CN110035763A - For treating the composition and its method of parasitic disease - Google Patents

Abstract

The disclosure of invention is related to the pharmaceutical composition for treating parasitic disease, and it includes praziquantel or its analogs and the extract separated from Schisandra chinensis (Schisandra chinensis).The parasitic disease is easy to use praziquantel treatment.The invention also discloses apply a effective amount of praziquantel and a effective amount of Schisandra chinens P.E to subject the method for the treatment of the parasitic disease of subject.The present invention further discloses the method for improving the biological stability of praziquantel or other CYP zymolytes.

Description

For treating the composition and its method of parasitic disease

Related application reference information

This application claims the U.S. Provisional Patent Applications 62/ submitted for 27th according to 35 U.S.C § 119 (e) in September in 2016 400,304 priority, content are fully incorporated the application by reference.

Technical field

The present invention, which discloses, is related to a kind of composition, and it includes praziquantel (such as S- praziquantel or R- praziquantel) or its is similar The combination of object and the extract or compound that are initially separated from Schisandra chinensis (Schisandra chinensis).Also disclosed herein is The method for preventing and treating parasitic diseases.There is further disclosed herein improve praziquantel or cytochrome P 450 enzymes other substrates Biological stability method.

Background technique

Snail fever is one of most common parasitic disease in torrid areas, is principally found in developing country, such as Africa, Some countries in Asia, Caribbean and South America.Currently, about 200,000,000 people of the whole world has infected snail fever, wherein most of infected Population lives fight the country of this disease in the necessary medical infrastructure of shortage.These are national due to lacking financial resource, More challenges are faced in terms of implementing extensive precautionary measures to reduce schistosomiasis propagation.

The main reason for blood fluke that blood fluke (Schistosoma) belongs to is snail fever.Once host is traveled to, it is parasitic Worm can lay eggs in blood vessel, enteron aisle and liver and deposit a large amount of ovum.Ovum in host in deposition can lead to it is serious Health problem, such as lesion, fibrosis, portal blood pressure height and hematuria etc..In addition, snail fever may cause immunologic derangement.

In the past few decades, several compounds are used to treatment snail fever.Wherein, praziquantel (" PZQ "), as The racemic mixture of R and S enantiomer is that this disease is most popular and almost unique treatment method.

Although carrying out treatment using PZQ has admittedly safety and validity, since its dissolubility is poor, Need high dosage that could reach necessary concentration at target organ.In addition, the bitter taste of PZQ often causes during application Nausea and vomiting.

Therefore, it is necessary to a kind of more effective drugs or pharmaceutical composition to be used to treat snail fever or other helminths Disease.

Summary of the invention

R-PZQ, one of the enantiomer of PZQ with R configuration is higher to bilharzial therapeutic effect, and bitter taste is lower than S- PZQ.Meister et al.,Antimicrobial Agents and Chemotherapy,58(9),5466-72(2014)； Meyeret al.,PLoS.Negl.Trop.Dis.,3(1):e357(2009).But while R-PZQ has higher therapeutic effect With lower toxicity, due to enzyme in subject's body, such as CYP3A4, degradation or metabolism, R-PZQ treatment nevertheless suffers from compound The low limitation low with biological stability of bioavilability.

Schisandra chinens P.E is effective substrate of the enzyme of CYP3A4 or other targetings R-PZQ, can be used as CYP3A4 and other The potential competition inhibitor of enzyme.

In order to improve the bioavilability, solubility and toxic characteristic of PZQ and/or R-PZQ, applicant is proved, Schisandra chinensis (Schisandra chinensis) extract can unexpectedly improve the biology benefit of PZQ and/or R-PZQ in subject Expenditure, biological stability and therapeutic effect.Therefore, the present invention provides one kind for treating and/or preventing subject helminth The pharmaceutical composition of disease is divided it includes PZQ and/or R-PZQ and initially from Schisandra chinensis (Schisandra chinensis) From extract or compound.In one embodiment, Schisandra chinensis (Schisandra chinensis) extract includes initial From the compound separated in Schisandra chinensis (Schisandra chinensis).In another embodiment, from Schisandra chinensis The compound isolated in (Schisandra chinensis) includes wuweizisu A (Schisandrin A), wuweizisu B (Schisandrin B), schisandrin C (Schisandrin C), wuweizi alcohol A (Schisandrol A), wuweizi alcohol B (Schisandrol B), Schisantherin A (Schisantherin) or combinations thereof.

On the one hand, the parasitic disease is easy to be treated with PZQ and/or R-PZQ.In another embodiment, described to post Infested disease is snail fever.In one embodiment, PZQ includes R-PZQ and S-PZQ.In one embodiment, R-PZQ includes R-PZQ compound or derivatives thereof or its analog.In another embodiment, PZQ and/or R-PZQ is every kg of body Between quality about 1 to about 200, between about 200 to about 400, between about 400 to about 600, between about 600 to about 800 or about 800 To the PZQ and/or R-PZQ of about 1000mg.In another embodiment, PZQ and/or R-PZQ be every kg of body's mass extremely Few about 50mg.On the one hand, in described pharmaceutical composition, Schisandra chinensis (Schisandra chinensis) extract is Between every kg of body's mass about 1 to about 200, between about 200 to about 400, between about 400 to about 600, about 600 to about 800 Between or about 800 to Schisandra chinensis (Schisandra chinensis) extract between about 1000mg.

On the other hand, described pharmaceutical composition is oral suspension, tablet, spray, capsule, lotion, gel or bubble The form of foam.In another embodiment, in described pharmaceutical composition, PZQ (or R-PZQ) and Schisandra chinensis (Schisandra Chinensis) mass ratio of extract be at least 1:100,1:10,1:5,1:3,1:2,1:1,2:1,3:1,5:1,10:1 or 100:1.In another embodiment, the mass ratio of PZQ (or R-PZQ) and Schisandra chinens P.E is 1:1 or 2:1.

On the one hand, described pharmaceutical composition also includes adhesive, flavoring agent, lubricant, flowable, disintegrating agent, delay Agent and their combination.

On the other hand, described pharmaceutical composition also includes antimicrobial component, anti-fungal composition, anti parasitic ingredient or its group It closes.In one embodiment, described pharmaceutical composition includes pharmaceutically acceptable carrier.On the one hand, with the medicine group The subject for closing object treatment is mammal.In one embodiment, the subject is people.

The content of present invention additionally provides treatment and/or prevents the method for the parasitic disease of subject comprising to subject Apply a effective amount of PZQ (or R-PZQ) and a effective amount of Schisandra chinensis (Schisandra chinensis) extract.Implement one In scheme, Schisandra chinensis (Schisandra chinensis) extract includes the compound separated from Schisandra chinensis.Another In one embodiment, the compound separated from Schisandra chinensis (Schisandra chinensis) includes wuweizisu A, five Taste element B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A.

On the one hand, it is easy to be treated with PZQ (or R-PZQ) by the parasitic disease that the method is treated.In an embodiment party In case, the parasitic disease is snail fever.In one embodiment, the R-PZQ that the method uses includes R-PZQ or it spreads out Biology or its analog.In another embodiment, PZQ (or R-PZQ) between every kg of body's mass about 1 to about 200, Between about 200 to about 400, between about 400 to about 600, between about 600 to about 800, between about 800 to about 1000.In another reality It applies in scheme, PZQ (or R-PZQ) is every kg of body's mass at least about 50mg.On the one hand, in described pharmaceutical composition In, the Schisandra chinens P.E between every kg of body about 1 to about 200, between about 200 to about 400, about 400 to about 600 Between, between about 600 to about 800 or between about 800 to about 1000.

It on the one hand, include antimicrobial component, anti-fungal composition, anti parasitic ingredient or drug the method also includes application Or combinations thereof composition.

Detailed description of the invention

Fig. 1 is the chemical structure of Rac-PZQ and R-PZQ.

Fig. 2 is the change of wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and Schisantherin A Learn structure.

After Fig. 3 shows to apply and not applying the rat R-PZQ of wuweizisu A (schisandrin A) application respectively Full blood concentration.

It is described in detail

After reading this specification, how to be realized in various alternate embodiments and alternate application of the invention for ability It is obvious for field technique personnel.However, not describing all embodiments of the invention herein.It should be appreciated that this In the embodiment that provides only property is realized as an example, not a limit.Therefore, the detailed description of various alternate embodiments is not answered When being construed as limiting the scope of the invention or range.

Before the present invention is disclosed and described, it should be understood that be described below and be not limited to described in specific composition, preparation The mode of composition or its purposes, these aspects all can change.It is to be further understood that terms used herein are only used In the specific aspect of description, and not restrictive.

Definition

Unless otherwise defined, all technologies used herein or the meaning of scientific term and field skill of the present invention The normally understood meaning of art personnel is identical.

In the present specification and claims, will refer to many terms, these terms should be defined as with Lower meaning:

Term used herein is only used for describing specific embodiment, it is not intended to the limitation present invention.It is used herein " one ", "one" and " described " also include plural form, unless the context is clearly stated.

All numeral marks, such as: pH, temperature, time, concentration, amount and molecular weight and range are all approximations, are fitted When variation (+) or (-) 10%, 1% or 0.1%.It will be appreciated that though simultaneously not always clearly state, all numeral marks it Before can have term " about ".It will also be understood that reagent as described herein is only exemplary examination although simultaneously not always clearly stating Agent, and the equivalent of such reagent known in the art.

Term " including/include (comprising or comprises) " be intended to indicate that composition and method including listed The element (elements) of act, but it is not excluded for other element.When being used to define composition and method, "consisting essentially of ..." Mean the other elements for excluding that there is any significance to combination.For example, be substantially made of element defined herein Composition is not excluded for substantially influencing the other element of the basic and novel features of claimed invention.In another implementation In scheme, contaminant trace species or inert carrier are substantially not excluded for by the composition that element defined herein forms." by ... group At " refer to the other compositions and the substantial method steps excluded more than trace.By these term (transition that make the transition Terms the embodiment of each definition is within the scope of the invention in).

" composition " also aims to the combination comprising activating agent and another carrier, such as: inertia (such as detectable reagent or Marker) or active compound or composition, such as adjuvant, diluent, bonding agent, stabilizer and buffer, salt, lipophilicity Solvent and preservative etc..In the context of this application, active constituent be PZQ or R-PZQ, its derivative, its analog or Its suitable homologue.Carrier further includes drug excipient and additive protein, peptide, amino acid, lipid and carbohydrate (such as: sugar, including monosaccharide, disaccharides, trisaccharide, tetrose and oligosaccharides；Derivative sugar such as aldehyde alcohol, glycuronic acid, esterified saccharides；And it is more Sugar or glycopolymers), they can exist alone or in combination, including alone or in combination include 1%-99.99%, with weight or Stereometer.Exemplary protein excipient includes seralbumin, such as human serum albumins (HSA), recombinant human albumin (rHA), gelatin, casein etc..Representative amino acid/antibody component, can also work as a buffer, including alanine, sweet Propylhomoserin, arginine, glycine betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, figured silk fabrics Propylhomoserin, methionine, phenylalanine, Aspartame etc..Carbohydrate excipients are intended to be included within the scope of the present invention, the example Including but not limited to monosaccharide, such as fructose, maltose, galactolipin, glucose, D-MANNOSE, sorbose etc.；Disaccharides, such as cream Sugar, sucrose, trehalose, cellobiose etc.；Polysaccharide, such as melitriose, melezitose, maltodextrin, glucan, starch etc.；Aldehyde Sugar alcohol, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and inositol.

" pharmaceutical composition " is intended to include the combination of active constituent and inertia or active carrier, so that the composition is suitable for In vitro, diagnosing and treating in vivo or in vitro.

