CN1144592C - Use of camptotheicin derivatives with reduced gastrointestinal toxicity - Google Patents

Use of camptotheicin derivatives with reduced gastrointestinal toxicity Download PDF

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CN1144592C
CN1144592C CNB998088366A CN99808836A CN1144592C CN 1144592 C CN1144592 C CN 1144592C CN B998088366 A CNB998088366 A CN B998088366A CN 99808836 A CN99808836 A CN 99808836A CN 1144592 C CN1144592 C CN 1144592C
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��H��̩˹
H·图泰恩
M·谷弗洛伊
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Aventis Pharma SA
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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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention relates to the use of camptothecin for preparing medicines for treating cancers of the gastrointestinal tract, provoking fewer gastrointestinal side effects, characterized in that a sodium chloride solution is administered while or before said medicine is administered.

Description

The application of camptotheicin derivatives with reduced gastrointestinal toxicity
The present invention relates to the application of camptothecin derivative, this derivant can not cause that stomach-intestinal does not tolerate side effect, or stomach-intestinal side effect is very little.The invention still further relates to sodium chloride solution and reducing the application in the caused gastrointestinal side-effect by camptothecin derivative.
People know, take camptothecin derivative and can cause many side effect.Especially in gastrointestinal tract, they often cause very serious vomiting and diarrhea, therefore may cause therapy discontinued.
Camptothecin derivative with following general formula was described in European patent EP 137145:
R in the formula 1Be hydrogen, halogen or alkyl, X is chlorine atom or NR 2R 3, R wherein 2And R 3Identical or different, can represent the alkyl that hydrogen atom, optional replace, carbocyclic ring or the heterocycle that optional replaces, or and form heterocyclic alkyl (the optional replacement) with its bonded nitrogen-atoms, this heterocycle optionally contains and is selected from O, S and/or NR 4Another hetero atom, R 4Be hydrogen atom or alkyl, wherein X-CO-O-is positioned at the 9th, 10 or 11 of ring A.These camptothecin derivatives are the anticarcinogen that suppress topoisomerase I, and wherein X-CO-O-is that the irinotecan of (4-(1-piperidino)-1-piperidino) carbonyl oxygen base is to entity tumor, particularly to the effective especially active component of colorectal carcinoma.
Patent application EP74256 has also described other camptothecin derivative, also mentions their useful asticancer agents, and particularly with said structure similar derivative thing, wherein X-CO-O-quilt-X ' R ' base replaces, and X ' is O or S, and R ' is hydrogen atom, alkyl or acyl group.Other camptothecin derivative was for example also described: EP56692, EP88642, EP296612, EP321122, EP325247, EP540099, EP737686, WO9003169, WO9637496, WO9638146, WO9638449, WO9700876, US7104894, JP57116015, JP57 116074, JP59 005188, JP60 019790, JP01 249777, JP01246287, JP91/12070 or at Canc.Res. in following patent or patent application 38(1997), make a summary 1526 or 95 (San Diego-April 12), Canc.Res., 55 (3), 603-609 (1995) or AFMC Int.Med.Chem.Symp. (1997) summary PB-55 (27-August 1 Seoul-July).
Usually camptothecin derivative adopts the injecting method medication, more specifically adopts sterile solution or emulsion intravenous injection medication.The camptothecin derivative of all right oral administration solid or forms of liquid compositions.
Camptothecin derivative also can be united use with other anticarcinogen, for example as cisplatin, oxaliplatin, Tomudex , Taxotere , 5-fluorouracil and thymidylate synthetase inhibitor.
Yet, in the clinical side effects relevant, diarrhea (3 or 4 grades), cholinergic syndrome, n or V are arranged especially with adopting the camptothecin derivative treatment.Especially observe, 38% serious diarrhea patient life danger can occur because of dehydration and/or infections relating.
