CN1092293A - Artemisia apiacea amber composition for anti toxoplasmagondii - Google Patents
Artemisia apiacea amber composition for anti toxoplasmagondii Download PDFInfo
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- CN1092293A CN1092293A CN 93102747 CN93102747A CN1092293A CN 1092293 A CN1092293 A CN 1092293A CN 93102747 CN93102747 CN 93102747 CN 93102747 A CN93102747 A CN 93102747A CN 1092293 A CN1092293 A CN 1092293A
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- artesunate
- new drug
- toxoplasma
- polypide
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Abstract
The sick new drug artesunate of a kind of resisting toxoplasmosis compositions is made up of the optimum dose proportion of Herba Artemisiae Annuae succinum monoesters and cyclic oligomer sugar substance beta-schardinger dextrin-.The pharmacological effect of said composition: be that the film system that destroys toxoplasma increases polypide inner liquid medicine concentration one; Two, be to suppress the polypide nucleus, make toxoplasma forfeiture reproductive capacity and appeal.Belong to the high-efficiency low-toxicity medicine, clinical safety wider range.
Description
The present invention relates to the sick new drug artesunate compositions (abbreviation compositions) of a kind of resisting toxoplasmosis, form, belong to field of medicine and chemical technology by the best proportioning of artesunate (Herba Artemisiae Annuae succinum monoesters) and beta-schardinger dextrin-(cyclic oligomer sugar substance).
The main component of artesunate compositions is dihydroartemisinine-2-a-succinum monoesters (Dihyroatemisinine-12-a-Sunccinate), is the novel antimalarial that China succeeds in developing, and now proves that after deliberation this medical instrument has the new purposes of resisting toxoplasmosis disease.Its chemical property is:
1. chemical structural formula:
5. character:
Colourless needle crystals or white crystalline powder, odorless, tasteless is soluble in and forms the water solublity sodium salt in ethanol, acetone, chloroform or the sodium bicarbonate solution.
Another composition of compositions is the cyclic oligomer sugar substance beta-schardinger dextrin-that is made of six or more glucose molecule, and its chemical structural formula is:
The toxoplasmosis that is caused by toxoplasma is the people, animal diseases that take a disease altogether, and whole world sufferer reaches more than 1,000,000,000 people.This disease is widely distributed in China, and average infection rate is 4-9% in the normal population.Propagation is fast in domestic animal, morbidity is anxious, mortality rate is high, and economic loss is big, and patient's multiple internal organs are invaded, and almost relate to clinical each subject.Suffer from the anemia of pregnant woman of toxoplasmosis, its fetus is subjected to infector to reach 40%, miscarriage, stillbirth that gestation can cause in early days, and late period, then deaf, visual disorder, microcephalus and mental retardation appearred in neonate.The aids patient of the immunodeficiency toxoplasmosis that mostly occurs greatly, the infection rate of people's toxoplasma of liking to play house pet (Canis familiaris L., cat) is up to 80%.
Toxoplasmosis does not still have specific drug, and existing pyrimethamine, sulfadiazine and spiramycin all have toxic and side effects in various degree.
The objective of the invention is to provide a kind of novel formulation of quick-acting low toxicities for the treatment of toxoplasmosis.
The objective of the invention is to be achieved through the following technical solutions.
One, determines the best proportion relation of cyclodextrin and artesunate in the artesunate compositions
Because the monomer composition of artesunate is difficult to abundant dissolving in general solution, thereby can not give full play to its stable insecticidal action, the cyclic oligomer sugar substance beta-schardinger dextrin-that utilization of the present invention filters out) makes the artesunate compositions, with the dissolubility of raising artesunate and the stability of insecticidal effect.Its proportion relation is by with artesunate 60mg, be added in the sodium bicarbonate solution of 0.6ml 5%, after treating fully dissolving, the beta-schardinger dextrin-that adds series concentration again, the ultimate density of the artesunate that obtains is 0.5%-20%, compositions that this series concentration is formed and simple artesunate solution paired observation are 24 hours then, get and do not occur concentration that precipitate separates out in the compositions as qualified matched proportion density, according to said method confirm artesunate composition prepared in the beta-schardinger dextrin-concentration range of 2-8%, have significant insecticidal effect, determine 20 thus: 1-5: 1 is the optimum dose proportion of compositions.
Two, the artesunate compositions is to the polypide of invasion body cell with press down to kill the assay method of effect cell internal breeding polypide
Hela cell culture cell sheet with toxoplasma gondii infection is an experimental model, treat matched group through variable concentrations compositions-treated group with without the blank group and the pyrimethamine of compositions-treated, compare respectively and observed 24,48 and 72 hours, calculate the group infection rate (%) of cell and the rate of increase (%) of the interior polypide of individual cells therebetween.The result prove the compositions-treated group to invasion Hela cell and press down 4-6 that the rate of killing is higher than pyrimethamine and the minimum effectively parasite killing dosage treatment group of sulfanilamide doubly at cell internal breeding toxoplasma; the minimum effectively parasite killing dosage of determining said composition thus is 3-5 μ g/ml; Effective Vate of Protection to the Hela cell is 67%, is higher than pyrimethamine 5-8 doubly.