Term " pharmaceutically acceptable carrier " (or medium) can make with the biocompatible carrier of term or medium exchange With, refer to reagent, cell, compound, material, composition and/or dosage form, not only with the cell applied in treatment and its other medicine Agent is compatible, and within the scope of reasonable medical diagnosis, suitable for the tissue of people and animal contact without excessive toxicity, Stimulation, allergic reaction or with reasonable benefit/risk than other complication for matching.Pharmaceutically may be used suitable for disclosed by the invention The carrier of receiving includes liquid, semisolid (such as gel) and solid material (such as cytoskeleton and matrix, tube sheet and this field Other such materials of known detailed description herein).These semisolids and solid material can be designed in antibody (not biodegradable) of degradation or (biodegradable, can bioerosion) that can be degraded in vivo.Biodegradable material Can further can be reabsorbed for biology or biological absorbable, i.e., it can dissolve and be absorbed into body fluid (such as water-soluble Property implantation material), or be converted into other materials or decompose after in the form of natural way be discharged.

Term " patient ", " subject ", " individual " etc. can be used interchangeably herein, and be referred to suitable for this paper institute Any animal for the method stated or cell, it is either external or in situ.In preferred embodiments, patient, subject or a Body is mammal.In some embodiments, the mammal be mouse, rat, cavy, non-human primate, dog, Cat or performing animal (such as horse, ox, pig, goat, sheep).In special preferred embodiment, patient, subject, individual are People.

Term " treatment (treating or treatment) " refers to and treats disease as described herein in subject such as people Disease or illness.Treatment disclosed by the invention is wrapped but is not limited to: (i) inhibits disease or illness, that is, prevents its development；(ii) alleviate disease Disease or illness, and cause disease regression；(iii) slow down the progress of disease；And/or (iv) inhibits, alleviates or slow down disease or disease The progress of one kind of multiple symptoms of disease.For example, the treatment of parasitic disease includes but is not limited to eliminate pathogen and/or by pathogen Caused infection is alleviated and infects, inhibits infection, at least one symptom for reducing or eliminating infection parasitic disease etc..

Phrase " being administered simultaneously ", which refers to, applies at least two medicaments to subject whithin a period of time.Be administered simultaneously including but Be not limited to respectively, sequence and be administered simultaneously.

" difference " application refers to, and at least two active constituents are substantially simultaneously administered simultaneously by different approaches.

" sequence " application refers in different time application at least two kinds of active components, and drug delivery route can be identical or not Together.More specifically, sequence application, which refers to, applies another effective component before application one or other active components.Therefore, Can several minutes before applying other active components, a few hours or a couple of days apply a kind of active constituent.

Term " simultaneously " application refers to through identical approach, at least two active constituents is substantially simultaneously administered simultaneously.

The term as used herein " therapeutic agent " refers to treatment and/or prevention.By inhibition, alleviation or eliminate disease symptoms Reach therapeutic effect.

Term " therapeutically effective amount " or " effective quantity " refer to be enough to generate the amount of the medicament of required effect in application.Example Such as, a effective amount of composition can be the amount be enough to treat, control, alleviating or improving the related illness in relation to parasitic disease. The medicament of therapeutically effective amount can be according to age, the weight etc. for the pathogen, its severity and patient to be treated treated And it is different.Those skilled in the art can determine suitable amount according to these and other factors.Composition can also with it is a kind of or A variety of other therapeutic compounds are administered in combination.In method described herein, therapeutic compounds can be applied to disease Or the subject of one or more S or Ss of illness.

As described herein, term " enzyme " refers to any protein of catalytic chemistry reaction.The catalysis of enzyme constitutes it " activity " or " enzymatic activity ".Enzyme is classified generally according to the type of its catalysis, such as the hydrolysis of peptide bond.For example, thin Born of the same parents' cytochrome p 450 is one of the enzyme that can be metabolized the intracorporal target compound of subject.

Term " Cytochrome P450 " or " CYP " they are the hemoglobin enzyme families for referring to metabolism exogenous material, such as Drug, carcinogenic substance, environmental contaminants, steroids, fatty acid and prostaglandin.As used herein, " CYP " refers to microorganism, nothing The CYP superfamily member of vertebrate and vertebrate origin.The non-limiting example of CYP enzyme includes but is not limited to come from: The enzyme of CYP1A, CYP2B, CYP2C, CYP2D, CYP2E, CYP3A family and such as institute in U.S. Patent No. 5786191 and 5478723 The other CYP enzyme stated, entire contents are incorporated herein by reference.In some embodiments, CYP enzyme includes mammal In CYP enzyme comprising but be not limited to CYP1, CYP2, CYP3, CYP4, CYP5, CYP7, CYP8, CYP1 1, CYP 17, CYP 19, CYP20, CYP21.CYP24, CYP26, CYP27, CYP39, CYP46 and CYP51.In one embodiment, mammal CYP enzyme include but is not limited to CYPlAl, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2FI、CYP2J2、CYP2R1、CYP2S1、CYP2U1、 CYP2W1、CYP3A4、CYP3A5、CYP3A7、CYP3A43、CYP4A11、CYP4A22、CYP4B1、CYP4F2、CYP4F3、 CYP4F8、CYP4F11、CYP4F12、CYP4F22、CYP4V2、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、 CYP8A1、CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17A1、CYP19A1、CYP19A1、CYP21A2、 CYP24A1, CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP39A1, CYP46A1 and CYP51A1。

As used herein, term " substrate " refer to enzyme play its catalytic activity on it with generate the substance of product (such as Compound).Such as there are many substrates for CYP enzyme, such as CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1 and CYP3A4.

The non-limiting example of CYP3A4 substrate includes but is not limited to: cyclosporin, tacrolimus, sirolimus, mostly west His match, tamoxifen, taxol, cyclophosphamide, adriamycin, Tarceva, Etoposide, ifosfamide, Teniposide, length Spring alkali, eldisine, Imatinib, Irinotecan, Sorafenib, Sutent, Wei Mofeini, replaces Xi Luomo at vincristine Department, Anastrozole, Gefitinib, ketoconazole, Itraconazole, macrolides, clarithromycin, erythromycin, Ketek, phenalgin Sulfone, tricyclic antidepressant, amitriptyline, clomipramine, imipramine, cyclobenzaprine, Citalopram, norfluoxetine, Sertraline Group (Sertalinesome), Mirtazapine, Nefazodone, Reboxetine, Venlafaxine, Trazodone, buspirone, haloperidol, Aripiprazole, Risperidone, Ziprasidone, Pimozide, Quetiapine, alfentanil, buprenorphine, codeine, fentanyl, hydrogen can Ketone, methadone, alphamethadol, C16H25NO2, Benzodiazepines, alprazolam, midazolam, triazolam, diazepam, assistant gram Grand, Zaleplon, zolpidem, donepezil, Atorvastatin, Lovastatin, Simvastatin, cerivastatin, diltiazem, How felodipine nifedipine, Verapamil, Amlodipine, Lercanidipine, nitrendipine, Nisoldipine, amiodarone, certainly reaches Grand, quinindium, silaenafil, Tadalafei, kassinin kinin, Finasteride, estradiol, progesterone, ethinyloestradiol, testosterone, Toremifene, Bicalutamide, RMI 9918, astemizole, chlorphenamine, indinavir, Ritonavir, inverase, Nai Feinawei, Nai Wei It evens up, budesonide, hydrocortisone, dexamethasone, Cisapride, aprepitant, caffeine, cocaine, Cilostazol, the right side Dextromethorphan, domperidone, eplerenone, lidocaine, Ondansetron, Propranolol, salmeterol, warfarin, clopidogrel, Omeprazole, Nateglinide, methoxy Xi Ting and montelukast.

The non-limiting example of CYP2D6 substrate includes: atomoxetine, desipramine, dextromethorphan, Yi Ligelusita (Eliglustat), nebivolol, nortriptyline, perphenazine, Tolterodine, Venlafaxine, amitriptyline, encainide, the third miaow Piperazine, metoprolol, Propafenone, Propranolol, C16H25NO2 and trimipramine.

The non-limiting example of CYP2C19 substrate includes S- mephenytoin, Omeprazole, stable, Lansoprazole, Lei Beila Azoles and voriconazole.

The non-limiting example of CYP2C9 substrate includes celecoxib, Glimepiride, phenytoinum naticum, orinase and Hua Fa Woods.

The non-limiting example of CYP2C8 substrate includes Repaglinide, montelukast, Pioglitazone and Rosiglitazone.

The non-limiting example of CYP2B6 substrate includes Bupropion and Sustiva.

The non-limiting example Alosetron of CYP1A2 substrate, caffeine, Duloxetine, epiphysin, ramelteon, he takes charge of Mei Qiong, theophylline, Tizanidine, Clozapine, pirfenidone and Ramosetron.

Term " inhibitor " refers to blocking, reduction, inhibition or the substance for suppressing enzymatic activity.For pressing down in of the invention disclose Preparation includes but is not limited to reversible, irreversible, competitive or noncompetitive inhibitor.In one embodiment, inhibit Agent is CYP inhibitor comprising but be not limited to CYP1A2 inhibitor, CYP2B6 inhibitor, CYP2C8 inhibitor, CYP2C9 and inhibit Agent, CYP2C19 inhibitor, CYP2D6 inhibitor, CYP2E1 inhibitor and CYP3A4 inhibitor.

The non-limiting example of CYP1A2 inhibitor includes: amiodarone, atazanavir, Cimetidine, Ciprofloxacin, western phthalein Pulan, clarithromycin, diltiazem, Enoxacin, erythromycin, estradiol, Fluvoxamine, interferon, isoniazid ketoconazole, first Oxygen XiLin, mibefradil, tegaserod.The non-limiting example of CYP2B6 inhibitor includes tespamin and Ticlopidine. The non-limiting example of CYP2C8 inhibitor includes Anastrozole, ezetimibe, gemfibrozil, montelukast, Buddhist nun's card Horizon, Sulfinpyrazone and methoxybenzyl aminopyrimidine.

The non-limiting example of CYP2C9 inhibitor includes: amiodarone, atazanavir, Cimetidine, clopidogrel, compound Radonil, delavirdine, disulfiram, efavirenz, fenofibrate, Fluconazole, fluorouracil, Prozac, Fluvastatin, fluorine volt Sha Ming, Gemfibrozil Capsules, Imatinib, isoniazid, Itraconazole, ketoconazole, leflunomide, Lovastatin, Methoxsalen, first nitre Azoles, mexiletine, modafinil, nalidixic acid, norethindrone, Norfloxacin, Omeprazole, contraceptive, Paxil, phenylbutazone, Probenecid, Sertraline, sulfamethoxazole, sulfaphenazolum, sulfa drugs, Tacrine, Teniposide, Ticlopidine (Ticlodipine), tipranavir, troleandomycin, voriconazole, zafirlukast, Zileuton or garlic (Allium Sativum) plain (Bergamottin) extract of extract, bergamot, wire grip careless (Harpagophytum procumbens) mention Take object and fructus lycii (Lycium barbarum) extract.

