CN1686139B - Application of ketanserin in a new type of analgesic for the treatment of inflammatory pain - Google Patents
Application of ketanserin in a new type of analgesic for the treatment of inflammatory pain Download PDFInfo
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Abstract
The invention is an application for a novel purpose and a novel usage of medicine, specifically relates to a preparation method of ketanserin, the exterior-applied analgesic medicine, for treating inflammatory pain and hypertension adjuvant therapy. According to the pathogeny of the pain and the blocking 5-HT2A receptor character of the ketanserin, the ketanserin is as the functional ingredient, and the adhesive containing gelatin and cellulose sodium CM, the humectant prepared from DMSO and propanetriol, and excipient prepared from kaolinite, levo-camphor and water are auxiliary material, in conclusion, the ketanserin exterior-applied analgesic medicine is prepared. According to the different of the used part or the status of the wound, the medicine is further prepared as patch type, mastic type and liquid type ketanserin exterior-applied analgesic medicine, by using the local delivery mode, the medicine can act on the inflammation part through the skin, and the medicine has stable and lasting analgesic curative effect and can reach the purpose of a permanent cure. The oral or injection ketanserin is prepared as a external used medicine, which is easy to use without toxic and side effects and also has no influence for the blood pressure of normal people.
Description
Technical field
The invention belongs to the application invention of new medicine use and new usage, relate to specifically a kind of being main component only clinically as the ketanserin of hypertension auxiliary treatment, the application on the topical application analgesic of preparation treatment pain.
Background technology
Pain is the symptom of many sufferers.Clinically, half being arranged at least among the patient is to seek medical advice because of pain.Pain causes patient and torments and misery, reduces the quality of life greatly; Pain make people's ability to work weaken, until completely losing, these all greatly influence people's lives.
Palliate the agonizing sufferings, improve quality of the life, just must pain management.To treatment of pain is main with medicine still at present basically.Used clinically analgesic can be divided into two types of central anesthesia type analgesic (like opium kind analgesics) and non-narcotic type analgesic (analgesic type of analgesic).The former effect is strong but side effect (Wheeler et al., 2002) such as addiction, drug resistance, inhibition are breathed, felt sick, constipation are arranged; Though a little less than latter's side effect slightly, analgesia effectiveness is not good enough.
Owing to lack analgesic high-effect, that have no side effect; And the market of analgesic is very big, so each big drugmaker has all dropped into a large amount of manpower and financial resources in the world, develops high-effect analgesic.External development work; Basically all concentrating on receptor such as opium, NMDA, NK1, COX, NO, Adenosine, VR1 and Cannabinoid or albumen is target spot or the derivant of seeking morphine, manages to change its structure to reach the purpose that reduces side effect.Like (United States Patent (USP)s 6150524 such as Hartmannd; On November 21st, 2000) and (United States Patent (USP) 6177438 such as Nagased; January 23 calendar year 2001).Because the exciting or inhibition of the similarity of structure and corresponding receptor still can produce the side effect beyond the analgesia.
In order to keep analgesic effect; Weaken the side effect of opium kind analgesics, CN1386505A discloses " Na-ion channel blocker and opioid analgesic are used for the application that mammal carries out the medicine of synergic antalgic in preparation " patent application case of Weikesi Medical Instrument Co Ltd's application.This invention design can prepare the application that is used for mammal is carried out the medicine of synergic antalgic with being combined in of opioid analgesic with the SS1 of the α-subunit of sodium-ion channel or the bonded Na-ion channel blocker of outer end acceptor site at SS2 position.Though this invention can reduce side effect and bad reaction on certain Cheng Du, but still has used the opiates medicine of doses.
Because the side effect of analgesic mainly comes from the central nervous system, closely during the last ten years, many researcheres have turned to periphery to attention.Big quantity research shows that the many receptors that exist in the peripheral nervous system all participate in pain and form or modulate, like opium (Hong and Abbott, 1995; Yaksh, 1997), glutamate (Carlton, 2001; Neugebauer, 2001), CB1 and CB2 (Palmer et al., 2002), prostaglandin (Francischi et al., 2002; Ito et al., 2001) or the like.The activation of these receptors or inhibition all can inhibition of pain, show that the analgesic mechanism of utilizing peripheral nervous system is eased pain to be well worth doing.
