duloxetine, or capsaicin, for the preparation of a medicament for the treatment of neuropathic pain.
6. The use according to any one of claims 1 to 5, wherein the pharmaceutical composition contains itraconazole or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers.
7. The use of claim 6, wherein the pharmaceutically acceptable carrier comprises diluents, fillers, binders, disintegrants, granulating agents, lubricants, wetting agents, absorption enhancers, surfactants, adsorption carriers or sustained-release preparation carriers, sweeteners, flavoring agents, colorants, and preservatives.
8. The use according to any one of claims 1 to 7, wherein the medicament is prepared in a desired dosage form, including tablets, dragees, lozenges, suspensions, powders, granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal, pills, powders, ointments, pellets, drops, patches, injections, suppositories, sprays, and sustained release formulations.
9. The use according to any one of claims 1 to 8, wherein the neuropathic pain is peripheral or central neuropathic pain resulting from damage to the sensory nervous system such as nerve/nerve root compression, nerve injury, diabetes, neuroma, ion channel-associated pathologies, cardiovascular diseases or autoimmune diseases.
10. The use according to any one of claims 1 to 9, wherein the neuropathic pain is selected from pain induced after chronic compression of nerve roots such as lumbar disc herniation and spinal degeneration, primary or secondary trigeminal neuralgia, post-herpetic neuralgia pain, neuropathic pain after peripheral nerve injury such as phantom limb pain and stump pain after cut-off, pain caused by multiple diseases such as diabetes and autoimmune diseases and the like, and central neuropathic pain such as stroke and spinal cord injury; preferably pain is caused after chronic compression of the nerve root.
11. Use according to any one of claims 1 to 10, wherein itraconazole is administered at a daily dose of 1.6-30mg/kg, preferably 2.6-26mg/kg, by weight.
12. The use according to any one of claims 2 to 5, wherein itraconazole or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing same is administered simultaneously, separately or sequentially with a non-steroidal anti-inflammatory drug, or an amide and ester local anesthetic, or a tricyclic antidepressant, or other drug useful for the treatment of neuropathic pain.
CN202210424298.3A 2022-04-21 2022-04-21 Application of itraconazole as analgesic Pending CN116966184A (en)

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