The non-limiting example of CYP2C19 inhibitor includes Cimetidine, Citalopram, delavirdine, Sustiva, non- Urethane, Fluconazole, Prozac, Fluvastatin, Fluvoxamine, Indomethacin, isoniazid, ketoconazole, Lansoprazole, Mo Dafei Buddhist nun, Omeprazole, Oxcarbazepine, probenecid, Topiramate and garlic (Allium sativum) extract and wire grip grass (Harpagophytum procumbens) extract.The non-limiting example of CYP2D6 inhibitor includes abiraterone, amine iodine Ketone, amoxapine (Asenapine), Bupropion, celecoxib, chloroquine, chlorphenamine, chlorpromazine, Cimetidine, Xi Naka Plug, Citalopram, clemastine, clomipramine, cocaine, darifenacin, desipramine, diphenhydramine, doxepin, how soft ratio Star, Duloxetine, escitalopram, Febuxostat, Prozac, fluphenazinum, halofantrine, haloperidol, hydroxychloroquine, hydroxyzine, she Imatinib, levomepromazine, methadone, metoclopramide, Mibefradil, midodrine, Moclobemide, Nefazodone, norfluoxetine, Paro Xi Ting, perphenazine, Propafenone, propoxyhene, inderal, quinacrine, quinindium, ranitidine, ranolazine, Ritonavir, Sertraline, tegaserod, Terbinafine, thioridazine, Ticlopidine (Ticlodipine), tipranavir, Tripelennamine and Galangal (Alpinia galanga) extract, common alstonia (Alstonia scholaris) extract, Herba Andrographitis (Andrographis paniculata) extract, catharanthus roseus (Catharanthus roseus) extract, rattleroot (Cimicifuga racemosa) extract, cinnamomum camphora (Cinnamomum burmannii) extract, wilsonii (Eleutherococcus senticosus) extract, Radix Glycyrrhizae (Glycyrrhiza glabra) extract, goldenseal (Hydrastis canadensis) extract, cajeputtree (Melaleuca leucadendron) extract, ginseng (Panax Ginseng) extract, American Ginseng (Panax quinquefolius) extract, pepper (Piper nigrum) extract, stone Pomegranate (Punica granatum) extract, sorrel (Rheum palmatum) extract, santal (Santalum album) It is extract, vomiting nut (Strychnos ligustrina) extract, cloves (Syzygium aromaticum) extract, green Packet rattan (Tinospora crispa) extract and ginger (Zingiber aromaticum) extract.

The non-limiting example of CYP2E4 inhibitor includes: disulfiram and kawakaw (Piper methysticum) Extract.

The non-limiting example of CYP3A4 inhibitor includes: amiodarone, anpunave, aprepitant, atazanavir, Bo Sai Sprinkle dimension, Cimetidine, Ciprofloxacin, clarithromycin, cyclosporin, danazol, delavirdine, diltiazem, Sustiva, red Mycin, ethinylestradiol, ezetimibe, Fluconazole, Prozac, Fluvoxamine, gestodene, Imatinib, indinavir, Isoniazid, Itraconazole, ketoconazole, methylprednisolone, Mibefradil, Miconazole, mifepristone, Nefazodone, Nai Feina Wei, nicardipine, nifedipine, norethindrone, Norfloxacin, norfluoxetine, Oxiconazole, posaconazole, prednisone, quinine, Ranolazine, Ritonavir, roxithromycin, inverase, Sertraline, telavi, Ketek, troleandomycin, Wella pa Rice, voriconazole, zafirlukast, Zileuton and garlic (Allium sativum) extract, ammi visnaga (Ammi Visnaga) extract, margosa tree tree (Azadirachta indica) extract, cimicifugae foetidae (Cimicifuga racemosa) Careless (Harpagophytum procumbens) extract of extract, wire grip, goldenseal (Hydrastis canadensis) mention Take object, naringenin (Naringenin) extract, ginseng (Panax ginseng) extract, American Ginseng (Panax Quinquefolius) extract, vomiting nut (Strychnos ligustrina) extract and uncaria white Mao Yang (Uncaria Tomentosa) extract.

Term " praziquantel " or " PZQ " refer to praziquantel compound, praziquantel derivative or the like, Suitable homologues or Its part can promote at least one biological respinse usually relevant to praziquantel.In one embodiment, PZQ includes But it is not limited to its salt, its ester, its solvate, its derivative, its polymorph or its hydrate.

It is used herein, term " R- praziquantel " or " R-PZQ " refer to R- praziquantel compound, R- praziquantel derivative or Analog, suitable homologue or part thereof can promote at least one biological respinse usually relevant to R- praziquantel.? In one embodiment, R-PZQ include but is not limited to its salt, its ester, its solvate, its derivative, its polymorph or its Hydrate.

Used herein, term " biological stability " refers to substance (such as chemical substance, protein, lipid, DNA, peptide, more Crystal form object) in blood circulation, blood plasma, serum, various living tissues and the various stability organized in homogenate.Measure Biostatic The method or parameter of property are well known in the art.For example, by measurement drug after administration and before applying the second dosage Maximum (or peak value) the blood concentration C reached in specific compartment or test zone_max, to assess biological stability.It can also make With the elimination half-life period in blood, this is the time needed for material concentration to be reduced to the half of substance maximum concentration.

Term " therapeutic effect " refers to the amount that can effectively realize beneficial or clinical effectiveness medicament.In an embodiment In, therapeutic effect to reduce cancer cell number, treatment parasitic disease or improve relevant with disease one or more symptoms extremely It is few a part of related.

Term " disease " refer to the normal condition of organism (such as plant, mammal and people) or its any component part by To damage, the performance or function of organism are interrupted or changed." parasitic disease " refers to the disease for being caused by helminth or being propagated. The example of parasitic disease includes: toxoplasmosis, malaria, African typanosomiasis nagana, South American trypanosomiasis, leishmaniasis, snail fever, Ah meter Bar disease, Giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, Filariasis, filaria volvulus Disease, drachunculiasis, trichuriasis, strongyloidosis (stronglyoidiasis), trichostrogylosis (trichostrongyliasis), trichomoniasis and taeniasis.

In another embodiment, parasitic disease is people's parasitic disease comprising but be not limited to: tapeworm-cestode infection, Bothrio-cephaliasis, echinococcosis-tapeworm, hymenolepiasis, taeniasis bovis (Beef tapeworm), cysticercosis-armed tapeworm, primary Special taeniasis, sparganosis, clonorchiasis (Clonorchiasis), lancet liver rot (Lancet liver Fluke), liver fluke-fascioliasis, Fasciola hepatica-distomatosis intestinalis, metagonimiasis-distomatosis intestinalis, secondary testis fluke disease, in State's liver rot (Chinese liver fluke), paragonimiasis (Paragonimiasis), paragonimiasis (lung Fluke), schistosomicide-blood fluke, schistosomiasis or snail fever (snail fever, all types), intestines blood are inhaled Parasitosis, urinary schistosmiasis, Schistosoma japonicum snail fever, Asia intestinal schistosomiasis, schistosome dermatitis (Swimmer's Itch), hookworm disease/hookworm (Ancylostomiasis/Hookworm), angiotrongylosis, anisakiasis, roundworm- Helminth pneumonia, roundworm-belleville roundworm disease (Roundworm-Baylisascariasis), ascarid Filariasis, the swollen tie lines of kidney Insect infection, Guinea worm-drachunculiasis, pinworm-enterobiasis, gnathostomiasis, demon's verminosis (Halicephalobiasis), loaiasis (Loa loa filariasis), Calabar swellings (Calabar Swellings), graceful gloomy filariasis, filariasis, river blindness, onchocercosis, strongyloidosis-helminth pneumonia, suck line Parasitosis, toxocarasis, trichinosis, trichuriasis, elephantiasis-Filariasis, acanthocephaliasis, fascioliasis syndrome, myiasis (Myiasis), spiral myiasis (Screwworm), screwfly sick (Cochliomyia), trombiculid flea (Chigoe flea) are smelly Worm, human botfly (Human botfly), head louse-louse disease, body louse-louse disease, hair lice-louse disease (Crab louse- Pediculosis), vermiform mite-demodicidosis, scabies, " trombiculid (Chiggers) " (Trombidiidae (Trombiculidae))-illness Acarodermatitis, flea (Flea), Siphonaptera (Siphonaptera), tick (Tick), granulomatous amebic encephalitis (ocular infection), spine Acanthamoeba keratitis, granulomatous amebic encephalitis (skin infection), Babesia Gibsoni, balantidiasis (Babesiosis), bud Capsule protozoosis (Balantidiasis), Cryptosporidiosis, cyclosporiasis, dientamoeba fragilis disease, amcbiasis, merchant the Parasitosis, isosporiasis, leishmaniasis, primary amebic meningo encephalitis (PAM), malaria, rhinosporidiosis, sarcocystis Disease, toxoplasmosis (acute and latency), trichomoniasis, difussa and South American trypanosomiasis.

In one embodiment, parasitic disease is snail fever.In another embodiment, parasitic disease is that blood is inhaled Caused by worm.

In some embodiments, the parasitic disease includes any patient's condition as caused by helminth.Helminth include but It is not limited to endoparasite and vermin.The non-limiting example of helminth includes: rafflesia, semen cuscatue spp, spine head Guiding principle, roundworm (roundworm), Cestoda (tapeworm) include: teniarhynchosis (Taenia saginata) (people teniarhynchosis), armed tapeworm (Taenia solium) (people armed tapeworm), fish tapeworm (Diphyllobothrium latum) (fish tapeworm), Echinococcus hydatid cyst (Echinococcosis) (Echinococcus granulosus), clonorchis sinensis (Clonorchis sinensis) (Chinese liver fluke), wheat That imperial nematode (Dracunculus medinensis) (Guinea worm) of ground, compacted shape live in pinworm (Enterobius Vermicularis) (pinworm/pinworm), filaria (Filariasis), hookworm, Loa loa (Loa loa), filaria volvulus (Onchocerciasis) (river blindness), blood fluke (Schistosomiasis), excrement class round wires tapeworm (Strongyloides Stercoralis), tapeworm, Toxocara canis (Toxocara canis) (dog roundworm), trichina (Trichinella), whipworm, Entamoeba histolytica (Entamoeba histolytica), amoeba coli (Entamoeba coli), Acanthamoeba (Acanthamoeba), baboon Baram wishes amoeba (Balamuthia mandrillaris), Giardia, Cyclospora Cyclospora cayetanensis), Cryptosporidium (Cryptosporidium), toxoplasma (Toxoplasma gondii), Leishmania (Leishmania) (L .tropica, L.donovani, and L.Mexicana), plasmodium (Plasmodium), babesia (Babesia), glue Rust (Gymnosporangium) and other rust-fungis, circle nuclear cavity bacteria (Pyrenophora teres), cordyceps sinensis (Cordyceps), arthropoda (Arthropoda), tick (Acari), Di This watt of mite (Varroa destructor), drop-head argulus (Cymothoa exigua), bedbug, Dulicidae (Culicidae) (mosquito Son), calyptra (Calyptra) (bloodsucker moth), hippoboscid Superfamily (Hippoboscoidea), tsetse fly, Lipoptena (Lipoptena), sheep hippoboscid (Melophagus ovinus) (sheepked) and similar, Destridae (Oestridae) (skin Fly), body fly, phlebotominae (Phlebotominae) (sand fly), Phthiraptera (Phthiraptera) (louse), body louse, hair lice, Head louse, Siphonaptera (Siphonaptera) (flea), Tabanidae (Tabanidae) (horse botfly), micro- shrimp guiding principle (Tantulocarida), cone Hunt Rhopalinae (Triatominae), pea crab, sacculus Trentepohlia (Sacculina), annelids (Annelids), Hirudinea (Hirudinea) (part Hirudo), monogenean (Monogeneans), Calydiscoides (Calydiscoides Euzeti), natural pearls algae (Lethacotyle vera), atom leaf natural pearls algae (Protocotyle euzetmaillardi), quasi- Fleahopper (Pseudorhabdosynochus spp.), mollusc, copper pine crab (Cancellaria cooperii), valve hook Larva (Glochidium), Chordata (Chordates), cigar Bodhidharma shark, is posted Pyramidellidae (Pyramidellidae) Raw catfish (Candiru) (Brazil suck blood fish, facultative parasite), lampreys, deep-sea angler, false cleaning fish, hood robin (Hood mockingbird), ox starling, Simenchelys parasiticus, vampire, sparrow of sucking blood (Vampire finch), mistletoe, Mou Xielan Flower, smut of maize and certain mushrooms.

In some embodiments, helminth is a kind of tapeworm, is flat in a kind of enteron aisle for living in mammal Flat segmentation worm.During infection, proscolex living is grouped in tumour.Once larva just may have grown into alimentary canal One very big Adult cestodes, causes host symptom occur.Tapeworm can cause alimentary infection.Such as cysticercosis is a kind of It is related to the disease of larva tapeworm in human body.Tapeworm includes armed tapeworm (Taenia solium), teniarhynchosis (Taenia Saginata), Diplacanthus nanus (Hymenolepis nana), Taenia elliptica (Dipylidium caninum) and band-like cysticercus (Taenia taeniaeformis)。

Term administering (administering) " or " application (administration) " medicament include any to subject Compound is introduced or is delivered to subject to realize the approach of its expectation function.Application can by any suitable approach, Including oral, intranasal, parenteral (intravenous, intramuscular, intraperitoneal or subcutaneous) or local drug delivery.Application include self-administration and It is applied by other people.