What the present invention proposed is the thinking and the plan of a new research and development analgesic.The present invention also not merely just keeps a close watch in the peripheral tissues these and participates in pain and form or synthetic receptor; The more important thing is from numerous link chains that peripheral pain forms; Find out main key link, medicament interrupts this link chain, thereby reaches the analgesic purpose.
Pain is divided fast pain (first pain) and slow pain (second pain).The fast pain of mechanoreceptor (mechanorecep-tors) impression, its accurate positioning stops and stopping with stimulation.More strong impulse then activates the nociceptors (polymodal nociceptor) of feeling more, produces disperse, persistent period pain more of a specified duration, i.e. slow pain.Pain during inflammation damnification mainly is slow pain character.Inflammation damnification makes tissue discharge many ions and molecule; Reduce the threshold value of many feel nociceptors; Cause periphery sensitization (peripheral sensitization), consequently non-nocuous stimulation also can be got excited to the maincenter granting by the excitement receiver, causes pain perception.These chemokineses comprise hydrion, potassium ion, PGE (prostaglandin), the peptide of releiving (bradykinin), 5-HT (five-hydroxy color amine), P material, ATP (ATP), norepinephrine (norepinephrine), adenosine (adenosine), nerve growth factor or the like.They all have effect in the formation of pain, each factor can both be drawn the survey article that a big piece of writing can comprise at least tens pieces of lists of references.
Hong Yanguo observes, same PGE
2, norepinephrine, bradykinin, substance P and histamine etc. compare, 5-HT plays a part in the formation of pain important and outstanding (Hong and Abbott, 1994).This inflammatory factor disengages (Lehtosalo et al., 1984 by platelet and mast cells when inflammation damnification; Anden and Olsson, 1967).In subcutaneous (Maeno et al., 1991) of being wound, neural (Anden and Olsson, 1967 located; Vogel et al., 2003) or intraarticular (Tominaga et al., 1999), the burst size of 5-HT increases greatly.With the content of 5-HT reuptake inhibitor increase intraarticular 5-HT, can obviously increase the weight of the inflammation edema (Harbuz et al., 1998) of rheumatic arthritis.Inject 5-HT and can cause a large amount of inflammatory exudations of synovium of joint (Grond et al., 2001) to the joint; And giving 5-HT antagonist, the inflammatory exudation and the arthralgia of synovium of joint significantly alleviates (Pierce et al., 1995).Human body data also confirms, (Ern-berg et al., 1999) and impaired intraarticular (Kopp, 1998 at the inflammation place; Pain degree when Alstergren and Kopp, 1997), the increase of 5-HT content is with hyperpathia or joint motion is directly proportional.The serum 5-HT level of rheumatic arthritis is apparently higher than healthy subjects, and pain caused also being proportionate with level serum 5-HT of patient's joint motion is (Kopp and Alstergren, 2002).Place people's tissues such as skin to 5-HT, can cause pain perception (Armstrong et al., 1953; Richardson et al., 1985b; Jensen et al., 1990).This explains that all periphery 5-HT is the important factor (Beck and Handwerker, 1974 bitterly of causing; Herbertand Schmidt, 1992).
