CN1555808A - Malaria fewer preventing medicinal composition - Google Patents

Malaria fewer preventing medicinal composition Download PDF

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Publication number
CN1555808A
CN1555808A CNA2003101103187A CN200310110318A CN1555808A CN 1555808 A CN1555808 A CN 1555808A CN A2003101103187 A CNA2003101103187 A CN A2003101103187A CN 200310110318 A CN200310110318 A CN 200310110318A CN 1555808 A CN1555808 A CN 1555808A
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azithromycin
malaria
benflumetol
resistance
medicine
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CN1218702C (en
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王京燕
李国福
王洪权
丁建新
张敏
纪晓光
赵京花
赵艳红
窦媛媛
贝祝春
马宏安
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Tibet Everlasting Investment Co ltd
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Institute of Microbiology and Epidemiology of AMMS
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

A composite medicine for preventing malaria is prepared from naphtholquine phosphate or benflumetol and azimycin. Its advantage is durable preventing effect.

Description

Malaria prophylactic agent compositions
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of compound medicines of prevention of malaria.
Background technology
Malaria is one of the most serious in the world arthropod borne infection.The whole world still has more than 90 country, 2,400,000,000 people to live in the popular district of malaria at present, 500,000,000 people morbidity is arranged, more than 200 ten thousand people's death every year.China's malaria in recent years is ascendant trend year by year, still has 19 provinces, cities and autonomous regions to have malaria popular.Since the sixties in last century, Plasmodium falciparum produced resistance to chloroquine, the Drug resistance plasmodium had been dispersed throughout the popular area of all subtertian malarias, the whole world, and resistance level constantly strengthens, and is developed to multi-drug resistance by single resistance.Arteannuin that China develops the seventies and derivant thereof are because its brand new and efficient, quick-acting is set up new milestone on the antimalarial research history.The research of China's antimalarial takes the lead in the world, except that arteannuin and derivant thereof, in recent years also develop benflumetol, NAPHTHOQUINE PHOSPHATE, Coartem (Artemether+benflumetol), compound naphthoquine phosphate new drugs such as (NAPHTHOQUINE PHOSPHATE+arteannuin), but all these medicines all belong to medicine for treatment, do not have preventive effect.Although abroad in the research of malaria preventive drug, do a lot of work, but the medicine of really taking out has only the mefloquine of U.S. army's development, though this medicine has long-acting preventive effect and since its serious nerve, Psychotoxicity and resistance occur rapidly make its application be subjected to very big restriction.Anti-II (sulfamethoxine+pyrimethamine) of the malaria preventive drug of using China seventies in last century and anti-III (piperaquine+sulfamethoxine), all former thereby ineffective owing to resistance.At present, the whole world does not all have selectable malaria preventive drug.Because it is also faster than the speed of new drug research that plasmodium produces the speed of resistance, WHO actively advocates and uses compound recipe to carry out malaria control.The present invention carries out the experiment of science compatibility by the medicine to existing the long half-lift, has potentiation in the hope of finding, preventive effect, overcomes the new compound that produces with delaying drug resistance, to solve the problem that does not have the malaria preventive drug at present.
Summary of the invention
The objective of the invention is to NAPHTHOQUINE PHOSPHATE and benflumetol serves as the main while 5 to join the component that other has lasting effect, provides a kind of malaria is had long-acting preventive effect, delays or overcome the resistance generation of medicine, the pharmaceutical composition of prolong drug effective life.
A kind of malaria prophylactic agent compositions provided by the invention comprises that a kind of and azithromycin in NAPHTHOQUINE PHOSPHATE, the benflumetol is compound.
Wherein, the compound weight ratio of described NAPHTHOQUINE PHOSPHATE or benflumetol and azithromycin is 4: 1~1: 4, is preferably 1: 1~1: 2; The best is 1: 1.
Above-mentioned malaria prophylactic agent compositions, also comprise other acceptable accessories, described adjuvant is one or more in starch, carboxymethyl starch sodium, microcrystalline cellulose rope, lactose, sucrose, polyvinylpyrrolidone, hydroxypropyl cellulose, amylum pregelatinisatum, micropowder silica gel, magnesium stearate, crospolyvinylpyrrolidone or the Polyethylene Glycol.
The present invention provides the application of aforementioned pharmaceutical compositions in the malaria prevention simultaneously.
