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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems
• • 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
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the field of pharmaceuticals, particularly to a medicament for treating aseptic inflammations, its preparation method and the effective component thereof, especially to the use of anemonin for treating aseptic inflammations.
• inflammations can be distinguished into two groups: bacterial inflammations and aseptic inflammations.
• Bacterial inflammations have been widely studied because they are likely to lead to the attack of acute diseases.
• Anti-bacterial drugs such as antibiotics including penicillin and carbapenems, have been developed as specific clinical medicaments aimed at bacterial inflammations.
• Prior to this invention there was no specific, or even established, effective medicament for aseptic inflammations. That is to say, there is a need for medicaments for specifically treating aseptic inflammations in the international medical field.
• pharmacies there are not any pharmaceutical companies which produce specific medicaments for aseptic inflammations.
• aseptic inflammations include cervical spondylosis, lumbar diseases periarthritis humeroscapularis, tennis elbow, muscular fascia syndrome, rheumatic arthritis, osteoarthritis, aseptic prostatitis, multiple neuritis, neurodermatitis, tenosynovitis, lumbar muscle strain, ischias, painful heel, migraine, chronic gastritis, early aseptic necrosis of femoral head, bronchial asthma, and other diseases belong to aseptic inflammations as defined in the medical field.
• hyperplastic spurs often stab peripheral soft tissue, then cause inflammatory exudation, edema, accumulation of metabolites and formation of adhesion, which stimulate nerve receptor and cause pain.
• Edema and adhesion which are caused by aseptic inflammations around muscle, fascia, ligament, peripheral nerve plexus, joint capsule and vascular wall, can compress the spinal cord, vertebral artery and nerve root and lead to complex symptoms of cervical and lumbar vertebral which are difficult to treat.
• Adhesion, calcificated ligament, fascia and myotasis are the main causes of many aseptic inflammatory diseases such as cervical and lumbar vertebral, periarthritis humeroscapularis, muscular fascia syndrome and osteoarthritis, etc.
• Hundreds of millions of people throughout the world suffer from diseases caused by aseptic inflammations which are mostly chronic diseases.
• the first aspect of the present invention is a medicament for treating aseptic inflammations containing anemonin as its effective component.
• the compound of anemonin can be obtained by chemical synthesis, or prepared from natural materials of Chinese herbs. It is evidenced by clinical tests that a medicament containing this active compound has notable curative effect on stubborn pain and body disorders/diseases, which are caused by aseptic inflammation.
• Such a medicament can eliminate the aseptic inflammations, edema, adhesion caused by aseptic inflammations, and stubborn pain, complex body disorders caused by aseptic inflammation, edema and adhesion. Consequently, it can rapidly cure varieties of aseptic inflammatory disease with high efficacy and safety. Furthermore, such medicament is neither toxic nor an irritant.
• the second aspect of the present invention is the use of the compound of anemonin or the natural abstracts containing anemoninin for treating aseptic inflammations is proposed.
• the present invention also provides a pharmaceutical preparation for treating aseptic inflammations containing anemonin as an effective component, especially in topical applications. Topical applications provide the best way of administering treatment of aseptic inflammations.
• the present invention also provides a naturally originated medicament for treating aseptic inflammations containing as effective component the extract liquor of anemonin obtained from natural Chinese herbs.
• the present invention provides a method for preparing a medicament according to the present invention, in particular by extracting and preparing anemonin from natural medical plants.
• protoanemonin which has strong toxicity and side effects, in raw material can be turned into non-irritant anemonin, which can then be produced on industrial scale.
• the medicament according to the present invention for treating aseptic inflammations comprises a therapeutically effective amount of anemonin.
• the chemical structural formula of anemonin is as following:
• This compound can be prepared from the extracts from any natural Chinese herb containing ranunculin or protoanemonin.
• Suitable natural Chinese herbs include Ranunculaceous plants and Graminaceous plants, etc.