Term " extract " can be used for referring to the target compound or powder of the target compound of powder type, liquid form Or the combination of any or any target compound of liquid form.It will be appreciated by the skilled person that term " extract " is available Target compound prior to, concurrently with, or after Yu Qi separation.

Extract from plant or biology includes but is not limited to the compound separated from plant or biology.On the contrary, coming It further include point that the compound separated with from plant or organism has same or similar function or structure from the extract of plant Son or chemical substance.In one embodiment, the compound initially separated from Schisandra chinensis includes but is not limited to directly from five The compound extracted in taste, and there is same or similar function or structure with the compound that directly separates from Schisandra chinensis Chemical substance or molecule.Chemical substance and molecule can be synthesized or be extracted from different sources.Such as wuweizisu A, one kind is most The compound just separated from Schisandra chinensis, can synthesize, it is commercially available or from separate sources separation obtain.

Term " separation " and " purifying " may be used interchangeably.In some embodiments, " separation " can be used for referring to from natural The extract taken out in chemical environment.

Term " analog " refers to one or more individual atoms in compound or functional group by not homoatomic or difference Functional group replaces, it will usually generate the compound with similarity.

Term " derivative " refers to and another molecule or atom are connected to initial compounds by similar Initiation Close the compound that object is formed.In addition, derivative according to the present invention includes one or more former by addition by precursor compound Son or molecule or one or more compounds by combining the formation of two or more precursor compounds.

Term " pharmaceutically acceptable carrier " refers to carrier commonly used in the art, to promote the storage of bioactivator It deposits, apply and/or Healing.

PZQ and R-PZQ

Praziquantel (" PZQ ") or 2- (cyclohexyl-carbonyl) -1,2,3,6,7,11b- hexahydro -4H- pyrazine simultaneously [2,1-a] isoquinoline Quinoline -4- ketone is as a kind of pest repellant.Research shows that PZQ increases parasitic cell film to the permeability of calcium ion, so as to cause posting Infested contraction.PZQ can further result in the vacuolation and disintegration of helminth crust.

PZQ is also referred to as Bay-8440 or MSC-1028703A, corresponding C₁₉H₂₄N₂O₂, it is made of R-PZQ and S-PZQ Racemic mixture (" Rac-PZQ ").The chemical formula of Rac-PZQ and R-PZQ is shown in Fig. 1.

The preparation of PZQ is described in US4362875, other synthetic methods be described in CN102093346, US2013289275, CN103570710, CN103638884, CN103739601, CN105237532 and CN105294679, It is incorporated herein by reference.PZQ can control the growth of helminth by destroying calcium channel, this is conducive to subsequent exempt from Epidemic disease attack and helminth later are removed.Therefore, PZQ is used to treatment by a plurality of types of interior/stomach and intestine and epizoon sense Disease caused by contaminating, including echinococcosis, cysticercosis, snail fever, clonorchiasis, paragonimiasis and fasciolopsiasis.PZQ is The common treatment method of snail fever, with some such as high dosage requirements and bitter taste.

Currently, PZQ is the key agents compound for treating a variety of parasitic diseases, including but not limited to echinococcosis, cysticercus Disease, snail fever, clonorchiasis, paragonimiasis or fasciolopsiasis, or the alimentary infection as caused by tapeworm, including dog silk ribbon Worm (Dipylidium caninum) or band-like cysticercus (Taenia taeniaeformis).In one embodiment, helminth Disease is snail fever.Particularly, PZQ has been used to infection caused by treatment blood fluke species, such as river bank public affairs blood fluke (Schistosoma mekongi), Schistosoma japonicum (Schistosoma japonicum), Schistosoma mansoni (Schistosoma mansoni) and Schistosoma haematobium (Schistosoma hematobium), and by liver fluke, magnificent branch testis Infection caused by fluke (Clonorchis sinensis)/opisthorchis viverrini (Opisthorchis viverrini).PZQ mesh The preceding clinical test for being used to treat cysticercosis, neural cysticercosis (NCC) and malaria.It is available that PZQ can also be used in treatment The healthy illness of anthelmintic, schistosomicide and nematocide treatment.In addition, PZQ can be used in veterinary science, such as Dog removes tapeworm, and combines with Pyrantel Pamoate and febantel for removing hookworm, roundworm and whipworm.In addition, PZQ It can be used for cat removal tapeworm, and also combine with Pyrantel Pamoate for removing various types of hookworms and roundworm.PZQ can To eliminate the tapeworm in the mankind, ferret, birds, chinchilla, mouse, rat, hamster, gerbil jird and cavy, and removal is creeped Tapeworm and fluke in animal.

The application of PZQ is often along with slight and of short duration adverse reaction, including aggravation (severity), the mind are not Peace, headache, dizzy, whether there is or not the abdominal discomfort of nausea, body temperature raising and nettle rash.In fact, some of which symptom may It is to be caused by parasitic infection itself.Because PZQ is the substrate of drug hepatic metabolism enzyme, such as Cytochrome P450, with enhancing enzyme Active compound or reagent apply the reduction that will lead to PZQ blood plasma level together.

The active reagent of enhancing hepatic metabolism enzyme includes but is not limited to: antiepileptic (such as phenytoinum naticum, phenobarbital and card Horse Xiping) and dexamethasone.On the other hand, reducing drug hepatic metabolism enzyme (Cytochrome P450) active reagent can increase The blood plasma level of PZQ.The active reagent that hepatic metabolism enzyme can be reduced includes but is not limited to: Cimetidine, ketoconazole, Yi Qukang Azoles and erythromycin.

When being administered alone, the half of only application PZQ remains the activity of its anti-schistosome.It is not bound to theory, PZQ The effect of when treating snail fever, is destroyed due to its low bioavilability in patient's body.Meyer T,et al., PLoS Negl Trop Dis 3(1):e357(2009).In addition, the well-known bitter taste of PZQ, influences it in child patient Use, cannot be covered by conventional approach, such as encapsulate and coating.DE102005062270.

A kind of enantiomer and the insect disinfestation component by X-ray measurement that R-PZQ is PZQ.Meyer T,et al.,PLoS Negl Trop Dis 3(1):e357(2009).Due to its lower bitter taste, R-PZQ is suitable for for bilharzial young trouble Person and school age patient.Compared with S-PZQ, R-PZQ has higher for bilharzial therapeutic effect and lower in vivo and in vitro Bitter taste.Meister et al.,Antimicrobial Agents and Chemotherapy,58(9),5466–72 (2014)；Meyer et al.,PLoS.Negl.Trop.Dis.,3(1):e357(2009).In addition, R-PZQ is compared to S-PZQ poison Property it is lower, clinical research has shown adverse reaction caused by the treatment using R-PZQ less than standard regimens.Sun et al.,Drug Des.Devel.Ther.,10,2061-2068(2016)；Wu et al.,Am.J.Trop.Med.Hyg.,45: 345–349(1991)；Xu et al.,Chin.Med.J.,107:771(1994).The preparation of R-PZQ is described in WO2016078765、WO2015055126、CN104327077、IN201201148、WO2013127354、WO2013127356、 WO2013060292 and US4362875, entire contents are incorporated herein by reference.

Similar with PZQ, R-PZQ is equally limited by its low bioavilability, this is because CYP3A quick stereo selectivity It is metabolized to inactive monohydroxy metabolite R-trans-4-OH-PZQ.Wang et al.,Biochem.Pharmacol., 15,90,166-178(2014)；Meister et al.,Antimicrobial Agents and Chemotherapy,58 (9),5466–72(2014).One studies have shown that behind 2.67 hours of the R-PZQ of oral 23.3mg/kg, healthy volunteer's C_maxFor 0.16 μ g/mL, AUC_0→∞For 0.87 μ g*h/mL per hour.Lima et al.,Br.J.Clin.Pharmacol., 2011,71:528–535。

It is another studies have shown that oral 25mg/ with opisthorchis viverrini (Opisthorchis viverini) infected patient Behind 5 hours of the R-PZQ of Kg, C_maxFor 0.2 μ g/mL, and AUC_0→24hFor 1.1 μ g*h/mL per hour.Meister et al., PLoS Negl.Trop.Dis.,2016,10(5):e0004700。

It is not bound to theory, the bioavilability of patient R-PZQ can be improved in the activity for limiting the enzyme of anti-R-PZQ.Competition Property inhibit be prevention or limit anti-R-PZQ enzymatic activity a kind of mode.

In Reverse transcriptase, the active site of inhibitor and targeting substrate competition enzyme.When inhibitor and active site knot When conjunction, the combination of enzyme-to-substrate will be blocked, to inhibit the enzymic digestion of substrate.Therefore R- of the application as competitive inhibitor The substrate of PZQ targeting enzymes can promote the bioavilability of R-PZQ in host.

Schisandra chinensis (Schisandra chinensis) extract

Schisandra chinensis (Schisandra sphenanthera) is a kind of protophyte of China, always for a long time As viral or drug hepatitis the ingredient for the treatment of in oriental medicine.Hancke JL et al.,Fitoterapia,70: 451–471(1999).The extract of schisandra chinensis (Schisandra sphenanthera) includes gomisin A (gomisin It A), can be by CYP3A hydroxylating, so as to effective substrate as this enzyme.Wu et al.,AAPS.J.,18(1),134-45 (2016)；CN 104892563A；Wu et al.,Drug Metab Dispos,42,94–104(2014).In addition, Central China five The extract of taste (Schisandra sphenanthera) can also be increased by inhibiting CYP3A4 enzymatic activity by CYP3A4 generation The haemoconcentration for the tacrolimus (FK506) thanked.Iwata et al.,Drug Metab Dispos,32,1351-1358 (2004)；Qin et al.Drug Metab Dispos,32,193-199(2014).http://www.baidu.com/ Link? url=U9ymdZSWJjshyrwfokuRDFqKtBRRgvZpttVn3XrFMbV6ygj4p6vo ZQjlgXvdAVl3bX JHm-P8-OppdXCzAMR5PB5CTXZi9ZY-CtkAujnSM17

Applicant is found surprisingly that Schisandra chinensis (Schisandra chinensis) extract can inhibit cytochromes The activity of P450 (CYP) enzyme, these enzyme induction compounds include the metabolism of R-PZQ.In one embodiment, Schisandra chinensis is extracted Object includes the compound separated from Schisandra chinensis.In another embodiment, the compound separated from Schisandra chinensis includes five Taste element A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B, Schisantherin A or combinations thereof.Above compound Structural formula it is as shown in Figure 2.

CYP is class of enzymes, targets the substrate of external source and endogenous compounds as enzymatic reaction.Disclosed by the invention one Aspect, Schisandra chinens P.E inhibit the activity of CYP enzyme.

Any method for inhibiting CYP is all for the purpose for the treatment of presented herein.CYP enzyme includes microorganism, invertebrate With the CYP superfamily member of vertebrate origin.The non-limiting example of CYP enzyme include but is not limited to come from CYP1A, CYP2B, The enzyme of CYP2C, CYP2D, CYP2E, CYP3A family, and described in U.S. Patent No. 5786191 and 5478723 other CYP enzyme, is fully incorporated herein each by reference.In some embodiments, CYP enzyme includes CYP in the mammalian body Enzyme, it includes but be not limited to CYP1, CYP2, CYP3, CYP4, CYP5, CYP7, CYP8, CYP11, CYP17, CYP19, CYP20, CYP21, CYP24, CYP26, CYP27, CYP39, CYP46 and CYP51.In one embodiment, the CYP enzyme packet of mammal Include but be not limited to CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2F1、CYP2J2、CYP2R1、CYP2S1、CYP2U1、CYP2W1、 CYP3A4、CYP3A5、CYP3A7、CYP3A43、CYP4A11、CYP4A22、CYP4B1、CYP4F2、CYP4F3、CYP4F8、 CYP4F11、CYP4F12、CYP4F22、CYP4V2、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、CYP8A1、 CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17A1、CYP19A1、CYP19A1、CYP21A2、CYP24A1、 CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP39A1, CYP46A1 and CYP51A1.