Three, determine that with animal model test the artesunate compositions to the protective effect of the body of toxoplasma gondii infection, is an experimental model with the mice, with containing 2-4 * 10
5Mice is attacked in individual/0.5ml toxoplasma solution abdominal cavity; begin after 2 hours with the administration of compositions coloclysis; every day 1 time; continuous 7 days; continue after the drug withdrawal to observe 7 days; other establishes pyrimethamine sulfanilamide treatment group is parallel control; write down general symptom, death and the survival condition of animal therebetween every day; the survival number and the time-to-live of result combinations thing treatment treated animal all are respectively 1.5 times and 2 times above pyrimethamine and sulfanilamide treatment group, show that compositions has the better protect effect to the animal body of toxoplasma gondii infection.
Four, with of the pharmacological action of electron microscope observation artesunate compositions to toxoplasma
Find that under ten thousand times of Electronic Speculum of 2-4 compositions acts on arc polypide film system on the one hand, because film is subjected to drug induced injury, entering the intravital drug level of worm increases, strengthened press down the kill ability of artesunate to toxoplasma, be the inhibitory action of compositions on the other hand, cause the polypide that contacts with medicine to lose fertility and appeal the polypide nucleus.
Five, measure the general pharmacological action of compositions in clinical practice by pharmacological method
With rat, mice and cat is test model, oral 10 in a times resisting toxoplasmosis dosage ED90(60-120mg/kg) compositions after, observed 28 days, animal does not have tangible pharmacological reaction.Dosage is brought up to 16 times to ED
90The time, the nervous system of animal (Cavia porcellus, rabbit, Canis familiaris L., monkey) does not all occur unusual, and dosage increases to 32 times to ED
90The time, the brain wave of rabbit presents the variation from excitement to inhibition, and dosage increases to 64 times to ED
90The time, breathing rate and the heart rate of Canis familiaris L. all slow down, and blood pressure drops, but electrocardiogram is no abnormal, the compositions that shows above-mentioned dosage serious pharmacologically active all do not occur to the systems such as nerve, cardiovascular and breathing of healthy animal body and change.
Six, press the safety evaluatio of toxicologic method to compositions
Acute toxicity identifies that being is test model with the mice, its median lethal dose(LD 50) (LD
50) be 1011mg/kg(♂) and 1358mg/kg(♀) to the animal gastric infusion, simultaneously with LD
50700mg/kg(♂) and 690mg/kg(♀) intraperitoneal injection; To rat LD
50Be 873mg/kg(♂) and 586mg/kg(♀) behind the gastric infusion, observed continuously 28 days, the result presses the evaluation of chemical toxicant grade scale, and the toxicity rank of said composition belongs to the low toxicity level medicine, and the safety index of experiment gained artesunate is 79.9mg/kg.The heavy dose of toxicity test of compositions is to be model with rat and Beagle Canis familiaris L., the compositions of rat test group is divided into dosage group 100mg/kg and low dose (50mg/kg) group Beagle Canis familiaris L. heavy dose (150mg/kg in heavy dose (150mg/kg) group, middle dosage 82.5mg/kg, low dose of 15mg/kg, oral administration, be once a day, serve on 28 days, therebetween the PATHOMORPHOLOGICAL OBSERVATION OF PULLORUM of index such as the diet of continuous review animal, body weight, blood and biochemistry and main organs and medicine target organ.The result prove heavy dose identify the group rat basic security dosage be 25MKD, be equivalent to 8 times of clinical dosage.The safe dose of Beagle Canis familiaris L. is 15MKD, is equivalent to 5 times of human dosage.The toxicity characteristicness of heavy dose of treated animal is that target organ pipe bone marrow, hemopoietic function are subjected to slight inhibition, and intestinal mucosa, liver, kidney, lung only have the minor injury, and drug withdrawal is after 28 days, removes bone marrow recovers slightly slowly the damage kitchen range complete obiteration of other internal organs.Damage to each internal organs is the property a crossed reversible reaction, belongs to low cytotoxic drug, safety range broad.
Seven, during the sick clinical contrast observation of the resisting toxoplasmosis of said composition and pyrimethamine sulfanilamide is actively carrying out by looking into new understanding, up to not seeing at present identical with technical solution of the present invention or the similar report that utilizes artesunate combination treatment toxoplasmosis (attached look into new testimonial).