• Ranunculaceous plants include: Ranunculus japonicus Thunb., Caltha palustris L, Ranunculus sceleratus L., Anemone hupehensis Lem., Pulsatilla chinensis (Bge.) Regel, Anemone raddeana Regel, Anemone altaica Fisch, Ranunculus Chinensis Regel, anemonin-containing Clematis including Clematis chinensis osbeck, Clematis flnetiana Ievi et Vant, Clematis hexapetala Pall, Clematis Manshurica Rupr., Clematis paniculata, Clematis florida, Clematis clasiandra Maxim, Clematis
• Graminaceous plants include root of Imperata cylindrical, ranunculin-containing plants of Helleborus (Ranunculaceae), Anemone (Anemoneae), Hepatica (Anemoneae), Ranunculus (Ranunculeae), Bratrachium (Ranunculeae), and Aconitum scaposum var. vaginatum (Delphineae).
• ranunculin is enzymatically cleaved to remove saccharides and converted protoanemonin. Through polymerization, protoanemonin is converted into dipolymer anemonin.
• Some natural herbs per se contain anemonin (mostly produced during the storage of the herbs). It has been found that anemonin has an inhibitory affect on staphylococcus, streptococcus, Bacillus diphtheriae, Mycobacterium tuberculosis, and E. coli, etc. Consequently, before this invention, [these] herbs containing protoanemonin or anemonin were used as antineoplastic, antiseptic and antiphlogistic drugs in clinic. In traditional Chinese medicine, such plants as Clematis chinensis are often used to treat rheumatism, promote circulation and relieve pain.
• the present inventor found that the natural Chinese herbs including the above raw herbs containing protoanemonin are all irritants to human body, whether administered orally or topically. With oral medication, the herbs result in severe gastro-enteritis and symptoms such as nausea, vomiting and diarrhea, they even stimulate the kidney and cause bloody urine and proteinuria. The herbs cause redness, swelling and blister when contacted with skin. But protoanemonin component exhibits strong antibacterial activity.
• anemonin can be a product of chemical synthesis, or an extracted product isolated from natural herbs, which is provided in the form of extract liquor of anemonin.
• a partial list of aseptic inflammations includes: cervical spondylosis, lumbar diseases, periarthritis humeroscapularis, tennis elbow, muscular fascia syndrome, rheumatic arthritis, osteoarthritis, aseptic prostatitis, multiple neuritis, neurodermatitis, tenosynovitis, lumbar muscle strain; ischias, painful heel, migraine, stubborn stomach-ache, cancerous pain, bronchial asthma, and early necrosis of femoral head caused by aseptic inflammations. Additional diseases defined aseptic inflammations are also defined in the medical field.
• an anemonin extract liquor or medicament formulated with anemonin according to the present invention has notable effects on varieties of aseptic inflammatory diseases.
• Topical application of the medicament may be sufficient for treating relevant diseases without requiring oral medicine, injection, infusion, operation, acupuncture, massage, manipulation or hospitalization.
• the relevant diseases can be cured by the application of a wet-compress with anemonin extract liquor three times.
• the therapeutic mechanism of the medicament according to the present invention may be that with trans-dermal wet-compressing with anemonin solution on the affected sites, anemonin displays its notable effects of analgesia, anti-inflammation, repercussion, relieving spasm, decomposing adhesion and its strong trans-dermal absorption ability.
• anemonin displays its notable effects of analgesia, anti-inflammation, repercussion, relieving spasm, decomposing adhesion and its strong trans-dermal absorption ability.
• Such a treatment can remove in a short time the aseptic inflammations, which have been deposited over many years in a muscle, muscle tendon, fascia, joint, synovial bursa, nerve plexus and among vascular walls. It can rapidly remove edema, decompose adhesion, and relieve tendons and calcified ligament.
• the mechanism is the same as that for treating cervical spondylosis, lumbar diseases, and muscular fascia syndrome through an operation to relieve pressure and eliminate stimulation. Swelling pain and dysfunction of movement caused by adhesion and calcification of muscle, fascia and ligament were relieved by the elimination of aseptic inflammations.
• the medicament according to the present invention contains anemonin as the active therapeutic component and optionally suitable pharmaceutically acceptable vehicle or excipient. Whether a vehicle or excipient is used and the choice of vehicle or excipient depends on the final dosage and form of the medicament.
• the medicament according to the present invention can be manufactured into preparations suitable for oral administration, injection and topical application.