Once implemented many schemes with antagonism because of taking the intestinal toxicity that this active component produces, its toxicity is reduced to minimum, but not achieving success up to now.This shows that camptothecin derivative is limited to the very oncologist use of rich experiences, only some patient can bear the effect of these derivants.
Find now that purpose also of the present invention just by taking sodium chloride solution, can obtain the protective effect of the stomach-damage of intestines of generation when treat with camptothecin derivative.This protective effect has reduced, even has suppressed stomach-intestinal side effect specifically, and the system's ability to bear or the anti-tumor activity of active component do not reduced.
The present invention relates to sodium chloride in a kind of application that is used for reducing or suppressing to use the medicine of the gastrointestinal side-effect that camptothecin derivative produced of preparation.According to the present invention, the medicine that is used to reduce or suppress to take the gastrointestinal side-effect that camptothecin derivative produces is a sodium-chloride water solution.
Take sodium chloride solution simultaneously with taking camptothecin derivative, perhaps a few days ago take sodium chloride solution taking camptothecin derivative, take camptothecin derivative then simultaneously and can reach this protective effect.
This wonderful effect has very favourable result, particularly can avoid and the unusual relevant therapy discontinued of serious adverse.
According to the present invention, the sodium chloride solution of use is an aqueous solution, and its concentration is the 4-13 grams per liter.This solution orally uses.
Preferably, the concentration of sodium chloride solution of use is 0.9 grams per liter.
Adopt the conventional method of sodium chloride water-soluble (for example purified water, sterilized water) to prepare this sodium chloride solution.This solution can also contain other material, and is concrete as sweeting agent or aromatic.
Continuously 1-5 days with the camptothecin derivative treatment during, stop back 1 day from preceding 5 days of treatment beginning to treatment, can take this sodium chloride solution every day once or secondary, its dosage be the 5-10 ml/kg/time.According to another application method, continuously 1-14 days with the camptothecin derivative treatment during, can take this sodium chloride solution every day once or secondary, its dosage be the 5-10 ml/kg/time, preferably, can take this sodium chloride solution secondary every day, its dosage be 10 ml/kg/time.Preferably, use this sodium chloride solution according to second kind of application method.
Adopt injecting method, preferably adopt intravenous methods, or orally use camptothecin derivative.
When adopting intravenous methods to use camptothecin derivative, these compositionss can also contain additive, particularly wetting agent, isotonic agent, emulsifying agent, dispersant and stabilizing agent.Use the solution of irinotecan (CPT-11) in the intravenous injection medium particularly, its dosage is 175-500 milligram/rice 2
The camptothecin derivative of all right Orally-administered solid composition form, for example snap fit capsule or semi-solid hydrophilic substrate capsule.They can also use with tablet, pill, capsule, capsule, powder or granule.Preferably.Orally administered composition can be made tablet.In all these compositionss, biologically active prod is mixed with one or more diluent or inert additwe, for example sugared, sugar derivatives or hydrophilic macromole, sucrose particularly, lactose, glucose, maltose, D-fructose, Sorbitol, starch, as wheaten starch, corn starch or rice starch, cellulose and derivant thereof, as ethyl cellulose or methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, the methyl hydroxy methocel, methylhydroxypropylcellulose or carboxymethyl cellulose, or natural gum, as arabic gum, Tragacanth, guar gum, alginate, carragenates or dextrin, or protein, sintetics, as polyvinylpyrrolidone, high molecular weight PEGs, or as inorganic product, as silica sol or silicate.These compositionss can also contain other material, and lubricant for example as magnesium stearate, or is used for the coating agent of sustained release.They can also use with pharmaceutically acceptable solution, suspension, emulsion, syrup and elixir form, wherein contain inert diluent, for example water or as the oil of paraffin oil and so on.These compositionss can also contain the material except that diluent, as wetting agent, sweeting agent or aromatic, particularly as sucrose or polyhydric alcohol.