The technical scheme embodiment that the present invention proposes is as follows:
Embodiment 1: beta-schardinger dextrin-and artesunate dosage ratio determines in the artesunate compositions
Extracting waste granular crystal artesunate 60mg is dissolved in 0.6ml 5% sodium bicarbonate solution, treat abundant dissolving, it is 0.5-20% solution that the beta-schardinger dextrin-of adding series concentration is made into the artesunate ultimate density, carry out parallel paired observation 24 hours with the artesunate compositions of this series concentration with the artesunate solution that does not add beta-schardinger dextrin-then, the optimal dissolution degree that the precipitate person of separating out is an artesunate not occur, obtain the optimum dose proportion of beta-schardinger dextrin-and artesunate thus in the beta-schardinger dextrin-concentration range of definite 2-8%.
Embodiment 2: but compositions enter invade body or at the authentication method of body cell internal breeding toxoplasma
Hela cell with toxoplasma gondii infection is a vitro trial model, sets three experimental grouies: (one) variable concentrations compositions-treated group; (2) pyrimethamine sulfanilamide processed group and (three) do not have the treatment positive controls, three groups of parallel paired observations 24,48 and 72 hours, calculate the variation of the rate of increase (%) of polypide in cell colony infection rate (%) and the individual cells therebetween, confirm the minimum effectively parasite killing dosage of compositions with the method.
Embodiment 3: the determining of the toxoplasma gondii infection animal body protective effect of compositions
To be subjected to the mice of arch insect infection (abdominal cavity attack) after 2 hours is model, with the administration of stomach feeding tube, every day 1 time, drug withdrawal in continuous 7 days continues to observe 7 days, observes with the positive controls parallel control of not treating simultaneously, therebetween, record the general symptom of two treated animals, death and survival condition, and (P value) handled in take statistics.
Embodiment 4: with the pharmacotoxicological effect of electron microscope observation artesunate compositions to toxoplasma, can see under ten thousand times of Electronic Speculum of 2-4: the toxoplasma polypide film system that 1. contacts certain hour with compositions is subjected to drug induced injury, causes entering increasing of the interior composition concentration of polypide; 2. the polypide intracellular nucleic acid is suppressed, and makes toxoplasma lose reproductive capacity and appeal.
Embodiment 5: determine pharmacological reaction in the compositions clinical practice by pharmacological method.
With three kinds of animals (mice, rat and cat) is test model, 10 times of Orally administered compositions are to ED90(mg/kg) resisting toxoplasmosis dosage, observed 28 days continuously, measure and write down the clinical response of animal, the pharmacologically active that comprises nerve, cardiovascular and the respiratory system of animal changes, and to determine it not pharmacology's influence is arranged.
Embodiment 6: press toxicologic method the toxicity of compositions is identified and safety evaluatio
Acute toxicity identifies that being is test model with the muroid, is 1011mg/kg(♂ to the median lethal dose(LD 50) (LD50) of mice) and 1358mg/kg(♀) gastric infusion, simultaneously with 700mg/kg(♂) and 690mg/kg(♀) intraperitoneal injection; LD50 to rat is 873mg/kg(♂) and 586mg/kg(♀) gastric infusion, observing continuously 28 days, the result presses the drug toxicity rank that the chemical toxicant grade scale is estimated compositions; The heavy dose of toxicity of said composition identifies that being is test model with rat and Beagle Canis familiaris L., compositions is divided into large, medium and small three dosage groups, wherein the heavy dose of group of rat is 100mg/kg for 150mg/kg, middle dosage group, small dose group is 50mg/kg, the heavy dose group of Beagle Canis familiaris L. is that 150mg/kg, middle dosage group are 82.5mg/kg, and small dose group is 15mg/kg.Each treated animal is all with oral administration, every day 1 time, successive administration 28 days, observed 28 days after the drug withdrawal, the morphological changes of various tissue components of index such as the diet of continuous review animal, body weight, blood, biochemistry and main organs and medicine target organ therebetween calculates the basic security dosage (MKD) of rat then according to the result; The safe dose of Beagle Canis familiaris L. (MKD).
Embodiment 7: the dosage form of composition product is the patient's needs according to different situations, makes tablet, capsule, soft gelatin capsule, suppository.
Embodiment 8: the Hela test cell line Preparation of model method of toxoplasma gondii infection, 1ml(contains 300 of polypides with RH strain toxoplasma suspension) to add pre-prepd Hela cell culture be in the infection cell sheet, hatch 24 with 37 ℃ then, 48 and 72 hours, again with Henks solution rinsing Hela cell, use acetone fixed, carry out Ji's nurse Sa dyeing of different time, microscopy, write down its infection cell number, polypide sum etc., press different time and calculate the cell infection rate of toxoplasma and the polypide mean of single infection cell, determine that at last can the Hela cell specimen of infection polypide as the experiment in vitro model.