• the preparations for topical use include liquid extract, plaster, suppository, liniment, paint and other preparations suitable for the trans-dermal absorption of active components.
• Anemoninin used in the preparation of the medicament of the present invention may be synthetic, or can be extracted from the mentioned above raw herbs according to previously known methods, e.g., the method as described in Chemistry of Chinese Herbs Components (in Chinese), page 226, published by Science Publishing House (1977).
• preparations for injection, oral or topical use can be prepared with purified anemonin crystal or anemonin extract liquor obtained from ranuculin-containing natural plants (the active component therein is anemonin).
• anemonin is stable.
• Anemonin functions as a treatment for varieties of aseptic inflammations without being affected by its combination with many Chinese herbs and their chemical components.
• the stability of anemonin is also demonstrated by the rapid and effective therapeutic effect of anemonin extract liquor on various aseptic inflammations is not reduced under unfavorable conditions such as high temperature, low temperature, molding and decaying.
• the medicament for treating aseptic inflammations is naturally originated, which comprises, as the active component, an extract liquor obtained through extraction from any natural plants or Chinese herbs containing anemonin or its precursors with an organic solvent, water, animal or vegetable oil, brewage vinegar or inorganic acid.
• this invention further provides a method for preparing anemonin extract liquor comprising a step of extracting a natural plant or Chinese herb containing anemonin or its precursor(s) in a sealed container with an organic solvent, water, animal or vegetable oil, brewage vinegar or inorganic acid. After filtering and clarifying the extracting mixture, the anemonin extract liquor is obtained.
• the starting materials include Ranunculaceous plants such as Ranunculus japonicus Thunb., Caltha palustris L, Ranunculus sceleratus L., Anemone hupehensis Lem., Pulsatilla chinensis (Bge.) Regel, Anemone raddeana Regel, Anemone altaica Fisch, Ranunculus Chinensis Regel, anemonin-containing Clematis including Clematis chinensis osbeck, Clematis flnetiana Ievi et Vant, Clematis hexapetala Pall, Clematis Manshurica Rupr., Clematis paniculata, Clematis florida, Clematis clasiandra Maxim, Clematis uncinata champ.ex Benth and C
• Useful organic solvents include ethanol, methanol, propylene glycol, glycerin, chloroform, or mixture thereof.
• the cold-maceration used in this invention refers to soaking and extracting the raw material with extracting liquid at room temperature to obtain anemonin extract liquor.
• Hot-maceration refers to soaking and extracting the raw material in heat extracting liquid to get the extract liquor.
• the method of the present invention for preparing anemonin extract liquor is characterized in that it converts protoanemonin contained in raw material into anemonin by polymerization, resulting in anemonin extract liquor having anti-bacterial and anti-inflammation effects, especially anti-aseptic inflammations.
• Preferred embodiments of the method for preparing anemonin extract liquor includes soaking the raw material at room temperature with 30%-50% ethanol for over 8 months or adding the raw material to the same solvent kept boiling, sealing the container and soaking for over 6 months.
• effective parts of the raw herb can be chosen for extraction, such as the whole grass or a mixture of the whole grass and root of fresh Ranunculus japonicus Thunb.
• the chosen effective part may be placed into an extraction jar, and an extractant is added in suitable proportion, then the jar is sealed to carry out the extraction.
• protoanemonin has been polymerized sufficiently and turned into anemonin, and the resultant anemonin has been dissolved in the solvent.
• a juice is obtained.
• the juice may be filtered, and the filtrate is settled.
• An anemonin extract liquor, a clear yellow transparent liquid, is obtained with the content of animonin in the extract can be determined through conventional detection methods.
• a method for converting protoanemonin contained in raw herbs into anemonin comprises the step of storing the raw herb and a suitable extractant in suitable amounts under sealed conditions for a prolonged period.
• the suitable extractants useful in the present invention are the same as described above.
• Methanol may be hot or cold and about 30% concentration.
• Vegetable oil may be castor oil, tea oil or peanut oil. Ethanol, methanol or water is preferably used as the extractant.
• One herb or any mixture of at least two herbs can be used as the raw herb.