The kit form that should be appreciated that camptothecin derivative and sodium chloride reagent combination also belongs in the scope of the present invention, and wherein the sodium chloride medicament is used for reducing or suppresses because of taking stomach-intestinal side effect that camptothecin derivative causes.
Any type of medicine box all may be fit to, particularly, as an example, with two bottle or many doleiforms formula packing, with the packaged of the ampoule of bottle that camptothecin derivative is housed and one or more dress sodium chloride medicaments, with transfusion bag that camptothecin derivative is housed and one or more bottle or ampoule packaged that the sodium chloride medicament is housed, relate to oral packing and the one or more bottle of sodium chloride medicament or packing of ampoule of being equipped with that camptothecin derivative is housed.Should be appreciated that sodium chloride can be powder or solution to be diluted in above-mentioned bottle or ampoule, the special i.e. solution of usefulness.
Experimentation:
The different researchs of carrying out with Mus and Canis familiaris L. have proved the present invention under the following conditions.
The preparation injection:
Preparation is the injection of main component with the DQ-2805, is 20 mg/ml in the presence of following component:
20 milligrams of DQ-2805
45 milligrams of D-Sorbitols
0.9 milligram of lactic acid
Sodium hydroxide is in right amount to pH=3.5
The ejection preparation water is in right amount to 1 milliliter
2, The experimentation of carrying out with mice
1.1/ Research I
Oral sodium chloride solution is to the evaluation of the enterotoxication protective effect of intravenous injection CPT-11.
CD1 male mice (5-6 age in week) is divided into two groups each 10, from the 6th day to the 10th day continuous 5 days during in, these two groups of all intravenous injections of Mus are (according to 0.5 ml/min, 20 ml/kg) aqueous solution of CPT-11 in 9 grams per liter sodium chloride, injected dose are (about 120 milligrams/meter of 40 mg/kg 2Body surface area).3 days (up to the 13rd days) for the treatment of for nothing after this treatment time.Wherein one group, also continuous 10 days (1-10 days) oral 9 grams per liter sodium-chloride water solutions of these Mus, its volume be 20 ml/kg/skies (be every day 2 times, 10 ml/kg/time, about 10 hours of blanking time) (CPT-11/NaCl group).The not oral 9 grams per liter sodium-chloride water solutions of second treated animal (CPT-11 group).
All these days have all been observed mortality rate and the clinical disease of these Mus.The the 1st, 6,11 and 13 day record body weight.At these Mus death without suffering of the 13rd angel and carry out obduction.Take out complete gastrointestinal tract from all Mus.Finish the gastrointestinal tract of all microexaminations always survival Mus up to this observation.
Observed the Mus mortality rate that uses camptothecin derivative at the 6th or 7 day, the CPT-11 group is 7/15 Mus, and the CPT-11/NaCl group is 2/10.After using CPT-11, observe once in a while and use motion function reduction that CPT-11 brought, tremble, spasm and/or dyspnea.During the CPT-11 treatment, observe losing weight of CPT-11 group and CPT-11/NaCl group Mus.Losing weight of CPT-11 group Mus is more than the CPT-11/NaCl group, and after treatment finished, the body weight of CPT-11 group Mus continued to reduce.
The damage of intestines state of microexamination is corresponding to using the state that anticarcinogen reached.Two groups of Mus all are mainly to cause injury of small intestine.These generally in by the time the feature of significant damage be that the crypts forfeiture is shortened with intestinal villus.The damage of intestines degree of CPT-11/NaCl group Mus is less, and especially this crypts forfeiture is very little, just observes once in a while.
Conclusion, 5 days in advance and during 5 days intravenous injection CPT-11,2 (20 ml/kg/sky) oral sodium chloride isosmotic solution every day (9 grams per liter), its dosage be 10 ml/kg/time, can prevent the appearance of the intestinal tissue pathology damage that CPT-11 causes.