Embodiment 9: artesunate is to being subjected to the protective effect of arch insect infection body; mice is attacked in the solution abdominal cavity that will contain 2-4 * 105 polypide/0.5ml; use the compositions gastric infusion after 2 hours; every day 1 time; continuous 7 days; continue to observe after the drug withdrawal 7 days, and write down the general symptom performance, dead and live and deposit situation of animal therebetween every day, and use statistical procedures.
Claims (8)
1, the optimum dose proportion of sick new drug artesunate (Herba Artemisiae Annuae succinum monoesters) of a kind of resisting toxoplasmosis and beta-schardinger dextrin-(cyclic oligomer sugar substance) is formed, and it is characterized in that: the best proportioning of 1. being determined beta-schardinger dextrin-and artesunate compositions by serial proportioning test method; 2. determine the minimum effectively parasite killing dosage of compositions with Hela cell model experimental technique; 3. with the protective effect of animal model experiment method proof compositions to body; 4. determine safety evaluatio with pharmacological toxicology method to compositions,
2, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions, it is characterized in that determining that the compositions optimum dose proportion closes the serial proportioning test method of employing and preferably comes out, promptly be dissolved in the sodium bicarbonate solution of 0.6ml 5% with artesunate 60mg, the powder-beta-dextrin that adds series concentration, the sample of getting optimal dissolution degree in its 0.5-20% concentration range presses down toxoplasma observation extremely, therefrom select minimum effectively parasite killing concentration as optimum dose proportion
3, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions, it is characterized in that the Hela cell with toxoplasma gondii infection is a model, give with the variable concentrations compositions-treated after 24,48 and 72 hours, measure the total infection rate (%) of cell and the situation of change of the interior polypide rate of increase (%) of individual cells and determine the minimum effectively parasite killing dosage of compositions
4, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions is characterized in that compositions determines it is to adopt through 2-4 * 10 to the body protective effect
5The mice that individual polypide/ml toxoplasma 0.5ml abdominal cavity is attacked carries out, with gastric infusion, and every day 1 time, continuous 7 days, observed again after the drug withdrawal 7 days, and be parallel control, the general symptom of observed and recorded animal with pyrimethamine sulfanilamide treatment group, survival and death condition, and take statistics is handled
5, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions, it is characterized in that being subjected to the compositions degree of impairment with ten thousand times of film systems that can observe toxoplasma down of ultramicroscope 2-4, and the polypide intracellular nucleic acid is suppressed and is lost the situation of reproductive capacity and appeal
6, according to claim 1, the sick new drug artesunate of a kind of resisting toxoplasmosis compositions, it is characterized in that the safety evaluatio to compositions is with mice median lethal dose(LD 50) (LD50) 1011mg/kg(♂) and 1358mg/kg(♀), to rat LD50 875mg/kg(♂) and 586mg/kg(♀) be 150mg/kg to the heavy dose of Beagle Canis familiaris L., middle dosage 82.5mg/kg, low dose is the 15mg/kg oral administration, observed respectively 28 days, press the toxicity rank of chemical toxicant grade scale evaluation compositions then, and (mg/kg) measured in the safety limit of measuring its safety index
7, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions, the dosage form that it is characterized in that combination product is to make oral tablet according to patient's different needs,
8, the sick new drug artesunate of a kind of according to claim 1 resisting toxoplasmosis compositions is characterized in that making oral soft gelatin capsule according to patient's different situations.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93102747A CN1043125C (en) | 1993-03-19 | 1993-03-19 | Artemisia apiacea amber composition for anti toxoplasmagondii |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93102747A CN1043125C (en) | 1993-03-19 | 1993-03-19 | Artemisia apiacea amber composition for anti toxoplasmagondii |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1092293A true CN1092293A (en) | 1994-09-21 |
| CN1043125C CN1043125C (en) | 1999-04-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93102747A Expired - Fee Related CN1043125C (en) | 1993-03-19 | 1993-03-19 | Artemisia apiacea amber composition for anti toxoplasmagondii |
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|---|---|
| CN (1) | CN1043125C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057682C (en) * | 1996-02-13 | 2000-10-25 | 孙宝江 | Drug and its prescription for curing toxocariasis |
| US10525464B2 (en) | 2014-09-02 | 2020-01-07 | Bio-Rad Laboratories, Inc. | Microscale fluidic devices and components having a fluid retention groove |
-
1993
- 1993-03-19 CN CN93102747A patent/CN1043125C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057682C (en) * | 1996-02-13 | 2000-10-25 | 孙宝江 | Drug and its prescription for curing toxocariasis |
| US10525464B2 (en) | 2014-09-02 | 2020-01-07 | Bio-Rad Laboratories, Inc. | Microscale fluidic devices and components having a fluid retention groove |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1043125C (en) | 1999-04-28 |
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