The remarkable enhance mechanical of 5-HT stimulates (Vinegar et al., 1989), thermostimulation (Rang et al., 1991) and other inflammatory factors (substanceP, noradrenaline, PGE
2, bradykinin etc.) cause pain effect (Hong andAbbott, 1994; Khalil and Helme, 1990).This specific character has more clinical meaning, because inflammation, the chemokines that discharges when damaging and their interaction just just causes clinical pain.In the middle of this factor that plays a major role must be arranged.The facilitation effect that 5-HT shows shows that it has special effect in the pathological process of pain.At formalin (formalin) (Abbott et al.; 1997), carrageenin (carrageenan) (Di Rosa et al.; 1971), adjuvant (complete Freund ' s adjuvant or CFA) (Okamoto et al.; 2002) and in the arthritis models such as (Pertsch et al., 1993), confirm that all 5-HT is the very important pain factor that causes.The excited C fiber of 5-HT ability (Beck and Handwerker, 1974; Herbert and Schmidt, 1992), the irritability (Cardenas et al., 2001) of increase dorsal root ganglion minicell causes that calcitonin gene-related peptide discharges (Tramontana et al., 1993).These are the neurological mechanism that 5-HT causes noxious stimulation.
Express several kinds of 5-HT receptor subtypes on the sensory neuron, as, 5-HT
1A, 5-HT
2, 5-HT
3, 5-HT
4Receptor etc., sexual stimulus (Richardson et al., 1985a all maybe sense of participation be hurt; Eschalier et al., 1989; Giordano and Rogers, 1989; Taiwo and Levine, 1992; Doak and Sawynok, 1997; Parada et al., 2001).The excited periphery nociceptor of the activation energy of its receptor, or improve the irritability of nociceptor, the former imports the central nervous system into, causes pain perception; The latter then also makes body be felt as pain when receiving the non-noxious stimulation that touches gently.
Hong Yanguo etc. confirm (1996 (Abbott et al., 1996)) first clearly, 5-HT to cause the pain effect mainly be by 5-HT
2AReceptor-mediated, rather than other 5-HT receptor (Abbott et al., 1996).This research conclusion receives publicity immediately, and obtains Canadian Sawynok (1997 (Sawynok et al., 1997)) successively; U.S. Coggeshall (1997 (Carlton and Coggeshall; 1997)), Japanese Senba and Okado (1998 (Tokunaga et al., 1998; Maeshima et al., 1998) confirmation) etc.
Ketanserin is a kind of oral medicine, and the injection dosage form is also arranged, and only is used for auxiliary treatment hypertension clinically, and up to now, never the someone uses ketanserin to be used to treat pain both at home and abroad.The ketanserin chemical structural formula is C22H22FN3O3.C4H6O6; The chemistry name be 3-[2-[4-(4-Fluoro-benzoyl)-1-piperdinyl] ethyl]-2,4 (1H, 3H)-quinazolinedione; Its molecular weight is near 400; Oral post-absorption is complete, bioavailability 50%, and plasma protein binding rate is up to 91%; At liver metabolism, most of metabolite is drained in urine, discharges with stool on a small quantity; Half-life 12-25 hour.Effect is slowly gentle after this medicine oral absorption, takes for a long time to have no drug resistance.Ketanserin is to 5HT
2The selective blocking effect of receptor also has faint α
1And H
1Receptor antagonism, thus the vasoconstriction that 5-HT brings out suppressed, reduce peripheral vascular resistance.Ketanserin can also suppress 5-HT makes platelet aggregation, suppresses the vasoconstriction effect of amine substance, and histamine H 1/2 receptor is had slight inhibitory action.Ketanserin is very little to normal person's heart rate and blood pressure influence.Simultaneously can reduce Peripheral resistance, more obvious to the reduction of renal vascular resistance, to blood fat good influence can be arranged, reduce serum total cholesterol, triacylglycerol, low density lipoprotein, LDL and high density lipoprotein increasing, do not influence carbohydrate metabolism.To occlusion vascular disease change person is arranged, can improve the lower extremity blood flow supply.To Raynaud disease person can improve tissue blood perfusion, SkBF is increased.Can reduce right atrial pressure, pulmonary artery pressure and pulmonary capillary mold pressing after the intravenous injection.
It is unclear so far that ketanserin can be used for treating hypertensive mechanism, but with itself primitive attribute-blocking-up 5-HT
2AReceptor is irrelevant basically.Ketanserin blocking-up 5-HT
2AThe primitive attribute of receptor, the present invention selects the basis of this medicine as new medicine use for use just.
