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WO2008028324A1 - Nouvelle préparation de lévamisole pour traiter une rhinite allergique - Google Patents

Nouvelle préparation de lévamisole pour traiter une rhinite allergique Download PDF

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Publication number
WO2008028324A1
WO2008028324A1 PCT/CN2006/002201 CN2006002201W WO2008028324A1 WO 2008028324 A1 WO2008028324 A1 WO 2008028324A1 CN 2006002201 W CN2006002201 W CN 2006002201W WO 2008028324 A1 WO2008028324 A1 WO 2008028324A1
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group
levamisole
nasal
allergic rhinitis
treatment
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Chinese (zh)
Inventor
Wenjie Zheng
Heyao Wang
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Jiangsu Simcere Pharmaceutical R&D Co Ltd
Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical R&D Co Ltd
Jiangsu Simcere Pharmaceutical Co Ltd
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Publication of WO2008028324A1 publication Critical patent/WO2008028324A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to levamisole nasal drops, sprays, aerosols, powders and nasal gels for the treatment of allergic rhinitis and their use. Background technique
  • Rhinitis refers to inflammation of the nasal mucosa, which is characterized by congestion or edema. Patients often have nasal congestion, runny nose, itchy nose, throat discomfort, and cough.
  • Allergic rhinitis is a type of rhinitis. Rhinitis also includes chronic rhinitis and acute rhinitis, the latter usually refers to a cold. Chronic rhinitis includes mild rhinitis with mild symptoms and hypertrophic rhinitis with nasal congestion. Both chronic rhinitis can be relieved by different treatments.
  • Allergic Rhinitis caused by the body's allergy to a substance is called Allergic Rhinitis and can cause a series of allergic symptoms. Allergic rhinitis is also known as allergic rhinitis.
  • allergic rhinitis only has a seasonal attack every year, the usual cause is pollen, catkins, etc.
  • the rhinitis at this time is called seasonal allergic rhinitis, also known as “hay fever” or “hay fever” (hayfever). , mostly related to the seasonal outdoor environment.
  • Perennial allergic rhintis refers to no obvious seasonal differences in the incidence, and allergic factors are related to the indoor environment.
  • allergens Various factors that cause allergic rhinitis such as pollen, catkins, dust mites, molds, etc. are called allergens. Allergens can be divided into inhaled and food allergens, which stimulate the body to produce certain chemicals. Causes the corresponding allergy symptoms.
  • IgE an antibody against foreign substances
  • Allergens such as pollen enter the nasal cavity and trachea; (2) Stimulate the body to produce specific antibody IgE; (3) IgE The antibody is combined with mast cells; (4) Allergens such as pollen re-enter the body, causing mast cells to release histamine and other substances; (5) Histamine causes sneezing, clear watery phlegm and nasal itching and nasal congestion.
  • Allergic rhinitis usually does not achieve a full cure, and the best way is to prevent it.
  • the purpose of treatment is to prevent, relieve symptoms and reduce the onset of allergic rhinitis.
  • the mechanism of different drug treatments may be different, with topical and systemic medications.
  • topical and systemic medications The following are the commonly used therapeutic drugs.
  • the body in the prevention of allergens, chlorpheniramine can cause drowsiness, anti-histamine, cisplatin, chlorpyrifos
  • Tremney prevention can cause drowsiness.
  • Ephedrine must pass, use no more than 3 days, longest short term
  • General medical treatment can have a better therapeutic effect on allergic rhinitis, but for severe allergic rhinitis, other related treatments can be used.
  • Desensitization therapy using the identified allergen as a desensitizing agent, start with a small dose for subcutaneous injection, and gradually increase the dose, to the maximum tolerance to maintain the amount until the symptoms disappear.
  • Patients treated by this method can produce a large number of specific IgG blocking antibodies in the body, which can block the binding of antigens and IgE antibodies, and reduce the sensitivity of the medium cells, thereby playing a therapeutic role, but because of the many possible allergens, it is often limited. Its effect.
  • Levamisole is a commonly used broad-spectrum anthelmintic drug. It selectively inhibits succinate dehydrogenase in the body of the worm, so that fumaric acid can not be reduced to succinic acid, thereby affecting the anaerobic metabolism of the muscles of the worm, and making the worm muscles Paralysis is excreted in the body with feces.