The compound-for including herein such as Schisandra chinensis (Schisandra chinensis) extract-can inhibit this public affairs Open the CYP enzyme of content.In one embodiment, compound is more more selective than another in terms of inhibiting a kind of CYP enzyme.Art Language " selectivity " refers to that compound inhibits the IC of CYP a kind of₅₀Value is less than the IC of another kind CYP enzyme₅₀Value.

As used herein, term " IC₅₀" refer to inhibitor (such as antibody or antibody fragment) peak response and baseline it Between half test in inhibit reaction inhibition concentration.In one embodiment, IC₅₀Referring to reduces the activity of CYP enzyme, presses down Make the concentration of the CYP inhibitor of (suppresses, or inhibits) 50%.In one embodiment, IC₅₀Refer to CYP The enzymatic activity of enzyme (such as CYP3A4) reduces, inhibits the Schisandra chinensis of (suppresses, or inhibits) 50% The concentration of (Schisandra chinensis) extract.In one embodiment, the compounds of this invention is inhibiting a kind of CYP Often there are at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 than another CYP in terms of the selectivity of enzyme Again, 20 times, 50 times, 100 times, 1000 times.In one embodiment, the compound of the present invention is in terms of inhibiting a kind of CYP enzyme Selectivity be at least 5 times of another kind CYP enzyme.

The IC of Schisandra chinensis (Schisandra chinensis) extract₅₀It is every kg of body's mass about 0.01mg to about 200mg, about 200mg are to about 400mg, about 400mg to about 600mg, about 600mg to about 800mg or about 800mg to about 1000mg. In one embodiment, the IC of Schisandra chinens P.E₅₀For every kg of body's mass at least 0.01mg, 0.1mg, 2mg, 5mg, 10mg, 20mg, 30mg, 50mg, 70mg, 100mg, 150mg, 200mg, 250mg, 500mg, 1000mg, 2000mg, 5000mg or 10000mg。

Compound as described herein, such as Schisandra chinensis (Schisandra chinensis) extract, can be with another kind CYP enzyme inhibitor can be reversible, irreversible, emulative and noncompetitive inhibitor, be applied in combination.CYP enzyme inhibits Agent includes but is not limited to: CYP1A2 inhibitor, CYP2B6 inhibitor, CYP2C8 inhibitor, CYP2C9 inhibitor, CYP2C19 suppression Preparation, CYP2D6 inhibitor, CYP2E1 inhibitor and CYP3A4 inhibitor.

The non-limiting example of CYP1A2 inhibitor includes amiodarone, atazanavir, Cimetidine, Ciprofloxacin, western phthalein Pulan, clarithromycin, diltiazem, Enoxacin, erythromycin, estradiol, Fluvoxamine, interferon, isoniazid ketoconazole, first Oxygen sarin, Mibefradil and tegaserod.

The non-limiting example of CYP2B6 inhibitor includes phosphinothioylidynetrisaziridine (Thiopeta) and Ticlopidine (Ticlodipine).The non-limiting example of CYP2C8 inhibitor includes Anastrozole, ezetimibe, Gemfibrozil, Meng Lu Take charge of spy, nicardipine, Sulfinpyrazone and trimethoprim (Trimethoprim).

The non-limiting example of CYP2C9 inhibitor includes amiodarone, atazanavir, Cimetidine, clopidogrel, compound Radonil, delavirdine, disulfiram, Sustiva, fenofibrate, Fluconazole, fluorouracil, Prozac, Fluvastatin, fluorine volt Sha Ming, Gemfibrozil Capsules, Imatinib, isoniazid, Itraconazole, ketoconazole, leflunomide, Lovastatin, Methoxsalen, first nitre Azoles, mexiletine, modafinil, acidum nalidixicum, norethindrone, Norfloxacin, Omeprazole, contraceptive, Paxil, phenylbutazone, third Sulphur relax, Sertraline, sulfamethoxazole, sulfaphenazolum (Sulfaphenazole), sulfa drugs, Tacrine, Teniposide (Teniposide), Ticlopidine (Ticlodipine), tipranavir, troleandomycin, voriconazole, zafirlukast, stay together Plain (Bergamottin) extract of logical or garlic (Allium sativum) extract, bergamot, wire grip grass (Harpagophytum procumbens) extract and fructus lycii (Lycium barbarum) extract.

The non-limiting example of CYP2C19 inhibitor includes Cimetidine, Citalopram, delavirdine, efavirenz, non- Urethane (Felbamate), Fluconazole, Prozac, Fluvastatin, Fluvoxamine, Indomethacin, isoniazid, ketoconazole, Lan Suola Azoles, modafinil, Omeprazole, Oxcarbazepine, probenecid, Ticlopidine (Ticlodipine), Topiramate (Topiramate) and garlic (Allium sativum) extract and wire grip are careless (Harpagophytum procumbens) Extract.

The non-limiting example of CYP2D6 inhibitor includes abiraterone, amiodarone, amoxapine (Asenapine), cloth Ibuprofen, celecoxib, chloroquine, chlorphenamine, chlorpromazine, Cimetidine, cinacalcet, Citalopram, clemastine, chlorine rice pa Bright, cocaine, Dary that new, desipramine, diphenhydramine, doxepin (Doxepin), Doxorubicin, Duloxetine, Yi Tapu Logical sequence (Escitalopram), Febuxostat, Prozac, fluphenazinum, halofantrine, haloperidol, hydroxychloroquine, hydroxyzine, she horse replaces Buddhist nun, left-handed promazine, methadone, Metoclopramide, mibefradil (Mibefradil), midodrine, Moclobemide, Nefazodone, Norfluoxetine, Paxil, perphenazine, Propafenone, propoxyhene, Propranolol, quinacrine, quinindium, ranitidine, thunder Promise piperazine, Ritonavir, Sertraline, tegaserod, Terbinafine, thioridazine (Thioridazine), Ticlopidine (Ticlodipine), tipranavir, Tripelennamine and Alpinia galanga (Alpinia glanga) extract, common alstonia (Alstonia scholaris) extract, Herba Andrographitis (Andrographis paniculata) extract, catharanthus roseus (Catharanthus roseus) extract, rattleroot (Cimicifuga racemose) extract, burmannii (Cinnamomum burmannii) extract, Siberia tiger ginseng (Eleutherococcus senticoccus) are extracted Object, licorice (Gycyrrhiza glabra) extract, goldenseal (Hydrastis canadensis) extract, mutual leaf are white Thousand layers of (Melaleuca leucadendron) extract, ginseng (Panax ginseng) extract, American Ginseng (Panax Quinquefolius) extract, pepper (Piper nigrum) extract, pomegranate (Punica granatum) extract, the palm Leaf rheum officinale (Rheum palmatum) extract, santal (Santalum album) extract, vomiting nut (Strychnos Ligustrina) extract, cloves (Syzygium aromaticum) extract, green packet rattan (Tinospora crispa) mention Take object and ginger (Zingiber aromaticum) extract.

The non-limiting example of CYP2E1 inhibitor includes that disulfiram and kawakaw (Piper Methysticum) extract Object.

The non-limiting example of CYP3A4 inhibitor includes amiodarone, anpunave, Aprepitant, atazanavir, Bo Sai Sprinkle dimension, Cimetidine, Ciprofloxacin, clarithromycin, cyclosporin, danazol, delavirdine, diltiazem, efavirenz, red Mycin, ethinylestradiol (Ethinyl Estradiol), ezetimibe, Fluconazole, Prozac, Fluvoxamine, pregnant diene Ketone, Imatinib, indinavir, isoniazid, Itraconazole, ketoconazole, methylprednisolone, Mibefradil, Miconazole, meter Fei Take charge of ketone, Nefazodone, Nai Feinawei, nicardipine, nifedipine, norethindrone, Norfloxacin, norfluoxetine, Oxiconazole, pool Saperconazole, prednisone, quinine, ranolazine, Ritonavir, roxithromycin, inverase, Sertraline, telavi, thyrite are mould Element, troleandomycin, Verapamil, voriconazole, zafirlukast, Zileuton and garlic (Allium sativum) are extracted Object, ammi visnaga (Ammi visnaga) extract, margosa tree tree (Azadirachta indica) extract, rattleroot (Cimicifuga racemose) extract, Harpagphytum extract, water grape (Procumbens) extract, white hair Gelsemium (Hydrastis canadensis) extract, naringenin (Naringenin) extract, ginseng (Panax ginseng) mention Take object, American Ginseng (Panax quinquefolius) extract, vomiting nut (Strychnos ligustrina) extract and hook Rattan white Mao Yang (Uncaria tomentosa) extract.

Pharmaceutical composition

On the other hand, the present invention relates to the pharmaceutical composition for treating and/or preventing subject's parasitic disease, packets Containing PZQ (such as R-PZQ) and Schisandra chinensis (Schisandra chinensis) extract or it is derived from Schisandra chinensis (Schisandra Chinensis compound).In one embodiment, Schisandra chinens P.E includes the compound separated from Schisandra chinensis.? In another embodiment, Schisandra chinens P.E includes wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, the five tastes Sub- alcohol B, Schisantherin A.In a further embodiment, composition include a effective amount of Schisandra chinens P.E, with reduce or Inhibit the enzymatic activity to PZQ and R-PZQ.

Pharmaceutical composition or composition of the invention can solid food in a variety of manners or liquid food exist, such as It is tablet, effervescent or powder, effervescent tablet, liquid, dispersible and/or soluble tablet, dispersible powder, suspension, close Sealed bag, premix syrup, jelly, glycerol, chewable tablets, particle or capsule (such as hard capsule), liquid beverage and food such as soup, Fruit juice, tea-drinking, milk, leben, soya-bean milk, cocoa and fruit syrup, semi-solid food products such as pudding or Yoghourt, face Packet, noodles such as Noodle, sweet food such as cookies, chocolate, candy or wafer and spread for example mix meal material, butter Or jam etc..In addition, pharmaceutical composition or composition are also possible to health food or treat the form of food.Do not have for its form Have a special limitation, preferred example includes the form that can continuously absorb, such as tablet, chewable tablets, particle or capsule (such as Hard capsule), it also include sweet food, soup, beverage and liquid food.

Parasitic disease is easy to by composition disclosed by the invention or medicine composite for curing.In one embodiment, described Parasitic disease includes echinococcosis, cysticercosis, snail fever, clonorchiasis, paragonimiasis or fasciolopsiasis.Another In embodiment, the parasitic disease is snail fever.In a further embodiment, parasitic disease includes being caused by tapeworm Alimentary infection, including Taenia elliptica (Dipylidium caninum) or band-like cysticercus (Taenia taeniaeformis).

The composition or pharmaceutical composition include PZQ, R-PZQ or its analog.It is well known that living in pharmaceutical composition Property compound effective dose depend on expected drug delivery route and other doctors commonly known such as patient age and weight Etc. factors.Dosage additionally depends on disease to be treated.For example, dosage is decided by the spy of pharmaceutical composition targeting disclosed by the invention Determine parasitic disease.

In one embodiment, the composition or pharmaceutical composition include every kg of body about 1 to about 200, about 200 To about 400, about 400 to about 600, about 600 to about 800 or about 800 to about 1000mg PZQ or R-PZQ.In another embodiment In, the composition includes every kg of body about 1 to about 1000, about 10 to about 500, about 20 to about 250, about 30 to about 200 Or about 40 to about 100mg PZQ or R-PZQ.In another embodiment, the dosage of PZQ or R-PZQ be every kg of body extremely Few about 50mg.In another embodiment, PZQ or R-PZQ that the composition or pharmaceutical composition include, dosage are less than 10000, the every kg of body of 100,80,50,30,20,10,5 or 1mg.