The present invention formed compound medicines with naphthols quinoline or benflumetol and azithromycin by 4: 1~1: 4, and malaria is had long-acting preventive effect, and prevention can reach for 3~4 weeks on animal model; The data show of toxicity test, the compound recipe that the present composition two component medicines are formed does not increase poison, and target organ does not have change; The cross-resistance experiment shows that compound recipe can delay the speed that single medicine resistance produces, and reduces resistance level; Delay the time that the Drug resistance experiment shows that the obvious delaying drug resistance of present composition energy produces, and can reduce resistance level.
Description of drawings
Fig. 1 is naphthols quinoline 5 usefulness azithromycin orthonormal design of experiments ED as a result 90The phase ledger line;
Fig. 2 is benflumetol 5 usefulness azithromycin orthonormal design of experiments ED as a result 90The phase ledger line.
The specific embodiment
For opener, below from several respects narration the present invention.
The present invention to provide for serving as that main composite other simultaneously has the component of lasting effect with NAPHTHOQUINE PHOSPHATE and benflumetol, malaria is had the pharmaceutical composition of long-acting preventive effect.The present invention has searched out appropriate compatibility component azithromycin by orthogonal experimental method.
Experiment one: compatibility test
Materials and methods
Adopting the orthogonal design prescription, with inhibition test method for measuring in 4 days, is experimental animal model with K173 strain of Bai Shi plasmodium and Kunming white mice.
Experiment and result
1, orthogonal design prescription experiment:
Adopt the method for orthogonal design and inhibition experiment in 4 days, the type of action with behind the phase ledger line judgement prescription calculates ED with statistical method 90The exponential theoretical value of potentiation is with the ED of component A medicine (naphthols quinoline or benflumetol) and B medicine (compatibility component) 90Connect and be called the phase ledger line.As A medicine in the prescription and B medicine ED 90Point drop on around the phase ledger line, and near the phase ledger line, be summation action; Drop on the phase ledger line and, be antagonism away from this line; Drop on phase ledger line below and, be collaborative or potentiation away from this line.
Naphthols quinoline 5 usefulness azithromycin orthonormal design of experiments the results are shown in Figure 1.Benflumetol 5 usefulness azithromycin orthonormal design of experiments the results are shown in Figure 2.
Experimental result shows the dosage range of naphthols quinoline and azithromycin compatibility, naphthols quinoline 0.75-6.00mk/kg, azithromycin 5.0-20.0mg/kg.At this dosage range compatibility, to Mus plasmodium suppression ratio greater than 70%, ED 50And ED 90Dosage shows that less than the component medicine prescription has stronger effect to the Mus plasmodium.From Fig. 1 phase ledger line as can be seen, naphthols quinoline and azithromycin compatibility are measured ED through experiment 90Each point is distributed near the phase ledger line or drops on phase ledger line below, and the point that has is away from the phase ledger line.Be judged as and have potentiation according to effect type between medicine.The dosage range of benflumetol and azithromycin compatibility, benflumetol 0.63-5.00mk/kg, azithromycin 5.0-20.0mg/kg.Fig. 2 shows, benflumetol and azithromycin compatibility, prescription medicine ED 90The each point majority drops on the below of phase ledger line, and the point that has is away from this line, and type of action is a synergistic function.
2, prescription proportioning test:
Measure the ED of each serial dosage group with inhibition experiment in 4 days 50And ED 90, and with component medicine ED 50And ED 90Relatively, obtain ED 90The potentiation index.The potentiation index big and prescription in two component drug effect indexes be best prescription ratio all preferably greater than 2 ratio.
Table 1-3 different proportion naphthols quinoline and azithromycin compatibility are to Mus malaria K 173The potentiation of strain
Naphthols quinoline: azithromycin ????ED 90(mg/kg) The potentiation index
Compound recipe naphthalene Ah Compound recipe naphthalene Ah
????4??∶??1 ????2??∶??1 ????1??∶??1 ????1??∶??2 ????1??∶??4 ??2.94????2.35????0.59 ??4.01????2.67????1.34 ??3.73????1.87????1.87 ??3.45????1.15????2.30 ??9.05????1.81????7.24 ??17.7????1.6????16.1 ??12.9????1.4????11.5 ??10.3????2.0????8.3 ??9.0?????3.0????6.0 ??4.2?????2.1????2.1
Experimental result shows that naphthols quinoline and azithromycin are with tabular ratio compatibility, compound recipe ED 90The potentiation index is all greater than 4, and the potentiation index of the single medicine of only indivedual ratio components is less than 2.Overall merit, the proper ratio scope of naphthols quinoline and azithromycin compatibility is 4: 1 to 1: 4, is preferably 1: 1 to 1: 2, best proportioning is 1: 1.
Table 1-4 different proportion benflumetol and azithromycin compatibility are to Mus malaria K 173The potentiation of strain
Benflumetol: azithromycin ????ED 90(mg/kg) The potentiation index
This Ah of compound recipe This Ah of compound recipe