1.2/ research II
The different schemes of oral sodium chloride solution is to the evaluation of the enterotoxication protective effect of CPT-11
CD1 male mouse (5 or 6 age in week) is divided into 5 groups, every group 10, in the 6th day to the 10th day continuous 5 days, intravenous injection is (according to 0.5 ml/min, 20 ml/kg) aqueous solution of CPT-11 in 9 grams per liter sodium chloride solutions, its dosage are that 40 mg/kg (are about 120 milligrams/meter 2Body surface area).The 1st group, from the 1st day to the 10th day every day secondary, according to 10 ml/kg/time (about 10 hours at interval); The 2nd group, from the 1st day to the 10th day every day secondary, according to 5 ml/kg/time; The 3rd group, from the 1st day to the 10th day once a day, according to 20 ml/kg/time; The 4th group, from the 6th day to the 10th day every day secondary, according to 10 ml/kg/time use, 9 grams per liter sodium chloride solutions.The 5th group is not used 9 grams per liter sodium chloride solutions.
All these days have all been observed mortality rate and the clinical disease of these Mus.Measured body weight at the 3rd, 6,10 and 13 day.At these Mus death without suffering of the 13rd angel and carry out obduction.Take out complete gastrointestinal tract from all Mus.Finish up to this observation period, all the gastrointestinal tract of the survival of microexamination always Mus.
Observe clinical diseases and above-mentioned research (studying I) similar of all group Mus.Observe losing weight of all group Mus.
The damage that observed microdamage reaches corresponding to anticarcinogen in intestinal.All group Mus mainly are injuries of small intestine.Only the group with the CPT-11 treatment is not serious for the damage of intestines of oral 9 grams per liter sodium chloride solution groups.On the contrary, 1-4 organizes 9 grams per liter sodium chloride solutions of oral different dosing regimes, and its damage of intestines consequence is identical with seriousness.
Conclusion, before the intravenous injection CPT-11 and during the injection or during only injecting, every day one, oral volume difference (5-20 mg/kg/time) stoped the situation that the intestinal tissue pathology damage that CPT-11 causes occurs similar to the oral sodium chloride of secondary (9 grams per liter) isosmotic solution in 5 days.
1.3/ research III
Oral sodium chloride isosmotic solution is to the system of CPT-11 and intestinal toxicity with to the evaluation of CPT-11 and major metabolite SN-38 toxicity kinetic effect thereof
CD1 male mice (5 or 6 age in week) is divided into 3 groups, every group 10, in the 1st day to the 5th day continuous 5 days, 2 groups of intravenous injections are (according to 0.5 ml/min, 20 ml/kg) aqueous solution of CPT-11 in 9 grams per liter sodium chloride, dosage are that 40 mg/kg (are about 120 milligrams/meter 2Body surface area).It after this treatment phase 3 day period (up to the 8th day) of not having treatment.The Mus of a group in these two groups, during continuous 5 days (1-5 days) in, also oral 9 grams per liter sodium-chloride water solutions, its volume be 20 ml/kg/skies (promptly 10 ml/kg/time, every day 2 times, about 10 hours of interval) (CPT-11/NaCl group).The not oral 9 grams per liter sodium chloride solutions of second group Mus (CPT-11 group).The 3rd group of not intravenous injection of Mus CPT-11, continuous 5 days (1-5 days) oral 9 grams per liter sodium-chloride water solutions, its volume be 20 ml/kg/skies (promptly 10 ml/kg/time, every day 2 times, about 10 hours of interval) (matched group).36 additional animals are used for measuring the plasma concentration of CPT-11 and major metabolite SN-38 thereof in CPT-11 and the CPT-11/NaCl group.
All these days have all been observed mortality rate and the clinical disease of these Mus.Measured body weight at the 1st, 3,6 and 8 day.Get blood plasma at the 1st day and the 5th day and carry out the toxicity dynamic analysis.At these Mus death without suffering of the 8th angel and carry out obduction.Measure the relative weight and the absolute weight of thymus, spleen and testis, and take out complete gastrointestinal tract, bone marrow of sternum, thymus, spleen, intestinal and testis and epididymis, carry out micrography from all Mus.