The composition or pharmaceutical composition include Schisandra chinensis (Schisandra chinensis) extract.Institute as above It states, the dosage of Schisandra chinens P.E in the composition depends on expected drug delivery route and other factors such as patient age and body The amount of PZQ or R-PZQ in weight and composition.In one embodiment, Schisandra chinensis (Schisandra chinensis) is extracted The dosage of object is at least 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, 50mg/kg, 70mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or The quality of 5000mg/kg subject.In some embodiments, the dosage of Schisandra chinensis (Schisandra chinensis) is every Kg of body's mass about 1 to about 200, about 200 to about 400, about 400 to about 600, about 600 to about 800 or about 800 is to about Schisandra chinensis (Schisandra chinensis) extract of 1000mg.

Schisandra chinensis (Schisandra chinensis) extract includes wuweizisu A, wuweizisu B, Schisandra chinensis Plain C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A.Therefore, the composition or pharmaceutical composition include schizandrin A, the dosage of wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A be at least 0.1mg, 1mg, 2mg、5mg、10mg、20mg、30mg、50mg、70mg、100mg、150mg、200mg、250mg、500mg、1000mg、2000mg、 The quality of the every kg of body of 5000mg or 10000mg.In another embodiment, the composition or pharmaceutical composition include Wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A dosage be about 1mg To about 200mg, about 200mg to about 400mg, about 400mg to about 600mg, about 600mg to about 800mg or about 800mg to about The quality of the every kg of body of 1000mg.In some embodiments, the composition or pharmaceutical composition include schizandrin A, the dosage of wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A is about 1mg to about 10000mg, about 10mg are to about 7000mg, about 100mg to about 5000mg, about 200mg to about 3000mg, about 500mg to about 2000mg and about 700mg to the every kg of body of about 1500mg quality.

On the one hand, described pharmaceutical composition is oral suspension, tablet, spraying or capsule, lotion, gel or foam Form.

On the other hand, the PZQ (such as S-PZQ or R-PZQ) and the Schisandra chinensis (Schisandra chinensis) The mass ratio of extract is at least 1:10000,1:1000,1:100,1:10,1:5,1:3,1:2,1:1,2:1,3:1,5:1,10: 1,100:1,1000:1 or 10000:1.In one embodiment, the PZQ and Schisandra chinensis (Schisandra Chinensis) mass ratio of extract is 1:1 or 2:1.In another embodiment, PZQ and Schisandra chinensis (Schisandra Chinensis) mass ratio of extract is at least 1:3,1:5,1:10 or 1:100.

Pharmaceutical composition of the invention includes other anti-parasite medicines or medicament (anti-of effectively treatment parasitic disease Parasitic drugs or medications), parasitic disease include but is not limited to toxoplasmosis, malaria, African typanosomiasis nagana, South American trypanosomiasis, leishmaniasis, snail fever, amcbiasis, Giardiasis, clonorchiasis, opisthorchiasis, lung fluke Disease, fasciolopsiasis, Filariasis, onchocercosis, drachunculiasis, roundworm disease, trichuriasis, strongyloidosis, Trichostrogylosis, trichomoniasis and taeniasis.In one embodiment, other anti-parasite medicines or medicament can effectively treat parasitism Parasitosis includes tapeworm-cestode infection, bothrio-cephaliasis, echinococcosis-tapeworm, hymenolepiasis, taeniasis bovis (Beef Tapeworm), cysticercosis-armed tapeworm, bertielliasis, sparganosis, clonorchiasis (Clonorchiasis), willow Leaf knife liver rot (Lancet liver fluke), liver fluke-fascioliasis, Fasciola hepatica-distomatosis intestinalis, after grow fluke Disease-distomatosis intestinalis, secondary testis fluke disease, Chinese liver fluke disease (Chinese liver fluke), paragonimiasis (Paragonimiasis), paragonimiasis (lung fluke), schistosomicide-blood fluke, schistosomiasis or blood fluke Sick (snail fever, all types), intestinal schistosomiasis, urinary schistosmiasis, Schistosoma japonicum snail fever, Asia intestines Snail fever, schistosome dermatitis (Swimmer's itch), hookworm disease/hookworm (Ancylostomiasis/ Hookworm), angiotrongylosis, anisakiasis, roundworm-helminth pneumonia, roundworm-belleville roundworm disease (Roundworm- Baylisascariasis), ascarid Filariasis, dioctophyma renale infection, Guinea worm-drachunculiasis, very little white Worm-enterobiasis, gnathostomiasis, demon's verminosis (Halicephalobiasis), loaiasis (Loa loa Filariasis), Calabar swellings (Calabar swellings), graceful gloomy filariasis, filariasis, river blindness, filaria volvulus Disease, strongyloidosis-helminth pneumonia, thelaziasis, toxocarasis, trichinosis, trichuriasis, elephantiasis-lymph silk Parasitosis, acanthocephaliasis, fascioliasis syndrome, myiasis (Myiasis), spiral myiasis (Screwworm), screwfly disease (Cochliomyia), trombiculid flea (Chigoe flea), bedbug, human botfly (Human botfly), head louse-louse disease, body Lice-louse disease, hair lice-louse disease (Crab louse-Pediculosis), vermiform mite-demodicidosis, scabies, " trombiculid (Chiggers) " (illness section (Trombiculidae))-trombidiosis, flea (Flea), Siphonaptera (Siphonaptera), tick (Tick), granulomatous amebic encephalitis (ocular infection), Acanthamoeba Keratitis, granulomatous amebic encephalitis (skin sense Dye), Babesia Gibsoni, balantidiasis (Babesiosis), bud capsule protozoosis (Balantidiasis), Cryptosporidiosis, ring spore Sub- parasitosis, dientamoeba fragilis disease, amcbiasis, Giardiasis, isosporiasis, leishmaniasis, primary amebic brain Meningocephalitis (PAM), malaria, rhinosporidiosis, sacrosporidiosis, toxoplasmosis (acute and latency), trichomoniasis, difussa With the parasitic disease of South American trypanosomiasis.

The suitable anti-parasite medicine of the others of composition disclosed by the invention or pharmaceutical composition includes sulphur first nitre miaow Azoles (tinidazole), metronidazole, melarsoprol, Eflornithine, rifampin, amphotericin B, pentamidine, gluconic acid amber Sour sodium, meglumine antimonate, Fluconazole, Artesunate, quinine, quinindium, chloroquine, atovaquone-proguanil (atovaquone- Proguanil), Artemether-benzoin alcohol, Mefloquine, fortimicin (doxycycline), clindamycin, paromomycin, atropic Cut down quinone, Nitazoxanide, azithromycin, fumidil, paromomycin, diloxan (diloxanide), secnidazole, Ornidazole, Moebiquin, diloxanide furoate, clindamycin, Atovaquone, azithromycin, diazonium phenalgin miaow (diminazen), trypan blue (trypan blue), Austria Sha Kuining (oxamniquinine), niclosamidum, albendazole, mebendazole, thiabendazole, thiophene Pyrimidine, diethylcarbamazine, ivermectin, selamectin, doractin and avermectin.In another embodiment, other anti-parasitisms Parasitosis drug include for treating bilharzial drug, including but not limited to nithiocyamine, arteether, Artemether, dichloroxylenol, Hycanthone, Lucanthone, Meclonazepam, niridazole (niridazole), Oltipraz and Oxamniquine (oxamniquine).

As described above, once applying, the enzymatic activity of CYP may be that PZQ (including S-PZQ and R-PZQ) bioavilability is low One of the reason of.Therefore, composition disclosed by the invention or pharmaceutical composition further comprise CYP inhibitor comprising CYP1A2 inhibitor, CYP2B6 inhibitor, CYP2C8 inhibitor, CYP2C9 inhibitor, CYP2C19 inhibitor, CYP2D6 inhibit Agent, CYP2E1 inhibitor or CYP3A4 inhibitor.The non-limiting example of CYP1A2 inhibitor include: amiodarone, atazanavir, Cimetidine, Ciprofloxacin, Citalopram, clarithromycin, diltiazem, Enoxacin, erythromycin, estradiol, Fluvoxamine, Interferon, isoniazid ketoconazole, methicillin, Mibefradil, tegaserod.The non-limiting example of CYP2B6 inhibitor includes Phosphinothioylidynetrisaziridine (Thiopeta) and Ticlopidine (Ticlodipine).The non-limiting example of CYP2C8 inhibitor includes Ah Nagqu Azoles, ezetimibe, Gemfibrozil, montelukast, nicardipine, Sulfinpyrazone and trimethoprim (Trimethoprim). The non-limiting example of CYP2C9 inhibitor include: amiodarone, atazanavir, Cimetidine, clopidogrel, Compound New Nomin, Delavirdine, disulfiram, efavirenz, fenofibrate, Fluconazole, fluorouracil, Prozac, Fluvastatin, Fluvoxamine, Ji Fei Luoqi, Imatinib, isoniazid, Itraconazole, ketoconazole, leflunomide, Lovastatin, Methoxsalen, metronidazole, Mei Xi Rule, modafinil, nalidixic acid, norethindrone, Norfloxacin, Omeprazole, contraceptive, Paxil, phenylbutazone, probenecid, Sertraline, sulfamethoxazole, sulfaphenazolum (Sulfaphenazole), sulfa drugs, Tacrine, Teniposide, thiophene chlorine Pyridine (Ticlodipine), tipranavir, troleandomycin, voriconazole, zafirlukast, Zileuton or garlic (Allium Sativum) plain (Bergamottin) extract of extract, bergamot, wire grip careless (Harpagophytum procumbens) mention Take object and fructus lycii (Lycium barbarum) extract.The non-limiting example of CYP2C19 inhibitor includes Cimetidine, west Phthalein Pulan, delavirdine, Sustiva, non-urethane, Fluconazole, Prozac, Fluvastatin, Fluvoxamine, Indomethacin, different cigarette Hydrazine, ketoconazole, Lansoprazole, modafinil, Omeprazole, Oxcarbazepine, probenecid, Ticlopidine (Ticlodipine) support Pyrrole ester and careless (Harpagophytum procumbens) extract of garlic (Allium sativum) extract and wire grip. The non-limiting example of CYP2D6 inhibitor includes abiraterone, amiodarone, amoxapine (Asenapine), brufen, fills in and Former times cloth, chlorphenamine, chlorpromazine, Cimetidine, cinacalcet, Citalopram, clemastine, clomipramine, can block chloroquine Cause, that new, desipramine, diphenhydramine, doxepin, Doxorubicin, Duloxetine, escitalopram, Febuxostat, fluorine west of Dary Spit of fland, fluphenazinum, halofantrine, haloperidol, hydroxychloroquine, hydroxyzine, Imatinib, left-handed promazine, methadone, Metoclopramide, Mibefradil (Mibefradil), midodrine, Moclobemide, Nefazodone, norfluoxetine, Paxil, perphenazine, Pu Luopa Ketone, propoxyhene, Propranolol, quinacrine, quinindium, ranitidine, ranolazine, Ritonavir, Sertraline, tegaserod, Terbinafine, thioridazine (Thioridazine), Ticlopidine (Ticlodipine), tipranavir, Tripelennamine and big Galangal (Alpinia glanga) extract, common alstonia (Alstonia scholaris) extract, Herba Andrographitis (Andrographis paniculata) extract, catharanthus roseus (Catharanthus roseus) extract, rattleroot (Cimicifuga racemose) extract, burmannii (Cinnamomum burmannii) extract, Siberia tiger ginseng (Eleutherococcus senticoccus) extract, licorice (Gycyrrhiza glabra) extract, goldenseal (Hydrastis canadensis) extract, narrow leaved tea tree (Melaleuca leucadendron) extract, ginseng (Panax ginseng) extract, American Ginseng (Panax quinquefolius) extract, pepper (Piper nigrum) mention Take object, pomegranate (Punica granatum) extract, sorrel (Rheum palmatum) extract, santal (Santalum Album) extract, vomiting nut (Strychnos ligustrina) extract, cloves (Syzygium aromaticum) are extracted Object, green packet rattan (Tinospora crispa) extract and ginger (Zingiber aromaticum) extract.CYP2E1 The non-limiting example of inhibitor includes disulfiram and kawakaw (Piper Methysticum) extract.CYP3A4 inhibits The non-limiting example of agent includes: amiodarone, anpunave, Aprepitant, atazanavir, Bo Saipowei, Cimetidine, cyclopropyl Sha Xing, clarithromycin, cyclosporin, danazol, delavirdine, diltiazem, Sustiva, erythromycin, ethinylestradiol, according to Replace rice shellfish, Fluconazole, Prozac, Fluvoxamine, gestodene, Imatinib, indinavir, isoniazid, Itraconazole, ketone in pool Health azoles, methylprednisolone, Mibefradil, Miconazole, mifepristone, Nefazodone, Nai Feinawei, nicardipine, nitre benzene Flat, norethindrone, Norfloxacin, norfluoxetine, Oxiconazole, posaconazole, prednisone, quinine, ranolazine, Ritonavir, sieve Erythromycin, inverase, Sertraline, telavi, Ketek, troleandomycin, Verapamil, voriconazole, Zha Lusi Special, Zileuton and garlic (Allium sativum) extract, ammi visnaga (Ammi visnaga) extract, margosa tree tree (Azadirachta indica) extract, rattleroot (Cimicifuga racemose) extract, Harpagphytum are mentioned Take object, water grape (Procumbens) extract, goldenseal (Hydrastis canadensis) extract, naringenin (Naringenin) extract, ginseng (Panax ginseng) extract, American Ginseng (Panax quinquefolius) extract Object, vomiting nut (Strychnos ligustrina) extract and uncaria white Mao Yang (Uncaria tomentosa) extract.