  • Levamisole also has immunomodulatory and immunostimulatory functions, can enhance the chemotactic response of human monocytes or polymorphonuclear leukocytes, and enhance the phagocytic function of monocytes. It is an immunomodulatory drug, but this regulation is only in the The suppressed immune function is regulated to normal levels without causing hyperimmunity.
  • Levamisole can be used for adjuvant therapy of tumors, autoimmune diseases, chronic and recurrent infections. To date, no reports or literatures have been published on the use of levamisole for the treatment of allergic rhinitis at home and abroad. Summary of the invention
  • the object of the present invention is to provide a dosage form for intranasal administration by using levamisole as a separate active ingredient or in combination with other drugs, and these dosage forms include, but are not limited to, nasal drops, sprays, aerosols. Agents, powders and nasal gels.
  • the levamisole refers to a compound formed by levamisole and other acid groups, including, but not limited to, levamisole hydrochloride, levamisole phosphate, and the like.
  • the nasal drops, sprays, aerosols, powders, and nasal gels are all in accordance with the Pharmacopoeia of the People's Republic of China (2000 Edition). About Nasal Drops, Sprays, Aerosols, Powders Formulations for aerosols and nasal gels.
  • Another object of the present invention is that the indications for nasal drops, sprays, aerosols and powders prepared by using levamisole or a compound containing levamisole are allergic rhinitis.
  • the allergic rhinitis of the present invention is well known to those skilled in the art and is well defined in modern medical books.
  • the beneficial effects of the present invention are that the nasal drops, sprays, aerosols and powders prepared by using the levamisole or the compound containing levamisole according to the present invention are directly nasally administered to patients with allergic rhinitis. Medicine, can effectively relieve symptoms Shape or make the symptoms disappear. According to the study, levamisole is equivalent to or better than the corticosteroids budesonide in the treatment of allergic gingivitis, and is safer and less side effects than corticosteroids. In addition, levamisole is similar to terfenadine in the treatment of allergic rhinitis. detailed description
  • levamisole nasal drops, sprays, aerosols, powders, and nasal gels of the present invention for the treatment of allergic gingivitis is described by the following examples. It is to be noted that the following examples are intended to illustrate and not to limit the invention, and that techniques for the treatment of allergic rhinitis by other routes of administration well known to those skilled in the art are within the scope of the invention.
  • Example 1 Treatment of allergic rhinitis with levamisole hydrochloride spray
  • levamisole hydrochloride treatment group was treated with levamisole hydrochloride spray.
  • the nasal spray was administered twice a day at a dose of lOOug/0. 14 ml per spray.
  • Mindi group oral Mindi (Tefenadine tablets, Jiangsu Lianhuan Pharmaceutical Co., Ltd., production batch number: 990102) 30 ⁇ 60mg/d, 2 times/d, both groups were treated for 1 week, during which other anti-antibiotics were banned Allergic drugs and various types of nasal drops.
  • the symptoms of nasal itching, runny nose, nasal congestion and sneezing were observed, and the symptoms disappeared within 1 week. The partial relief of the symptoms was effective, and the symptoms were not improved.
  • the levamisole hydrochloride treatment group was effective in 34 cases, effective in 4 cases, ineffective in 0 cases, and the effective rate was not 89.5%.
  • the sensitive group was effective in 18 cases, effective in 4 cases, ineffective in 1 case, and the effective rate was not 78.5%. There was no significant difference between the two groups (P > 0.05) by X 2 test.
  • Example 2 Treatment of allergic rhinitis with levamisole hydrochloride aerosol
  • Example 1 Treatment of allergic rhinitis with levamisole hydrochloride nasal drops
  • Example 4 Treatment of allergic rhinitis with levamisole hydrochloride powder spray
  • Example 5 Treatment of allergic rhinitis cases with levamisole phosphate spray
  • levamisole treatment group was treated with levamisole phosphate nasal gel and sprayed twice daily with nasal dose at a dose of lOOug/0. 14ml per spray.
  • Renault group nasal spray (Budesonide spray, Rhinocort®, Astrazeneca, lot number: EM308), starting dose of 256 ug / day (4 spray / day), this dose can be sprayed once in the morning Inject it two times in the morning and evening.