Summary of the invention
One of content of the present invention is a use of approved drugs for nonapproved uses.The present invention has blocking-up 5-HT according to the pathogeny and the ketanserin of pain
2AThe characteristic of receptor only as the ketanserin of hypertension auxiliary treatment, is used to treat pain with clinically.
Ketanserin is used for treating the application of inflammatory pain medicine in manufacturing.
Said medicine contains adhesive, wetting agent and the excipient that promotes skin absorbs, and said adhesive comprises gelatin and CM cellulose sodium salt, and said wetting agent comprises DMSO and glycerin; Said excipient comprises Kaolin, left-handed Camphora and water, and each proportion of raw materials is: ketanserin 0.25g, Kaolin 1.9g; Left-handed Camphora 0.125g, glycerin 0.725ml, DMSO 50ml; Gelatin 0.7g, CM cellulose sodium salt 1.4g, water 20ml.
The dosage form of said medicine is patch type, putty-type or water aqua type.
The medicine coating layer thickness of said patch type medicine is 0.5mm.
Said inflammatory pain is an arthritis pain.
Two of content of the present invention is the pathogeny according to pain; With ketanserin is main functional ingredient; The excipient that is aided with wetting agent, Kaolin and the left-handed Camphora and the water of the adhesive, DMSO and the glycerin that contain gelatin and CM cellulose sodium salt, system respectively becomes the former medicine of ketanserin external application analgesic medicine.
According to the difference of using the position or the situation of wound, further be mixed with patch type, putty-type, water aqua type ketanserin external application analgesic medicine, adopt topical, the multiple inflammatory pain sufferer of treatment mammal, especially human body.
The concrete technical scheme of the present invention is following:
1, former medicine composition of ketanserin external application analgesic medicine and proportioning
Ketanserin 0.25g
Kaolin 1.9g
Left-handed Camphora 0.125g
Glycerin 0.725ml
DMSO 50ml
Gelatin 0.7g
CM cellulose sodium salt 1.4g
Water 20ml
Process for preparation:
1) take by weighing ketanserin 2.5g, add DMSO50ml, glycerin 7.25ml, it is subsequent use to mix well formation medicinal liquid A;
2) get a certain amount of Kaolin and in mortar, grind into fine powder after, take by weighing 19 and restrain in the ceramic whiteware bowl, add left-handed Camphora 1.25g, mix well the formation medical liquid B;
3) merging A becomes C subsequent use with B;
4) take by weighing gelatin 7 grams, CM cellulose sodium salt 14 grams respectively, add water 200 grams in 61 ℃ hot baths, the heated and stirred dissolving, it is subsequent use to process medicinal liquid D;
5) C and D are mixed, modulation evenly, the former medicine of pasty state ketanserin external application analgesic medicine.
2, ketanserin external application analgesic plaster agent
Process for preparation: the aforementioned former medicine of ketanserin external application analgesic medicine for preparing, be uniformly coated on the rubber plaster, coating thickness is about 0.5mm, the agent of ketanserin external application analgesic plaster.
3, ketanserin external application analgesic ointment agent:
Process for preparation: the aforementioned former medicine of pasty state ketanserin external application analgesic medicine for preparing; Add in advance through the dissolved 3.5 gram gelatin of 61 ℃ hot bath, 7 gram CMC, 100 gram aqueous solutions; Stir; Process semi-fluid paste medicinal liquid, inject in the soft package bodies such as aluminum matter like the toothpaste shelly, plastics matter, the agent of ketanserin external application analgesic ointment.Can extrude during use and be applied in the affected part.
4, ketanserin external application analgesic liquid medicine agent
Process for preparation: the aforementioned former medicine of pasty state ketanserin external application analgesic medicine for preparing, add 250 ml water solution, stir, process the flow-like medicinal liquid, inject in the Packaging Bottle such as vial, plastic bottle, the agent of ketanserin external application analgesic liquid medicine.Can use absorbent cotton etc. to be applied in the affected part during use or soak the affected part.