On the one hand, described pharmaceutical composition includes a kind of selected from adhesive, flavoring agent, lubricant, flowable, disintegration The medicament of agent, delayed-action activator and combinations thereof.In one embodiment, described adhesive includes starch, modified starch, cellulose, changes Property cellulose, brewer's yeast, sucrose, dextrose (dextrose), whey, Dicalcium Phosphate or combinations thereof.In another embodiment In, the flavoring agent includes dry liver, liver extract, cheese, cheese product, natural perfume material, artificial perfume, newborn flavour product, big Beans flavoring products, brewer's yeast or combinations thereof.In a further embodiment, the lubricant includes magnesium stearate, tristearin Acid, starch, modified starch, modified cellulose or combinations thereof.In yet another embodiment, the flowable include silica, Improved silica, fumed silica, talcum or combinations thereof.In another embodiment, the disintegrating agent includes crosslinking carboxylic Sodium carboxymethylcellulose pyce, sodium starch glycollate, starch, modified starch or combinations thereof.In some embodiments, the delayed-action activator Including stearic acid, stearate, magnesium stearate, polyethylene glycol, starch, modified starch, methacrylate polymers or its group It closes.

It will be readily appreciated by those skilled in the art that any suitable pharmaceutically acceptable liposome can be used as this The carrier of the composition of invention.This lipid composition is active to many microorganisms, is similar to above-mentioned discussed in detail The activity of other combinations of the present invention.In addition, these compositions can be such as various routines discussed in detail above and well-known Mode apply.

On the other hand, described pharmaceutical composition further include antimicrobial component, anti-fungal composition, anti parasitic ingredient or A combination thereof.On the one hand, described pharmaceutical composition further includes pharmaceutically acceptable carrier.

Pharmaceutically acceptable carrier for application includes or basically comprises or further include sterile, water or non-aqueous Solution, suspension or emulsion.The non-limiting example of nonaqueous solvents include propylene glycol, polyethylene glycol, vegetable oil such as olive oil and The organic ester of injectable such as ethyl oleate.The non-limiting example of aqueous carrier includes water, alcohol/aqueous solution, emulsion or suspension, Including physiological saline and buffer medium.The non-limiting example of injection carrier includes sodium chloride solution, woods grignard glucose, the right side Rotation sugar and sodium chloride, Lactated Ringer'S Solution or fixing oil.Activating agent or therapeutic component are usually mixed with excipient, pharmaceutically It is acceptable and compatible with active constituent.The non-limiting example of suitable excipient includes water, physiological saline, dextrose, glycerol And ethyl alcohol, or combinations thereof.Venous transfusion carrier includes but is not limited to liquid and nutritional supplement, electrolyte replenisher such as base In the replenishers etc. of woods grignard glucose.There may also be preservative and other additives, for example, it is antimicrobial, anti-oxidant Agent, chelating agent and inert gas etc..

On the one hand, the subject is mammal.It is in one embodiment, described that subject is a human.

In one embodiment, the pharmaceutical compositions are injection formula.

In another embodiment, the composition includes pharmaceutically acceptable excipient.Acceptable excipient is It is nontoxic, facilitate application, and will not have an adverse effect to the curative effect of claimed composition.These excipient can To be any solid, liquid, semisolid or gaseous excipient that those skilled in the art are commonly available.

Solid pharmaceutical excipients include starch, cellulose, talcum powder, glucose, lactose, sucrose, gelatin, malt, rice, Flour, chalk, silica gel, magnesium stearate, odium stearate, glycerin monostearate, sodium chloride and dry skimmed milk powder etc..Liquid and half Solid excipient can be selected from glycerol, propylene glycol, water, ethyl alcohol and various oils, and wherein oils includes petroleum, animal, plant or conjunction At the oil in source, such as peanut oil, soybean oil, mineral oil and sesame oil etc..Preferred liquid-carrier, especially injectable are molten Liquid, including water, physiological saline, aqueous dextrose and glycols.Other suitable pharmaceutical excipients and formula by Remington ' s Pharmaceutical Sciences that E.W.Martin is edited (Mack Publishing Company, 18th ed., 1990) by being described in detail in.

Dosage and application

As described herein, described pharmaceutical composition is applied with effective dose.The effective dose is decided by method of application, just In the specific patient's condition and desired result for the treatment of.It additionally depend on the stage of the patient's condition, the age of subject and physical condition, Similar factor known to the property of (if having) synchronous therapeutic and doctor.For treatment use, its amount sufficiently achieves doctor Desired result on.

In addition, the dosage or concentration of PZQ (or R-PZQ) or Schisandra chinens P.E in described pharmaceutical composition depend on mentioning Take absorption, inactivation and the rate of discharge and other factors well known by persons skilled in the art of object.It should be noted that dose value Also changed according to the severity of the patient's condition to be alleviated.It should further be appreciated that for any specific subject, specific agent Amount scheme should be adjusted according to the needs of individual and the professional judgement of the personnel of application or supervision application, and concentration described herein Range only makees example, it is not intended that limits the range and use of composition claimed.The composition can be with primary It applies or is divided into several smaller doses and apply at various time intervals.In some embodiments, described pharmaceutical composition Insecticide-applying way is oral.Orally administered composition generally includes inert diluent or edible carrier.They can be encapsulated in gelatine capsule In or it is tabletted.For the purpose of oral medication application, the reactive compound can merge with excipient with tablet, ingot The form of agent or capsule uses.A part that the adhesive and/or Adjuvanting material of pharmaceutically compatible can be used as composition is included in It is interior.

The dosage of PZQ or R-PZQ depends on type, health status, temperature or other bodies or physiological status of subject. Normally, the dosage of PZQ or R-PZQ is daily subject's weight about 1mg/kg to about 200mg/kg, about 200mg/ in the present invention Kg to about 400mg/kg, about 400mg/kg are to about 600mg/kg, about 600mg/kg to about 800mg/kg or about 800mg/kg to about 1000mg/kg, including all values and range between it, including endpoint.In one embodiment, the dosage be daily about 10mg/kg to 200mg/kg.In another embodiment, the dosage is daily about 200mg/kg to 400mg/kg.

In one embodiment, the dosage of the PZQ or R-PZQ is no more than daily about 1000mg/kg.In another embodiment party In case, the dosage of the PZQ or R-PZQ are every kg of body's mass at least about 50mg.In another embodiment, described group Closing object or pharmaceutical composition includes PZQ or R-PZQ, dosage less than every kilogram of 100,80,60,50,30,20,10,5 or 1mg by Examination person's quality.In some embodiments, it is every kilogram that the composition or pharmaceutical composition, which include the dosage of PZQ or R-PZQ, Subject's mass about 20mg to about 60mg.

The dosage of Schisandra chinensis (Schisandra chinensis) extract is subject's mass at least 0.1mg/kg, 1mg/ kg、2mg/kg、5mg/kg、10mg/kg、20mg/kg、30mg/kg、50mg/kg、70mg/kg、100mg/kg、150mg/kg、 200mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or 5000mg/kg.In some embodiments, five The dosage of taste (Schisandra chinensis) be every kg of body's mass about 1 to about 200, about 200 to about 400, about 400 to about 600, about 600 to about 800 or about 800 to about 1000mg Schisandra chinens P.E.

In one aspect of the invention, the application of pharmaceutical composition as described herein is pulsation (pulsatile).It is real one Apply in scheme, the composition or pharmaceutical composition were applied with every 1 hour to every 24 hours, for example, every 1 hour, it is 2 hours every, Every 3 hours, it is 4 hours every, 5 hours every, 6 hours every, 7 hours every, for every eight hours, it is 9 hours every, 10 hours every, 11 hours every, every 12 hours, it is 13 hours every, 14 hours every, 15 hours every, 16 hours every, 17 hours every, 18 hours every, 19 hours every, every 20 small When, it is 21 hours every, 22 hours every, every 23 hours or 24 hours every.In one embodiment, the composition or pharmaceutical composition Every 1 day, 2 days every, 3 days every, 4 days every, 5 days every, 6 days every, 7 days every, 8 days every, every 9 days or application in every 10 days.

Schisandra chinensis (Schisandra chinensis) extract includes wuweizisu A, wuweizisu B, Schisandra chinensis Plain C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A.Therefore, the composition or pharmaceutical composition include schizandrin A, the dosage of wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A is every kg of body's matter Measure at least 0.1mg, 1mg, 2mg, 5mg, 10mg, 20mg, 30mg, 50mg, 70mg, 100mg, 150mg, 200mg, 250mg, 500mg, 1000mg, 2000mg, 5000mg or 10000mg.

In another embodiment, the composition or pharmaceutical composition include wuweizisu A, wuweizisu B, Schisandra chinensis Plain C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A dosage be subject's mass about 1mg/kg to about 200mg/kg it Between, about 200mg/kg between about 400mg/kg, about 400mg/kg between about 600mg/kg, about 600mg/kg to about 800mg/ Between kg or about 800mg/kg is between about 1000mg/kg.In some embodiments, the composition or pharmaceutical composition packet The dosage for including wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B and/or Schisantherin A is every thousand Gram subject about 1mg between about 10000mg, about 10mg between about 7000mg, about 100mg between about 5000mg, about 200mg between about 3000mg, about 500mg is between about 2000mg and about 700mg is between about 1500mg.

In one aspect of the invention, described pharmaceutical composition dosage is to apply to be enough to generate for a period of time in a manner of pulsation Anti parasitic effect (such as mitigating or inhibit disease caused by helminth).In one embodiment, certain time is about 1 day To between about 10 days.For example, the period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days.

To use various drug delivery routes.Generally speaking, pharmaceutical composition of the invention can be used medically acceptable Any insecticide-applying way is implemented, it is intended that in the case where not generating clinical unacceptable side effect, generate effective activity at Divide horizontal any mode.