For the 1st day and the 5th day CPT-11 and CPT-11/NaCl group Mus, the CPT-11 of mensuration was identical with SN-38 (its major metabolite) maximal plasma concentration (Cmax) with area under curve (AUC).
Observe, the mortality rate that injection CPT-11 observed on the 8th day is 1/10 Mus in the CPT-11/NaCl group.In CPT-11 and CPT-11/NaCl group, observe once in a while behind the use CPT-11 and use motion function reduction and the dyspnea that CPT-11 brought, even more serious in the CPT-11/NaCl group.During the CPT-11 treatment, it is identical with losing weight of CPT-11/NaCl group Mus to observe the CPT-11 group.After treatment finished, the body weight of Mus continued to reduce.
The damage that observed thymus and intestinal microdamage reach corresponding to anticancer preparation.Observed CPT-11 is similar with the thymus microdamage of CPT-11/NaCl group Mus, it is characterized in that reducing relevant lymph sample depletion with this organ weight and size.CPT-11 group and the main intestinal microdamage of CPT-11/NaCl group Mus is characterized in that crypts forfeiture and Villus atrophy in small intestinal.CPT-11/NaCl group Mus damage of intestines does not have the CPT-11 group serious.
Conclusion, during 5 days, the oral 9 grams per liter sodium chloride isosmotic solution of secondary every day when intravenous injection CPT-11, be 10 ml/kg (20 ml/kg/skies) at every turn, the system that does not change CPT-11 and SN-38 exposes, do not change the thymus toxicity of CPT-11 yet, but optionally reduced the damage of intestines seriousness that CPT-11 causes.
1.4/ Research IV
Oral sodium chloride solution is to the anti-tumor activity impact assessment of intravenous injection CPT-11
Be divided into two groups at the 1st day female mice C3H/HeN with subcutaneous methods transplanting mammal adenocarcinoma MA16/C, the aqueous solution of every group of all intravenous injections (20 ml/kg) CPT-11 in 5% glucose, its dosage are 14.6-23.6-38.0 or 61.3 mg/litre in continuous 5 days from the 6th day to the 10th day.One group of Mus in continuous 10 days (the 1st day to the 10th day) also every day 2 oral 9 grams per liter sodium-chloride water solutions, its volume be 20 ml/kg/skies (promptly 10 ml/kg/time, every day 2 times, about 10 hours of interval) (CPT-11/NaCl group).The not oral 9 grams per liter sodium chloride of second treated animal.
Estimate the anti-tumor activity of CPT-11 with maximum non-toxic dosage.Cause and lose weight more than 20% or intravenous injection CPT-11 mortality rate is that dosage more than 20% is thought the dosage that toxicity is too strong.Evaluating comprises that inhibition rate of tumor growth (T/C), the tumor growth represented with percent delay rate (T-C) and kill tumor cell number (doubling time of Log kill tumor cell=T-C/3.32 * tumor).Log kill tumor cell value is 0.7 corresponding to minimum active, and is higher than 2.8 value corresponding to the high activity level.
For the CPT-11 treated animal, the maximum non-toxic dosage of CPT-11 is 23.6 mg/kg/day, and promptly adding up accumulated dose is 118 mg/kg, and at the 11st day, losing weight mostly was 10% most, and Log cell killing value is 1.7.For the CPT-11/NaCl treated animal, the maximum non-toxic dosage of CPT-11 is 38.0 mg/kg/day, and promptly adding up accumulated dose is 190 mg/kg, and at the 12nd day, losing weight mostly was 14.0% most, and Log cell killing value is 2.3.
Conclusion, 5 days in advance and when 5 days intravenous injection CPT-11,2 (20 ml/kg/sky) oral sodium chloride isosmotic solution every day (9 grams per liter), its dosage be 10 ml/kg/time, do not reduce the anti-tumor activity of CPT-11.