• the method according to the present invention can be carried out in the so-called hot-extraction manner as follows. The fresh Ranunculus japonicus Thunb.
• Hot ethanol in suitable concentration such as about 40%, used in an amount such that the weight ratio of the fresh Ranunculus japonicus Thunb. to ethanol is about 1:1, is then added to the container containing the fresh Ranunculus japonicus Thunb.
• the contents in the container are heated, and then the container is sealed and stored, to polymerize protoanemonin contained in the fresh Ranunculus japonicus Thunb. into anemonin and dissolve the resultant anemonin in the solvent.
• a juice is obtained.
• the juice is filtered, and the filtrate is settled.
• An anemonin extract liquor, a yellow transparent liquid, is obtained.
• the method of the present invention can be carried out in the so-called cold-extraction manner as follows.
• the fresh Ranunculus japonicus Thunb. whole grass and its root or only the whole grass, after being pulverized, is placed into a container.
• a solution of ethanol at approximately 40% concentration or methanol at about 30% concentration is added to the container in an amount such that the weight ratio of the fresh Ranunculus japonicus Thunb. to the ethanol or methanol is about 1:1.
• the container is sealed and stored for a long period, to polymerize protoanemonin contained in the fresh Ranunculus japonicus Thunb. into anemonin and dissolve the resultant anemonin in the solvent.
• a juice is obtained.
• the juice is filtered, and the filtrate is settled.
• An anemonin extract liquor, a yellow transparent liquid, is obtained.
• the anemonin extract liquor can be obtained by the hot-extraction or cold-extraction method using herbal pieces for decoction as raw material, such as Clematis chinensis osbeck herbal pieces or Pulsatilla chinensis (Bge.) Regel herbal pieces. More particularly, the raw material is extracted with ethanol in suitable concentration, such as 40%, in such amount that the weight ratio of ethanol to the raw material is about 3:1, according to the hot-extraction or cold-extraction method.
• herbal pieces for decoction such as Clematis chinensis osbeck herbal pieces or Pulsatilla chinensis (Bge.) Regel herbal pieces.
• the raw material is extracted with ethanol in suitable concentration, such as 40%, in such amount that the weight ratio of ethanol to the raw material is about 3:1, according to the hot-extraction or cold-extraction method.
• the container is sealed and stored for 3 to 6 months while the contents are stirred once a day to dissolve the anemonin contained in Clematis chinensis osbeck or Pulsatilla chinensis (Bge.) Regel herbal pieces into ethanol completely. After filtration and settling, a brown anemonin extract liquor is obtained.
• the present method can be carried out in the so-called hot-extraction or cold extraction manner as follows.
• Water used in amount such that the weight ratio of the fresh Ranunculus japonicus Thunb. to water is about 1:1, and suitable amount of preservative (foodstuff grade) are added directly into a container containing the pulverized fresh Ranunculus japonicus Thunb.
• the container is then sealed and stored to polymerize protoanemonin contained in the fresh Ranunculus japonicus Thunb. into anemonin and to dissolve the resultant anemonin in water.
• a juice is obtained.
• the juice is filtered, and the filtrate is settled.
• An anemonin extract liquor, a yellow transparent liquid, is obtained.
• a suitable extractant is used to carry out the extraction under specific conditions.
• the aim is to extract the protoanemonin and anemonin contained in the raw material and to polymerize the extracted protoanemonin into anemonin, so as to obtain an anemonin extract liquid.
• the anemonin extract can then be adjusted to desired concentration for therapeutical use or be further processed into suitable preparations. Therefore, the ratio of the extractant to the raw material herb in the present method is not essential.
• the stability of the extracted anemonin or anemonin extract liquor is not affected by combination with one or more Chinese herbs, chemical pharmaceuticals or chemical components contained therein, and the amenonin can still effectively treat various aseptic inflammations.
• a stability test for prolonged storage shows, anemonin in the present medication is stable over at least 5 years.
• a suitable method can be selected with respect to the practical conditions in industry.
• the anemonin compound synthesized in advance, bought in the market, or the anemonin extract obtained by extracting the raw material as described above can be used to further prepare various preparations.