  • reduce the dose to the minimum dose required to control the symptoms such as 64 ug per nostril every morning.
  • Both groups were treated for 1 week, during which other anti-allergic drugs and various types of nasal drops were banned. Observing the symptoms of nasal itching, runny nose, nasal congestion and sneezing, the symptoms disappeared within 1 week, and the symptoms were partially relieved, and the symptoms were not improved.
  • Positive control drug budesonide, formulated with Rhinocort® manufactured by AstraZeneca Pharmaceutical Co., Ltd., product batch number EM308.
  • the concentration of levamisole hydrochloride nasal drops 122. 5 ⁇ g/ml, 245. 0 ⁇ g/ml and 367. 5 ⁇ g/ml, and the batch numbers were 20050113- 1, 20050113-2, 20050113-3, respectively.
  • the dosage range of levamisole hydrochloride was determined based on preliminary tests.
  • Natural control group (Group Sa): In the process of sensitization, stimulation and administration, only 0.9% NaCl 40 ⁇ ⁇ / side, bilateral nasal drops.
  • Allergic rhinitis group (Group AR): After standard sensitization and challenge, only 0.9% NaCl 40 ⁇ 1 / side, bilateral nasal drops were administered.
  • Budesonide treatment group (Group BUD): After standard sensitization and challenge, give 100 ⁇ g/ml budesonide, 40 ⁇ l/side, bilateral nasal drops.
  • Low-dose treatment group of levamisole (Group LL): After standard sensitization and challenge, 122. 5 ⁇ g/ml levamisole hydrochloride, 40 ⁇ l/side, bilateral nasal drops were administered.
  • Levamisole hydrochloride medium dose group (Group ML): After standard sensitization and challenge, 245. 0 ⁇ g/ml levamisole hydrochloride, 40 ⁇ l/side, bilateral nasal drops were administered.
  • High dose treatment group of levamisole (Group HL): After standard sensitization and challenge, 367. 5 ⁇ g/ml levamisole hydrochloride, 40 ⁇ l/side, bilateral nasal drops were administered.
  • Sensitization Except for the natural control group, the animals were given nasal saline, and the other groups were sensitized (10% TDI, olive oil emulsion) 5. 0 ⁇ 1/side, bilateral nose for 7 consecutive days.
  • Stimulation The first day after the sensitization is over, the excitation begins. On the challenge, 10% TDI, olive oil emulsion nasal drops, 5 ⁇ 1 / side, bilateral nasal drops.
  • Treatment lh after each challenge, the corresponding drug treatment is administered according to the group.
  • the animals were observed for nasal symptoms the next day from the sensitization, and the nasal symptoms after local challenge and administration were observed every other day after the sensitization. The observation time was 30 minutes after administration, and 30 minutes after 2 hours after administration. Nose The three indicators of secretion, scratching and sneezing were scored according to the following criteria: Nasal itch score: 1 point, mild, clear nose several times; 2 points, severe, scratching the nose, face more than, rubbing everywhere. Sneeze score: 1 point, 1 ⁇ 3 sneezes; 2 points, 4 ⁇ 10 sneezes; 3 points, 11 sneezes or more.
  • Qingyi score 1 point, flow to the front hole; 2 points, flow more than the nose hole; 3 points, turbulent flow is.
  • Total early symptom scores The itching score, sneezing score and clearing score at the same time point of the superposition method were the total scores of early clinical symptoms.
  • the average number of eosinophils in the high power field is 26 ⁇ 50; 3 points, the distribution of eosinophils is more, the average number of eosinophils in the high power field More than 50. 10 or more visual eosinophil counts were continuously performed under high power field (40 X 10 times), and the average was scored.
  • the nasal mucosa of the sacrificed animal was stripped and the liquid nitrogen was frozen.
  • the nasal mucosa was weighed, and 25% trichloroacetic acid solution was added to the homogenizer for slurrying, centrifugation, and the supernatant was taken.
  • the histamine content in the nasal mucosa of the test animals was determined according to the modified Shore method, and comparison between the groups was performed. Result
  • Nasal secretions, scratching and sneezing Early response symptoms of allergic rhinitis are induced by a range of mediators including histamine, leukotrienes and IL-4, IL-5, IL-6 and TNF- a cytokine.