??4???∶???1 ??2???∶???1 ??1???∶???1 ??1???∶???2 ??1???∶???4 ??4.04????3.23????0.81 ??4.62????3.08????1.54 ??5.53????2.77????2.77 ??6.11????2.04????4.07 ??11.3????2.26????9.04 ??19.2????1.8????17.4 ??11.6????1.9????9.7 ??8.7?????3.3????5.4 ??6.8?????3.1????3.7 ??4.5?????2.8????1.7
Experimental result as seen, benflumetol and azithromycin are with tabular ratio compatibility, compound recipe ED 90The potentiation index is all greater than 4, and the potentiation index of the single medicine of only indivedual ratio components is less than 2; Overall merit, the proper ratio scope of benflumetol and azithromycin compatibility is 4: 1 to 1: 4, is preferably 1: 1 to 1: 2, best proportioning is 1: 1.
Experiment two: the Mus malaria test of pesticide effectiveness
This test is with Bai Shi plasmodium K 173Experimental system in strain and the mice body adopts different time behind 4 days inhibition tests of orthogonal design and the medicine to attack the method for worm, naphthols quinoline azithromycin compound recipe and benflumetol azithromycin compound recipe is carried out the effect experiment of system and observes.
The cross-resistance test
Adopt and suppressed laboratory method in 4 days, with prescription the best when the component medicine respectively to high resistance chloroquine strain (RCQ/K 173) carry out sensitivity tests, and calculate the ED of each medicine with return law of the straight line 50And ED 90, with sensitive strain ED 90With drug resistance strain ED 90Ratio, obtain resistance index I 90, with I 90Judge the degree of cross-resistance.Standard is: I 90<2 is responsive; I 90=2-10 is that slight resistance is intersected; I 90=11-100 intersects for the moderate resistance; I 90>100 are severe resistance intersection.
Experimental result shows, naphthols quinoline and azithromycin compatibility, its resistance index I 90Be 1.9.Benflumetol and azithromycin compatibility, its resistance index I 90Be 2.2.The chloroquine resistance index I of parallel assay 90Be 163.4, see table 2-1 for details.This experimental result shows that compound recipe can reduce the resistance level of single medicine, and does not have cross tolerance with chloroquine.
Table 2-1 naphthols quinoline, benflumetol, azithromycin and compatibility thereof are to the anti-chloroquine strain of Mus malaria cross tolerance result of the test
The anti-chloroquine strain of sensitive strain
Drug resistance index (I 90)
ED 90(mg/kg)????????ED 90(mg/kg)
Naphthalene Ah compatibility 3.73 7.07 1.9
This A Peiwu 2.38 5.24 2.2
Naphthols quinoline 3.81 10.85 2.9
Benflumetol 2.61 9.49 3.6
Azithromycin 15.47 20.07 1.3
Arechin (Polfa) 2.11 344.81 163.4
The suppressive prophylaxis test
Select naphthols quinoline and azithromycin different proportion with 2: 1,1: 1 and 1: 2, benflumetol and azithromycin are with the different proportion of 2: 1,1: 1 and 1: 2,7 days, 14 days, 21 days and 28 days are taken out 10 animals respectively from each experimental group and matched group after administration, and worm 10 is attacked in the abdominal cavity 7The erythrocyte of individual protozoon parasitism.Attack behind the worm and to get tail blood respectively in 7-10 days and coat thin smear film, the inspection plasmodium.Relatively the different proportion compositions is to the plasmodial guard time of Mus.
Experimental result shows that two compositions has the protection fully in two weeks with 2: 1 ratio compatibilities, and third and fourth week is the part protection.Two compositions was with 1: 2 ratio compatibility, and a week is protected fully, part protection all around.Two compositions was with 1: 1 ratio compatibility, and protective rate all around is 90-100%, sees Table 2-2.This shows that two compositions was with 1: 1 ratio compatibility, its preventive effect is better than other ratio.
The compositions of table 2-2 different proportion is to Mus malaria K 173The strain preventive effect relatively
Number positive/sum (only)
Naphthalene (basis): around the 3rd week of second week of Ah first week the
Naphthalene: Ah
2∶1?????????????0/10????????0/10???????????2/10??????????4/10
1∶1?????????????0/10????????0/10???????????0/10??????????0/10
1∶2?????????????0/10????????3/10???????????5/10??????????5/10
This: Ah
2∶1?????????????0/10????????0/10???????????3/10??????????3/10
1∶1?????????????0/10????????0/10???????????0/10??????????1/10
1∶2?????????????0/10????????3/10???????????4/10??????????4/10
Delay resistant test
Adopt drug dose to increase progressively the method for cultivating resistance.Passed a generation in per 7 days, in per generation, established two dosage groups, D 3-D 5Every day gastric infusion once, every mice of D7 is got tail blood and coats thin smear film, microscopy plasmodium behind the normal dyeing.Select high dose group protozoon parasitic rate the mice more than 2% as the follow-on blood supply Mus of transferred species.Cultivating starting dose is the ED of each medicine 90, take the circumstances into consideration to increase drug dose with backsight protozoon parasitic rate situation, wherein keep previous generation dosage for one group, another group increases drug dose.In cultivating process, per 5 substitute 4 days suppresses the ED that each medicine is measured in experiment 90, and with the ED of parental generation 90Relatively, obtain resistance index I 90Calculate time that medicine produce resistance from sensitivity to slight resistance occurring with protozoon; With resistance index I 90Size judge the resistance level of medicine.Its standard is: I 90<2 is responsive; 2-10 is slight resistance; 10-100 is the moderate resistance;>100 is the severe resistance.