Description of drawings
Fig. 1: the rat foot preclinical situation of change that bounces back is observed in the effect that the ketanserin patch brings out arthritic mechanical hyperalgesia to Kaolin (kaolin) and carrageenin (carrageenan).
Among Fig. 1, gave rat intraarticular injection 100 μ l4% Kaolin, inject 100 μ l2%carrageenan behind the movable 5min again in same position, use with quadrat method for other two groups and make arthritis model at 0 hour.Illustrated time point respectively the inflammation foot of test animal to mechanical stimulus (50g, contract (paw withdrawal latency or PWL) during foot reflex 10s).Before injectable drug, test (in 10 minutes) PWL 3 times, its mean values is as basic value (baseline).Second group and the 3rd group is on arthritis model, to use the patch that does not contain and contain 1% ketanserin respectively to spread on the affected part, and patch used for two weeks continuously.Numerical value among the figure is all represented meansigma methods ± standard error.
*Represent the statistical procedures result between second group and the 3rd group; Wherein * representes P<0.05;
* *Expression P<0.001.---be illustrated in and use patch between Day2 and the Day14 continuously.
Fig. 2: the ketanserin patch brings out the knee joint swelling degree change situation of arthritis to Kaolin and carrageenin.
Among Fig. 2, gave rat intraarticular injection 100 μ l4%kaolin at 0 hour, inject 100 μ l2%carrageenan behind the movable 15min again in same position, movable again 5min uses with quadrat method for other two groups and makes arthritis model.Measure the kneed girth of animal, i.e. swelling degree respectively at illustrated time point.Before injectable drug, measure the kneed girth of rat, as basic value.Second group and the 3rd group all is on the basis of arthritis model, to use the patch that does not contain and contain 1% ketanserin respectively to spread on the affected part, and patch used for two weeks continuously.Numerical value among the figure is all represented meansigma methods ± standard error.* represent the statistical procedures result between second group and the 3rd group; Wherein * representes P < 0.05; * * representes P < 0.001.---be illustrated in and use patch between Day2 and the Day14 continuously.
The specific embodiment
Topical application " ketanserin patch " is to the analgesic activity of rat arthritis
1 materials and methods
1.1 reagent and material
Carrageenan (U.S. Sigma company); Ketanserin (Sigma company); Kaolin (Shanghai chemical reagents corporation of Kaolin Chinese Medicine group); Gelatin (Gelatin Tianjin chemical reagents corporation); CM cellulose sodium salt 800～1200 (Shanghai chemical reagents corporation of CM-Cellulose Na Salt Chinese Medicine group); Synthetic left-handed Camphora (chemical plant, Huangpu, Guangzhou); Glycerin (Glycerol Shanghai chemical reagent company limited); Dimethyl sulfoxine (Dimetyl Sulfoxide, Shanghai chemical reagents corporation of DMSO Chinese Medicine group); Medical rubber cream (Yongning, Hangzhou that pharmaceutcal corporation, Ltd).
The patch manufacture method: adhesive (gelatin, CMC), wetting agent (glycerin), excipient (Kaolin) were with 1: 2: 1 mixed, and ketanserin is by the weighing of pain weight.The actual content that specifically is the various prescriptions of A part is: Kaolin 1.9g, left-handed Camphora 0.125g, ketanserin 0.25g, DMSO5ml, glycerin 0.725ml.Because of the solvent of ketanserin is DMSO, so regard DMSO as wetting agent, about 5g adds the glycerin of 1g, about 0.725ml again.The actual content of the various prescriptions of B part is: gelatin 0.7g, CMC1.4g, water 20ml.After AB two parts dissolve separately, remix, modulation is evenly, and is subsequent use.Coat on the rubber plaster, about 0.5mm is thick.Time spent is cut into required size, is affixed on rat knee joint place.