  • mediators including histamine, leukotrienes and IL-4, IL-5, IL-6 and TNF- a cytokine.
  • the three doses of high, medium and low levamisole and the budesonide treatment group were analyzed. The scores were lower than those in the allergic rhinitis group, indicating that levamisole hydrochloride and budesonide for nasal administration can reduce the early response score of inflammation in guinea pigs with allergic rhinitis.
  • HE staining pathological sections showed partial mucosal epithelial shedding in the allergic rhinitis group, obvious goblet cell hyperplasia, lamellar vasodilation, glandular hyperplasia, tissue edema, and a large number of eosinophil infiltration.
  • the mucosal epithelial cells were intact, the mucosal structure was normal, and eosinophil infiltration was rare or not seen.
  • the histopathological morphology was improved after treatment with different doses of levamisole hydrochloride, which showed a decrease in goblet cells, a decrease in tissue edema and a small amount of eosinophil infiltration in mucosal epithelial cells.
  • Group AR compared with Group ⁇ , eosinophilic infiltration was significant, P ⁇ 0.01; Group BUD, Group LL, Group ML and Group HL compared with Group AR, the eosinophil infiltration was significantly reduced, indicating that budesonide and levamisole hydrochloride can significantly inhibit eosinophil infiltration, all P ⁇ 0.01; Group LL, Group ML and Group HL Compared with Group BUD, there was no significant difference, P>0.05, indicating that budesonide and levamisole hydrochloride had no significant difference in inhibiting eosinophil infiltration; there was no difference between Group LL, Group ML and Group HL, indicating hydrochloric acid Levamisole inhibited eosinophil infiltration, and no dose-effect relationship was observed in this study.
  • the histamine content in the nasal mucosa was determined according to the Shore method.
  • the results showed that the histamine content of Group AR was significantly higher than that of Group NM, indicating that the histamine content in the mucosal tissue of allergic rhinitis was significantly increased, P ⁇ 0.01 ; the histamine content of Group BUD compared with Group AR Significantly decreased (P ⁇ 0.01), Group ML and Group HL also significantly reduced histamine content (P ⁇ 0.05), but Group LL histamine content and Group AR ratio was not significantly different (P > 0.05) ).
  • levamisole can significantly inhibit the infiltration of AR in animal AD. Eosinophils are not only effector cells of type I allergic reaction, but also play a key role in delayed phase allergy, and the inflammatory response of AR includes both rapid development. Also included is the delayed phase, indicating that levamisole may treat AR from both aspects. In addition, levamisole also has a therapeutic effect on allergic rhinitis by directly inhibiting the release of histamine or promoting the decomposition of histamine, and lowering the histamine content in the mucosa.
  • the budesonide treatment group and the levamisole treatment group in this experiment failed to significantly alleviate the clinical symptoms such as nasal secretion, scratching and sneezing, and the budesonide reported by other scholars can be relieved by nasal administration.
  • the above symptoms of small animals suffering from allergic rhinitis are different. The reason is that it is more difficult to accurately and objectively evaluate these indicators for each group of small animals. Therefore, the results of different laboratories are inevitably different.
  • levamisole at least can treat allergic rhinitis by inhibiting eosinophil infiltration and reducing histamine levels.
  • Example 14 Nasal administration of levamisole was used to treat allergic rhinitis in mice, and local immunomodulation was induced by inhibiting Th2 type cytokines and simultaneously inducing Thl type cytokines.
  • Ovalbumin Ovalbumin (OVA, Grade V, Sigma), aluminum hydroxide (Alum, Sigma), phosphate left Spinal imidazole (Guilin Pharmaceutical Co., Ltd.), Reynolds (AstraZeneca Pharmaceutical Co., Ltd., product batch number: EM308), rat IgG2b (rat anti-mouse IL-4, BD PharMingen), rat IgGl (rat anti-rat Mouse IL-12, Biosource), Biotinylated Rabbit Anti-Rat IgG (Vector), RNAeasy Column (Qiagen), Superscript ⁇ III Platinum ⁇ One-Step qRT-PCR Trial U Box (Invitrogen), Ribosomal RNA Control Reagents ( TaqMan All other reagents used were of analytical grade.