2/ The experimentation of Canis familiaris L.
Oral sodium chloride solution is to the evaluation of intravenous injection CPT-11 intestinal toxic effect
Six female beagles (age 10-12 month) are divided into two groups, and 3 every group, every group all at the aqueous solution of an intravenous injection in the 6th day (5 ml/kg, 2 ml/min) CPT-11 in 9 grams per liter sodium chloride, and dosage is (about 400 milligrams/meter of 20 mg/kg 2Body surface area).One group of Canis familiaris L. in the past 5 days behind the injection CPT-11 in 1 day continuous 7 days (the 1st day to the 7th day), also oral 9 grams per liter sodium-chloride water solutions, its volume be 20 ml/kg/skies (promptly 10 ml/kg/time, every day 2 times, about 8 hours at interval) (CPT-11/NaCl group).The not oral 9 grams per liter sodium chloride of second treated animal (CPT-11 group).2 days (up to the 9th day) be not to animals administer behind the in the end oral 9 grams per liter sodium chloride.
Mortality rate and clinical disease are all observed in all these skies.During trial test and at the 5th day and the 9th day, write down body weight.At these Mus death without suffering of the 9th angel and carry out obduction.Take out representational stomach intestinal tissue sample from all these animals, and carried out micrography.
The influence of CPT-11 administration comprises that sialism, dysphoria, vomiting (during the CPT-11 administration or after the administration at once), diarrhea and body weight alleviate a little during treating.It is coarse to observe big intestinal mucosa appearance, and the CPT-11 group this phenomenon occurs more frequently than the CPT-11/NaCl group.Viewed these damages are that the constitutional pathological changes by the hypertrophy chamber causes, and comprise that mucosa degenerates, these damages in the CPT-11 group be in by the time significantly, be minimum to slightly in the CPT-11/NaCl group.
Conclusion is given only CPT-11 of intravenous injection of female Canis familiaris L., and its dosage is 20 mg/kg, and the stomach that causes-intestinal toxicity can be compared with the resisting mitosis activity of product.In the past 5 days to injection CPT-11 the 1st day, 2 (20 ml/kg/sky) oral sodium chloride isosmotic solution every day (9 grams per liter), dosage be 10 ml/kg/time, stoped the unexpected appearance of the intestinal tissue pathology damage that CPT-11 causes.

Claims (7)

1, sodium chloride is used for reducing or suppressing to use the application of the medicine of the stomach-intestinal canal side effect that camptothecin derivative caused in preparation.
2, application according to claim 1, it is characterized in that being used to reduce or suppressing to use the medicine of the stomach-intestinal canal side effect that camptothecin derivative caused is sodium-chloride water solution.
3, application according to claim 2 is characterized in that sodium-chloride water solution concentration is the 4-13 grams per liter.
4, application according to claim 3 is characterized in that sodium-chloride water solution concentration is 9 grams per liters.
5, according to claim 3 or 4 described application, it is characterized in that the sodium chloride solution using dosage be the 5-10 ml/kg/time.
6, according to the described application of arbitrary claim among the claim 1-5, it is characterized in that during using camptothecin derivative or before using described derivant and during, use sodium chloride solution.
7, application according to claim 1 is characterized in that adopting injection or oral route administering camptothecin derivant.
CNB998088366A 1998-08-05 1999-08-03 Use of camptotheicin derivatives with reduced gastrointestinal toxicity Expired - Fee Related CN1144592C (en)

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Application Number Priority Date Filing Date Title
FR9810043A FR2782009B1 (en) 1998-08-05 1998-08-05 USE OF COMPTOTHECIN DERIVATIVES WITH REDUCED GASTROINTESTINAL TOXICITY
FR98/10043 1998-08-05

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CN1354667A CN1354667A (en) 2002-06-19
CN1144592C true CN1144592C (en) 2004-04-07

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