1.2 main experimental apparatus
Photoelectricity stimulates appearance UGO BASILE (7340 types, Italian instrument and equipment company limited);
1.3 laboratory animal
Male Sprague-Dawley rat, body weight 250～300 grams.Provide by Medical University Of Fujian's Experimental Animal Center.
1.4 experimental technique
1.4.1 experiment is prepared
Per three mouse are put in the same cage, food and water sufficient supplies, and bedding and padding are clean.Adopt illumination/12 hour dark circulation illumination in 12 hours, illumination is sufficient, and temperature remains on 22 ± 1 ℃; Begin to train mouse in the first five sky of experiment, make it adapt to experimental situation.Every day is section training mouse at one time.In the experimentation, every mouse is only used once.
1.4.2 behavioristics's experiment
Male SD rat is divided into blank group (Kaolin+Carrageenan), experiment contrast group (Kaolin+Carrageenan-patch substrate) and drug group (Kaolin+Carrageenan+ ketanserin-1% ketanserin patch) at random.Day0 is (the Paw Withdrawal Latency during to the foot rebound reflex of the sole rear portion mensuration rat of rat with the light electric stimulating instrument earlier; PWL), again rat is anaesthetized with that (65mg/kg) of pentobarbital, in rat knee joint cavity injection 4%Kaolin100 μ l; Articular cavity is stretched bent alternating movement 15min; The injection 2%Carrageenan100 μ l in same position again makes the joint 5min that moves equally again, makes arthritis model.Measure PWL behind the 4h once more.Blank group, experiment contrast group and drug group every day continue 14 days, and all measure the situation of change of knee joint girth every day in same timing PWL; Wherein, after the experiment contrast group is measured PWL every day, do the not patch of drug at the knee joint place; After experimental group is measured PWL every day, apply 1% ketanserin patch at the knee joint place.
1.5 date processing
PWL numerical value to blank group, experiment contrast group and drug group is added up with one-way ANOVA, and data are with average ± standard deviation (x ± s) expression.< 0.05 shows that significant difference is arranged to P; < 0.01 has significant differences to P; < 0.001 has utmost point significant difference to P.
2 results
2.1 experimental phenomena
The normal rat extremity are movable normal, WD.Kaolin and Carrageenan are after 4 hours in injection, and rat injection side hind leg can not bear a heavy burden, normal cyllopodia and going, and this phenomenon lasting 5 days always can alleviate gradually later on, and the body weight of rat obviously alleviates.But, apply the patch that contains 1% ketanserin every day after, rat hindlimb can be born body wt, the cyllopodia phenomenon obviously alleviates.
The preclinical situation of change 2.2 the rat foot bounces back
Visible from Fig. 1, the basic PWL value (before being injectable drug) of blank group, experiment contrast group and drug group all about 9sec, statistical comparisons there was no significant difference between three groups; Behind the 4h, PWL obviously descends, and with basic value significant difference (P < 0.001) (figure on less than demonstration) is arranged relatively; And blank group and experiment contrast group more all have significant difference (P < 0.001) in the PWL of whole experimental stage and basic value, and PWL touches the bottom when 4h.Promptly in whole arthritis model, Kaolin and Carra-geenan can cause hyperpathia, and its time can continue for two weeks, and 4h is ebb.
In the whole experimental stage, the blank group is compared with the experiment contrast group does not all have significant difference at each time point; And experiment contrast group and drug group are relatively; Three time points that do not have applicator (containing 1% ketanserin) (4h) there was no significant difference; (be significant difference during at Day2 and Day14, P < 0.05 and at ten time points of other applicator (containing 1% ketanserin) significant difference is arranged all; When Day3～Day12 is utmost point significant difference, P 0.001).