  • levamisole hydrochloride nasal drops three doses, 20 ⁇ g/ml (batch number: 031001-1), 40 ⁇ g/ml (batch number: 031001-2) and 160wg/ml (batch number: 03001-3).
  • the dose range of levamisole phosphate was determined based on a pretest.
  • Sensitizing solution 50 mg of ovalbumin, 1000 mg of aluminum hydroxide and 0.5 ml of heat-killed C. sinensis at a concentration of 4 ⁇ 10 12 /ml in 500 ml of physiological saline.
  • Natural control group (Group NM): During sensitization, challenge and administration, only 0.9 aCl 5. ⁇ 1/side was given, bilateral nasal drops.
  • Allergic rhinitis group (Group AR): After standard sensitization and challenge, only 0.9% NaCl 5 ⁇ l side was administered at the time of administration, bilateral nasal drops.
  • Budesonide treatment group (Group BUD): After standard sensitization and challenge, 97.3 ⁇ g/ml budesonide, 5 ⁇ 1/side, bilateral nasal drops were given.
  • Low-dose treatment group of levamisole (Group LL): After standard sensitization and challenge, 20 ⁇ g/ml levamisole phosphate, 5 ⁇ 1/side, bilateral nasal drops were administered.
  • High dose treatment group of levamisole phosphate (Group HL): After standard sensitization and challenge, 160 g/ml levamisole phosphate, 5 ⁇ l side, bilateral nasal drops were administered.
  • Sensitization Mouse intraperitoneal injection of sensitizing solution 0.5ml / only, once every other day, a total of 7 times; the control group was replaced by normal saline; Excitation: On the 2nd day after sensitization, local nasal immunization with 5% ovalbumin saline , daily nasal drops ⁇ / only, 5.0 ⁇ 1 per side. The control group was replaced with physiological saline;
  • Method of administration Local nasal nasal drip administration 60 min before challenge, daily nasal drops ⁇ , 5.0 ⁇ l per side, 5 days after continuous administration for 5 days, stopped for two days for 3 weeks; Group AR and Group NM changed The rhinitis group and the natural control group were replaced with physiological saline; Specimen collection: After the animal was decapitated, the nasal mucosa was separated and placed in formalin solution. Paraffin sections were prepared according to conventional tissue preparation techniques, and HE staining and IL-12 and IL-4 immunohistochemical staining were performed respectively. 8 On the seventh day after the end of immunohistochemical treatment, the animals in each group were sacrificed.
  • the nasal septum mucosa was removed and fixed in 10% neutral formalin, embedded in paraffin, sectioned, and immunohistochemically stained.
  • the primary antibodies to IL-4 and IL-12 were rat IgG2b and rat IgGl, respectively, and the biotinylated secondary antibody was rabbit anti-rat IgG.
  • Pathological sections of the nasal mucosa were incubated with primary antibodies overnight, washed, and then incubated with secondary antibodies. After washing, the avidin-biotin horseradish peroxidase complex was added in sequence to diaminobiphenyl (DAB). 1% PBS-saponin was used for each wash section.
  • DAB diaminobiphenyl
  • IL-4 and IL-12 were judged according to the following scoring criteria: 0 points, negative staining; 1 point, tissue staining was weak, positive cells ⁇ 25%; 2 points, staining positive, positive cells 25 ⁇ 50% 3 points, tissue staining is strong, positive cells >50%.
  • IL-12 immunohistochemical staining is negative, in allergic Rhinitis mice (Group AR) are negative or weakly positive in the nasal mucosa. Because Group AR's IL-12 immunohistochemical staining score is significantly different from Group, it may indicate an increase in IL-12 expression in allergic rhinitis. After treatment with levamisole phosphate, the expression of IL-12 was significantly increased in the nasal mucosa (Group ML compared with Group AR, P ⁇ 0 ⁇ 05; Group HL compared with Group AR, P ⁇ 0 ⁇ 05).
  • mice in Group AR were positive for IL-4 immunohistochemical staining, and 80% of them were strongly positive with a score of 2 or 3 points. Of the mice in the normal group, only 2 were only positive for IL-4 staining and the score was only 1 point (Group NM vs Group AR, P ⁇ 0 ⁇ 01).