• the present invention also provides a pharmaceutical composition useful for treating aseptic inflammations comprising a therapeutically effective amount of anemonin and a pharmaceutically acceptable vehicle/excipient (if necessary).
• the composition according to the present invention can be manufactured into preparations suitable for oral administration, injection and topical application.
• the preparations for topical use include liquid extract, plaster, suppository, liniment, paint and other preparations suitable for the trans-dermal absorption of active components.
• said liquid extract can be the anemonin extract liquor obtained by extracting with 30-40% ethanol according to the method of the present invention. This liquid extract can be used to paint the affected sites or applied to the affected sites with gauze soaked therewith.
• An anemonin ointment containing ethanol as preservative can be made as follows: 90% ethanol is added to fine powder of fresh Ranunculus japonicus at proportion of 1:3 (the fine powder/ethanol) in a container, the mixture is stirred thoroughly and sealed or heated and stored for a prolonged period. During the process, protoanemonin contained in the fresh Ranunculus japonicus will be polymerized into anemonin. Herbal pieces of Clematis chinensis osbeck or/and of Pulsatilla chinensis (Bge.) Regel can be extracted in the same way. The extract liquor may be decocted and concentrated into herbal granules (suitable additives can be added if necessary). The main active ingredient of such granules is anemonin which can be used for treating aseptic inflammations administered either orally or by topical use.
• Anemonin liquid or anemonin extract liquor is prepared which contains 12.5 mg anemonin per 25 ml of the liquid or solution.
• 25 ml of the anemonin extract liquor is applied to the affected area or painful sites of various aseptic inflammatory diseases with soaked gauze, once per week.
• the transdermal application may be carried out on an area of about 100 cm 2 for about four hours.
• the curative ratio in one cycle of treatment is as high as 90%. This medicament relieves pain in short time. Notable therapeutic effects can be obtained after the first application.
• Some patients may be cured with only one application. There's no side effect such as redness, swelling, blistering, running liquid, allergic reaction or pain. This treatment has minimal toxicity.
• Anemonin liquid or anemonin extract liquor can be prepared into liquid extract, plaster, suppository, liniment, paint and other preparations for topical use.
• Anemonin can also be formulated into oral tablet, injection, drop pills, oral liquid and medicated wines.
• the medicament or pharmaceutical composition according to the present invention can also contain any herbal abstract compatible with anemonin including that from Mucuna birdwoodiana Tutcher, Sargentodoxa cuneata (Olic.) Rehd.et Wils, Pittosporum glabratum Lindl, Tetrastigma obtectum Planch, Lespedeza cuneata (Dum.Cours.) G. Don, Helledorus thidetanus Franch, Serissa Serissoides Druce and the like.
• any herbal abstract compatible with anemonin including that from Mucuna birdwoodiana Tutcher, Sargentodoxa cuneata (Olic.) Rehd.et Wils, Pittosporum glabratum Lindl, Tetrastigma obtectum Planch, Lespedeza cuneata (Dum.Cours.) G. Don, Helledorus thidetanus Franch, Serissa Serissoides Druce and the like.
• the present invention is based on finding and providing the use of anemonin or medicament containing anemonin in treating aseptic inflammations. Additionally, protoanemonin contained in raw herbs is effectively polymerized into anemonin according to the method of the present invention. Because of the conversion of protoanemonin to anemonin, the irritant effect of protoanemonin to the body, especially to skin is eliminated. The medicament can effectively treat various aseptic inflammatory diseases by topical application.
• the maximal tolerating dose for guinea pig was 266 g/kg without any intoxication or death.
• topical administration no intoxication or death was observed when the area of administration reached 10% of animal's body surface area.
• topical administrations for 4 weeks no abnormal or pathologic change was observed on the weight, visceral coefficient, hemogram, liver function, kidney function, internal organs and skin of the tested guinea pigs.
• the medicament of the present invention is non-irritant and non-allergenic, especially for skin. It won't cause pathologic change to injured skin by repeated use. So it will not hamper the skin wound from healing.
• 50 kg of the raw material was placed into a ceramic or plastic container.
• Fifty kg of ethanol at 40% concentration was heated to its boiling point, then added into the container containing the fresh Ranunculus japonicus Thunb.