2.3 rat knee joint swelling degree change situation
Visible from Fig. 2, the basic value (before the injectable drug) of blank group, experiment contrast group and drug group all between 7.5～8cm, statistical comparisons there was no significant difference between three groups; Behind the 4h, the knee joint swelling degree of three groups of rats all obviously increases, and peaks during Day1, and the swelling degree is maximum.In two weeks subsequently, the swelling degree descends to some extent, but does not get back to original basis value level all the time.Blank group and experiment contrast group are relatively; Each time point does not all have significant difference, and experiment contrast group and drug group are relatively, is obvious difference (P < 0.05) at Day2; Day14 until after this is variant, and is utmost point significant difference (P < 0.001).Promptly the patch of drug Ketanserin1% does not play antiinflammation to the swelling that arthritis causes, and the patch of drug Ketanserin1% has good antiinflammation to the inflammation that Kaolin and Carrageenan cause.
It is main medicine that the present invention's use has been widely used in treating hypertensive ketanserin clinically, is aided with the additive that promotes skin absorbs, according to the difference of using the position or the situation of wound; Process patch, unguentum, water preparation,, make it see through skin through local percutaneous dosing; Act on inflammation part; Interrupt the inflammation loop chain, the 5-HT that in inflammatory pain, plays an important role can't be played a role, effect a permanent cure and pain relieving.In addition, according to our nearest experimentation, ketanserin also takes stopgap measures and pain relieving.Effect a permanent cure and take stopgap measures, make thus pain palliation efficacy not only really, but also lasting.Oral or injection ketanserin are mixed with medicine for external use, easy to use, have no side effect, degree of safety is big, and does not influence normal person's blood pressure.
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| CN1923206A (en) * | 2006-09-21 | 2007-03-07 | 中国人民解放军第二军医大学 | Application of ketanserin in preparing medicine for preventing cerebral apoplexy |
| CN101579346B (en) * | 2008-05-14 | 2011-01-19 | 中国人民解放军第二军医大学 | Pharmaceutical composition and kit containing amlodipine and ketanserin and application thereof |
| CN101732317B (en) * | 2009-12-05 | 2012-09-05 | 洪炎国 | Analgetic composition and application thereof |
| CN114712378B (en) * | 2022-05-06 | 2024-10-22 | 延安大学 | Application of ketanserin and glycyrrhizic acid in the preparation of drugs for treating pain |
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| WO1991002527A1 (en) * | 1989-08-21 | 1991-03-07 | Beth Israel Hospital Association | Method and composition for the treatment of cutaneous, ocular, and mucosal hypersensitivity, inflammation, and hyperproliferative conditions using topical preparations of serotonin antagonists |
| CN1123171A (en) * | 1994-11-23 | 1996-05-29 | 沈阳市科进工程技术有限公司 | Technology for preparation of "Barbe" preparation and product thereof |
| US6214884B1 (en) * | 1998-04-10 | 2001-04-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Composition comprising ketanserin and L-carnitine or an alkanoyl L-carnitine for the treatment of CRPS |
| CN1306862A (en) * | 2000-01-24 | 2001-08-08 | 中国中医研究院中药研究所 | Matrix for Chinese medicine plaster and its preparation technology |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991002527A1 (en) * | 1989-08-21 | 1991-03-07 | Beth Israel Hospital Association | Method and composition for the treatment of cutaneous, ocular, and mucosal hypersensitivity, inflammation, and hyperproliferative conditions using topical preparations of serotonin antagonists |
| CN1123171A (en) * | 1994-11-23 | 1996-05-29 | 沈阳市科进工程技术有限公司 | Technology for preparation of "Barbe" preparation and product thereof |
| US6214884B1 (en) * | 1998-04-10 | 2001-04-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Composition comprising ketanserin and L-carnitine or an alkanoyl L-carnitine for the treatment of CRPS |
| CN1306862A (en) * | 2000-01-24 | 2001-08-08 | 中国中医研究院中药研究所 | Matrix for Chinese medicine plaster and its preparation technology |
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| 刘国树，黄大显，杨兴生，等..ketanserin治疗原发性高血压病的临床观察.临床内科杂志11 4.1994,11(4),16-17. |
| 刘国树,黄大显,杨兴生,等..ketanserin治疗原发性高血压病的临床观察.临床内科杂志11 4.1994,11(4),16-17. * |
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