Experimental result sees Table 2-3, when cultivating for 40 generations as can be seen from the table, and the resistance index I of azithromycin, naphthols quinoline, benflumetol 90Be respectively 28.9,28.6 and 205.And the resistance index of naphthalene Ah combination and this A Zuhe is respectively 7.4 and 7.8.Show the time that the obvious delaying drug resistance of this compositions energy produces, and can reduce resistance level.
Table 2-3 naphthols quinoline, benflumetol and azithromycin compatibility delay the resistant test result
Medicine algebraically natural law ED 90I 90
Azithromycin 20 140 177.7 11.5
40????????280????????447.5????????28.9
Naphthols quinoline 20 140 75.0 19.7
40????????280????????108.8????????28.6
Benflumetol 20 140 100 40
40????????280????????500??????????205
Naphthalene Ah prescription 20 140 6.6 1.8
40????????280????????27.6?????????7.4
This A Zufang 20 140 4.7 1.6
40????????280????????23.4?????????7.8
Can show by the experiment of this group: naphthols quinoline Azithromycin composite and benflumetol Azithromycin composite have potentiation, and the best proportioning of two medicine compatibilities is 1: 1.Two compositions has the long-acting preventive effect in 4 weeks on Mus malaria model, and does not have cross-resistance with chloroquine.Naphthols quinoline Azithromycin composite and benflumetol Azithromycin composite can delay the speed that single medicine resistance produces, and reduce resistance level.This shows that this compositions is a promising malaria prevention compound recipe.
Experiment three: toxicity test
The present invention has carried out the single-dose of compositions and the toxicity test of repeat administration according to the requirement of new drug registration.
The acute toxicity test of single-dose is a model with the mice, by oral administration, has done the oral test of the single medicine of component.Animal all is administered once, and observes continuously 14 days, and record poisoning manifestations and death condition are calculated half lethal dose (LD with the Bliss method 50), the results are shown in Table 3-1, belong to low toxicity level according to the toxicity grading standard.Mix toxic mensuration with the FinneyShi formula, according to this formula: theoretical L D 50/ actual measurement LD 50Ratio as being the toxicity addition between 0.5-2.6, ratio<0.4 is an antagonism, ratio>2.7 are for increasing poison.Naphthols quinoline Azithromycin composite theoretical L D 50/ actual measurement LD 50=0.63, toxicity is slight addition.Benflumetol Azithromycin composite theoretical L D 50/ actual measurement LD 50=0.83, toxicity is slight addition.
Table 3-1. acute toxicity test in mice result
Group LD 50(mg/kg)
Naphthalene Ah compositions 1865 (1718.0-2024.0)
Naphthols quinoline 679.5 (614.6-751.3)
Azithromycin 4 372 (3913.0-4884.7)
Ben A makes up 4555 (3729.3-4988.5)
Benflumetol>10000
The present invention has also carried out the long term toxicity test of the single medicine of compound recipe and component to rat and Beagle dog.120 of rats are divided into 6 groups, and 20 every group, male and female half and half.24 of Beagle dogs, 6 every group, male and female half and half, continuous oral administration 14 days.24h after the last administration, each treated animal live and kill 1/2, carry out inspections such as blood, blood biochemistry, pathology, determine toxic dose and target organ.Whether all the other 1/2 continuation are observed to live after 28 days and are killed, and carry out same index and detect, reversible with the understanding toxic reaction.The result shows that the toxic dose of rat is 160MKD, and safe dose is 40MKD; The toxic dose of dog is 80MKD, and safe dose is 10MKD.Toxic target organ is a liver, and sensitive indicator is serum AST, ALT, ALP.Toxic reaction is reversible.The long term toxicity test of the single medicine of compound recipe of making of rat and component shows that compound recipe does not increase poison, and target organ does not have change.
Malaria prophylactic agent compositions of the present invention, can also when naphthols quinoline and azithromycin or benflumetol and azithromycin combination, add other acceptable accessories, as starch, carboxymethyl starch sodium, microcrystalline Cellulose, lactose, sucrose, polyvinylpyrrolidone, hydroxypropyl cellulose, amylum pregelatinisatum, micropowder silica gel, magnesium stearate, crospolyvinylpyrrolidone or Polyethylene Glycol etc., make various acceptable dosage forms with known method, as conventional tablet, capsule, dispersible tablet, conventional formulations such as granule, also can make slow release and controlled release form, not exemplify one by one at this.