• the contents of the container were heated to boiling.
• the container was sealed and stored for a half year or more in order to polymerize protoanemonin contained in the fresh Ranunculus japonicus Thunb. into anemonin and to dissolve the resultant anemonin in the solvent.
• the anemonin extract can be obtained by cold-extraction for one year or more with ethanol.
• japonic Thiunb.
• an anemonin extract was obtained by hot-extraction or cold-extraction with ethanol, and a preparation suitable for topical application or a liniment was obtained according to the method of Example 1 (dried plants of the herbs can alternatively be used as the raw material).
• Clematis chinensis osbeck herbal pieces or a mixture of Clematis chinensis osbeck herbal pieces and Pulsatilla chinensis (Bge.) Regel herbal pieces was used as raw material.
• the raw material was placed in a container.
• the contents in the container were heated to boiling, and then the container was sealed and stored for 3 months, the contents were stirred once a day to dissolve the anemonin contained in Clematis chinensis osbeck and/or Pulsatilla chinensis (Bge.) Regel herbal pieces into ethanol completely. After filtration and settling a brown anemonin extract liquor was obtained which can be concentrated, refined and granulated to form a granule preparation.
• Clematis chinensis osbeck and Pulsatilla chinensis (Bge.) Regel herbal pieces can be used as the raw material to replace Clematis chinensis osbeck herbal pieces.
• Pulsatilla chinensis (Bge.) Regel whole grass as raw material was steam distillated.
• the resultant distillate was extracted with diethyl ether.
• the anemonin crystal was obtained (which is also market available), which can be used further to prepare preparations for topical application, oral administration, injection, suppository, liniment, etc.
• a liquor which contains about 12.5 mg anemonin per 25 ml liquor was prepared with the anemonin extract obtained in Example 1, and 100 cm 2 wet towels were prepared by soaking non-woven fabrics with the liquor.
• Anemonin powder was added into landline and mixed thoroughly to form an ointment that contains 12.5 mg anemonin per 25 ml.
• the oinment is for topical application that is applied on skin for 5-6 hours per dosage.
• Example 1 commercial name, Guanyin Dew
• mice totaling 80 and each weighed 18-22 g: high concentration group, moderate concentration group, low concentration group (Guanyin Dew was administered at 12.5 mg/25 ml, 8.75 mg/25 ml, and 6.25 mg/25 ml respectively), dolantin group (25 mg/kg) and control group (same volume of 25% ethanol).
• Dolantin was intraperitoneal injected and other groups received test medication on left and right hind feet. 15 minutes after administration, 0.03 ml of 2.5% formalin was given to each mouse by subcutaneous injection on right hind foot and then the test medication was applied again. Then, the number of times of each mouse's licking its right hind foot in 15 minutes was counted.
• This experiment included 4 groups of female mice, totaling 64 and each weighed 18-22 g, selected for normal pain reaction with 55° C. hot plate: high concentration group, low concentration group, dolantin group and control group.
• the route of administration and dosage are the same as described in the test with formalin.
• Dolantin was intraperitoneal injected and other groups received test medication on left and right hind feet and abdomen. 30, 60 and 90 minutes after the administration, the mice were put on a 55° C. hot plate and the latent time of each mouse for pain reaction was determined.
• This experiment included 4 groups of rats totaling 40 and each weighed 200-250 g: high concentration group, low concentration group (12.5 mg/25 ml, 6.25 mg/25 ml respectively), fluocinolone acetonide group, control group (the same volume of 25% ethanol). Fluocinolone acetonide was given using a 0.025% ointment, and other groups received corresponding medicament on the left and right hind feet prior to subcutaneous injection of 0.1 ml of 1% carrageenan on the metatarsus of each rat's right hind foot. Immediately after the administration of carrageenan, corresponding medicament was applied on the right hind foot.
• the metatarsal perimeters of right and left hind foot of each rat were measured 2, 3, 4, and 5 hours after the final administration.
• the difference between the metatarsal perimeters of the two feet of each rat is taken as a measure of swelling.
• Corresponding medicament was applied again on rat's right hind foot after each measurement.

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