  • Levamisole phosphate can significantly inhibit the expression of IL-4 in the nasal mucosa of mice with allergic rhinitis at a dose of 160 ⁇ g/ml X 10 ⁇ 1 (Group HL) (Group HL vs Group AR, P ⁇ 0.05) .
  • mice after sensitization and stimulation for 21 consecutive days, compared with the normal group, IL, IL-4 mRNA, IL-5 mRNA and IL-13 mRNA levels increased by 48. 2 times, 55.6 times And 78. 6 times.
  • these elevated Th2 cytokine mRNA levels were inhibited by budesonide and levamisole phosphate.
  • IL-4 mRNA was significantly inhibited (Group AR vs Group BUD, P ⁇ 0 ⁇ 05; Group AR vs Group ML, P ⁇ 0 ⁇ 05; Group AR vs Group HL, P ⁇ 0 ⁇ 05).
  • the inhibitory effect of budesonide on IL-4 mRNA at 104 g/ml X 10 ⁇ was not significantly different from that of medium and high doses of levamisole (Group BUD vs Group ML, P>0 ⁇ 05; Group BUD pair) Group HL, P>0 - 05)
  • the inhibition of IL-4 mRNA by levamisole is dose-dependent (Group LL vs Group ML, P>0 ⁇ 05; Group LL vs Group HL, P ⁇ 0 ⁇ 05; Group ML For Group HL, P>0 ⁇ 05).
  • IL-5 mRNA levels were also inhibited by budesonide and levamisole (Group AR vs Group BUD, P ⁇ 0.05);
  • Group AR X inch Group LL P ⁇ 0 ⁇ 05; Group AR X inch Group ML, P ⁇ 0 ⁇ 05; Group AR pair Group HL, P ⁇ 0 ⁇ 05).
  • Inhibition of IL-5 mRNA by levamisole was also dose-dependent (Group LL vs Group ML, P ⁇ 0 ⁇ 01; Group LL vs Group HL, P ⁇ 0 ⁇ 01; Group ML vs Group HL, P>0 ⁇ 05).
  • Group HL and Group BUD showed similar inhibition (Group A vs Group BUD, P ⁇ 0 ⁇ 05; Group AR vs Group LL, P > 0 ⁇ 05; Group AR vs Group ML, P > 0 ⁇ 05; Group AR to Group HL, P ⁇ 0 ⁇ 05; Group BUD to Group HL, P>0 ⁇ 05).
  • the inhibitory effect of levamisole phosphate on IL-13 mRNA was also dose-dependent (Group LL vs Group ML, P>0 ⁇ 05; Group LL vs Group HL, P ⁇ 0 ⁇ 05; Group ML vs Group HL, P>0 ⁇ 05).
  • levamisole phosphate and budesonide enhance their expression.
  • budesonide and levamisole promote down-regulation of Th2 type cytokine mRNA, their different effects on different cytokines indicate that the mechanism of action is different.
  • levamisole phosphate can selectively induce the upregulation of Th1 type cytokines, and can more effectively reverse the AR Thl/Th2 balance, which is mainly Th2-type immune response, to the Th1 type immune response.
  • glucocorticoids in the nasal cavity selectively inhibits the synthesis of Th2 cytokines IL-4, IL-5, IL-6 and IL-13, but has no or only a weak effect on the level of Th1 cytokines; Imidazole not only inhibits the Th2 immune response, but also stimulates the Th1 immune response. Therefore, local administration of levamisole in the nasal cavity can reverse the AR Thl/Th2 balance, which is dominated by the Th2-type immune response, to the Th1-type immune response, and levamisole phosphate may More effective than budesonide.

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Abstract

La présente invention concerne l'utilisation de lévamisole dans la fabrication d'un médicament utilisé pour traiter une rhinite allergique, lequel lévamisole se présente sous forme de gouttes nasales à pulvériser, d'aérosol, d'aérosol de micropoudres à inspirer ou de gel nasal.
PCT/CN2006/002201 2006-08-28 2006-08-28 Nouvelle préparation de lévamisole pour traiter une rhinite allergique Ceased WO2008028324A1 (fr)

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Citations (2)

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CN1606980A (zh) * 2003-10-14 2005-04-20 郑文婕 治疗慢性鼻炎的左旋咪唑新剂型

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