Claims (7)

1, a kind of malaria prophylactic agent compositions comprises that a kind of and azithromycin in NAPHTHOQUINE PHOSPHATE, the benflumetol is compound.
2, malaria prophylactic agent compositions according to claim 1 is characterized in that, the compound weight ratio of described NAPHTHOQUINE PHOSPHATE or benflumetol and azithromycin is 4: 1~1: 4.
3, malaria prophylactic agent compositions according to claim 1 is characterized in that, the compound weight ratio of described NAPHTHOQUINE PHOSPHATE or benflumetol and azithromycin is preferably 1: 1~and 1: 2.
4, malaria prophylactic agent compositions according to claim 1 is characterized in that, compound weight ratio the best of described NAPHTHOQUINE PHOSPHATE or benflumetol and azithromycin is 1: 1.
5, according to the arbitrary described malaria prophylactic agent compositions of claim 1 to 4, it is characterized in that, also comprise other acceptable accessories.
6, malaria prophylactic agent compositions according to claim 5, it is characterized in that described adjuvant is one or more in starch, carboxymethyl starch sodium, microcrystalline Cellulose, lactose, sucrose, polyvinylpyrrolidone, hydroxypropyl cellulose, amylum pregelatinisatum, micropowder silica gel, magnesium stearate, crospolyvinylpyrrolidone or the Polyethylene Glycol.
7, the application of the arbitrary described pharmaceutical composition of claim 1 to 5 in the malaria prevention.
CNB2003101103187A 2003-12-30 2003-12-30 Malaria fewer preventing medicinal composition Expired - Fee Related CN1218702C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110368513A (en) * 2019-07-16 2019-10-25 成都新柯力化工科技有限公司 A kind of deodorant and preparation method for toilet

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110368513A (en) * 2019-07-16 2019-10-25 成都新柯力化工科技有限公司 A kind of deodorant and preparation method for toilet

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