Insecticide-applying way includes oral, rectum, external application (topical), nasal cavity, intradermal or parenteral (parenteral) way Diameter." parenteral " term includes subcutaneous, intravenous, intramuscular or perfusion.Intravenously or intramuscularly interior approach is not well suited for Long-term treatment and prevention.But in case of emergency they may be preferred.Prophylactic treatment first choice is oral, because to patient with And the convenience of application plan.

Composition suitable for oral administration can be used as separate unit, such as capsule, tablet and pastille exist, each independence Unit contains the activating agent of predetermined amount.Other compositions include waterborne liquid in suspension and non-aqueous solution such as syrup, Elixir or emulsion.

The preparation of parenteral administration includes aseptic aqueous solution or non-aqueous solution, suspension and emulsion.The example of nonaqueous solvents There is the organic ester such as ethyl oleate of propylene glycol, polyethylene glycol, vegetable oil such as olive oil and injectable.Aqueous carrier include water, Alcohol/aqueous solution, emulsion or suspension, including physiological saline and buffer medium.Parenteral vehicles include sodium chloride solution, woods grignard Glucose, dextrose and sodium chloride, Lactated Ringer'S Solution or fixing oil.Intravenous vehicles include liquid and nutritional supplement, electricity Solve matter replenishers (such as replenishers based on woods grignard glucose) etc..Preservative and other additives also may be present, such as anti- Microorganism agent, antioxidant, chelating agent, inert gas etc..Other forms application may cause lower dosage, such as intravenously Application.It, can be in the case where patient tolerance's ability allows using higher if the underaction of subject in application dose Dosage (or by different, local drug delivery route effectively improves dosage).In order to reach the system water of suitable compound It is flat, it is contemplated that use a variety of dosage daily.

Other conveyer systems may include delay release, sustained release or Sustained release delivery system.These systems can be to avoid Repetitive administration pharmaceutical composition of the invention increases the convenience of subject and doctor.A plurality of types of release conveyer systems pair It is known and available for those skilled in the art.They include polymer based systems, such as poly (glycolide-lactide) (poly (lactide-glycolide)), copolymerized oxalate (copolyoxalates), polycaprolactone, polyesteramide, polyorthoester, poly- Hydroxybutyric acid and polyanhydride.The microcapsules of aforementioned polymer containing drug describe in such as U.S. Patent No. 5075109. Delivery system further includes following non-polymer systems: lipid includes sterol such as cholesterol, cholesteryl ester and fatty acid or neutral fats Fat such as monoglyceride, diglyceride and triglycerides；Hydrogel discharges system；Silicon rubber system (sylastic systems)； Peptide based systems；Wax coating；Use the compressed tablets of traditional binders and excipient；Member fusion implant etc..

In one embodiment, described pharmaceutical composition is with the release that is delayed, sustained release or Sustained release delivery systemic application.? In one embodiment, it will be inserted directly into comprising the delay of pharmaceutical composition of the present invention release, sustained release or Sustained release delivery system To in lump (tumor).

In application, pharmaceutical preparation of the invention is applied with pharmaceutically acceptable amount and pharmaceutically acceptable composition With.These preparations can be routinely containing salt, buffer, preservative, compatible carrier and optional other therapeutic agents.When in medicine In use, salt should be pharmaceutically acceptable in object, but acceptable salt can be to be advantageously used in the preparation of it in non-pharmaceutical Pharmaceutically acceptable salt, and be not precluded within except the scope of the present invention.These are pharmacologically and pharmaceutically acceptable salt Including but not limited to by the salt of following acid preparation: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, lemon Lemon acid, formic acid, malonic acid, succinic acid etc..And pharmaceutically acceptable salt can be prepared into alkali metal salt or alkali salt, Such as sodium salt, sylvite or calcium salt.

Treatment method

The present invention also provides the methods for treating and/or preventing subject's parasitic disease, including apply effectively to subject The PZQ or R-PZQ of dosage and Schisandra chinensis (Schisandra chinensis) extract of effective dose.In an embodiment In, Schisandra chinensis (Schisandra chinensis) extract includes the compound separated from Schisandra chinensis.In another reality It applies in scheme, it includes wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, the five tastes that compound is separated from Schisandra chinensis Sub- alcohol B and/or Schisantherin A or combinations thereof.

The parasitic disease of method sensitivity disclosed by the invention includes but is not limited to echinococcosis, cysticercosis, snail fever, China Clonorchiasis, paragonimiasis or fasciolopsiasis, or by tapeworm (caused alimentary infection, including Taenia elliptica (Dipylidium caninum) or band-like cysticercus (Taenia taeniaeformis).In another embodiment, helminth Disease includes toxoplasmosis, malaria, African typanosomiasis nagana, South American trypanosomiasis, leishmaniasis, snail fever, amcbiasis, giardia lamblia Disease, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, Filariasis, onchocercosis, Medina dragon line Parasitosis, roundworm disease, trichuriasis, strongyloidosis, trichostrogylosis, trichomoniasis and taeniasis.In one embodiment, other Anti-parasite medicine or medicament can effectively treat parasitic disease include tapeworm-cestode infection, bothrio-cephaliasis, echinococcosis-tapeworm, Hymenolepiasis, taeniasis bovis (Beef tapeworm), cysticercosis-armed tapeworm, bertielliasis, sparganosis, magnificent branch testis Fluke disease (Clonorchiasis), lancet liver rot (Lancet liver fluke), liver fluke-fascioliasis, liver Piece fluke-distomatosis intestinalis, metagonimiasis-distomatosis intestinalis, secondary testis fluke disease, Chinese liver fluke disease, paragonimiasis, lung fluke Disease, schistosomicide-blood fluke, schistosomiasis or snail fever (all kinds), intestinal schistosomiasis, urinary tract blood fluke Disease, Schistosoma japonicum snail fever, Asia intestinal schistosomiasis, schistosome dermatitis (Swimmer's itch), hookworm disease/12 Duodenum 12 disease (Ancylostomiasis/Hookworm), angiotrongylosis, anisakiasis, roundworm-helminth pneumonia, roundworm- Belleville roundworm disease, ascarid Filariasis, dioctophyma renale infection, Guinea worm-drachunculiasis, pinworm-pinworm Disease, gnathostomiasis, demon's verminosis, loaiasis, Calabar swellings, graceful gloomy filariasis, filariasis, river blindness, disk Tailfiber parasitosis, strongyloidosis-helminth pneumonia, thelaziasis, toxocarasis, trichinosis, trichuriasis, elephantiasis- Filariasis, acanthocephaliasis, fascioliasis syndrome, myiasis, spiral myiasis, screwfly disease, trombiculid flea, sand hopper, bedbug, Human botfly, head louse-louse disease, body louse-louse disease, hair lice-louse disease, vermiform mite-demodicidosis, scabies, " trombiculid (Chiggers) " (illness section (Trombiculidae))-trombidiosis, flea, Siphonaptera, tick (Tick), granulomatous amoeba brain Scorching (ocular infection), Acanthamoeba Keratitis, granulomatous amebic encephalitis (skin infection), Babesia Gibsoni, balantidiasis, Bud capsule protozoosis, Cryptosporidiosis, cyclosporiasis, dientamoeba fragilis disease, amcbiasis, Giardiasis, isospora Disease, leishmaniasis, primary amebic meningo encephalitis (PAM), malaria, rhinosporidiosis, sacrosporidiosis, toxoplasmosis are (anxious Property and latency), trichomoniasis, the parasitic disease of difussa and South American trypanosomiasis.

In one embodiment, the parasitic disease is snail fever.In another embodiment, the parasitic disease is As caused by blood fluke.

In another embodiment, the parasitic disease includes any patient's condition as caused by helminth.Helminth include but It is not limited to endoparasite and vermin.The non-limiting example of helminth includes rafflesia, semen cuscatue spp, spine head Guiding principle, roundworm (roundworm), Cestoda (tapeworm) include: teniarhynchosis (Taenia saginata) (people teniarhynchosis), armed tapeworm (Taenia solium) (people armed tapeworm), fish tapeworm (Diphyllobothrium latum) (fish tapeworm), echinococcosis (Echinococcosis) (Echinococcus granulosus), clonorchis sinensis (Clonorchis sinensis) (Chinese liver fluke), wheat That imperial nematode (Dracunculus medinensis) (Guinea worm) of ground, compacted shape live in pinworm (Enterobius Vermicularis) (pinworm/pinworm), filariasis (Filariasis), hookworm, Loa loa (Loa loa), filaria volvulus (Onchocerciasis) (river blindness), blood fluke (Schistosomiasis), excrement class round wires tapeworm (Strongyloides Stercoralis), tapeworm, Toxocara canis (Toxocara canis) (dog roundworm), trichina (Trichinella), whipworm, Entamoeba histolytica (Entamoeba histolytica), amoeba coli (Entamoeba coli), Acanthamoeba (Acanthamoeba), baboon Baram wishes amoeba (Balamuthia mandrillaris), Giardia, Cyclospora Cyclospora cayetanensis), Cryptosporidium (Cryptosporidium), toxoplasma (Toxoplasma gondii), Leishmania (Leishmania) (L .tropica, L.donovani, and L.Mexicana), plasmodium (Plasmodium), babesia (Babesia), glue Rust (Gymnosporangium) and other rust-fungis, circle nuclear cavity bacteria (Pyrenophora teres), cordyceps sinensis (Cordyceps), arthropoda (Arthropoda), tick (Acari), Di This watt of mite (Varroa destructor), drop-head argulus (Cymothoa exigua), bedbug, Dulicidae (Culicidae) (mosquito Son), calyptra (Calyptra) (bloodsucker moth), hippoboscid Superfamily (Hippoboscoidea), tsetse fly, Lipoptena (Lipoptena), sheep hippoboscid (Melophagus ovinus) (sheepked) and similar, Destridae (Oestridae) (skin Fly), body fly, phlebotominae (Phlebotominae) (sand fly), Phthiraptera (Phthiraptera) (louse), body louse, hair lice, Head louse, Siphonaptera (Siphonaptera) (flea), Tabanidae (Tabanidae) (horse botfly), micro- shrimp guiding principle (Tantulocarida), cone Hunt Rhopalinae (Triatominae), pea crab, sacculus Trentepohlia, annelids (Annelids), (portion Hirudinea (Hirudinea) Point Hirudo), monogenean (Monogeneans), Calydiscoides (Calydiscoides euzeti), natural pearls algae (Lethacotyle vera), atom leaf natural pearls algae (Protocotyle euzetmaillardi), quasi- fleahopper (Pseudorhabdosynochus spp.), mollusc, copper pine crab (Cancellaria cooperii), glochidium (Glochidium), Pyramidellidae (Pyramidellidae), Chordata (Chordates), cigar Bodhidharma shark, candiru (Candiru) (Brazil suck blood fish, facultative parasitism animal), lampreys, deep-sea angler, false cleaning fish, hood robin (Hood Mockingbird), ox starling, Simenchelys parasiticus, vampire, sparrow of sucking blood (Vampire finch), mistletoe, certain orchids, jade Rice smut and certain mushrooms.

In view of CYP to the enzymatic activity of PZQ, method disclosed by the invention further includes that a effective amount of CYP suppression is applied to subject Preparation.CYP inhibitor includes but is not limited to CYP1A2 inhibitor, CYP2B6 inhibitor, CYP2C8 inhibitor, CYP2C9 inhibition Agent, CYP2C19 inhibitor, CYP2D6 inhibitor, CYP2E1 inhibitor or CYP3A4 inhibitor.

The non-limiting example of CYP1A2 inhibitor includes: amiodarone, atazanavir, Cimetidine, Ciprofloxacin, western phthalein Pulan, clarithromycin, diltiazem, Enoxacin, erythromycin, estradiol, Fluvoxamine, interferon, isoniazid ketoconazole, first Oxygen XiLin, mibefradil, tegaserod.The non-limiting example of CYP2B6 inhibitor includes tespamin and Ticlopidine (Ticlodipine).The non-limiting example of CYP2C8 inhibitor include Anastrozole, ezetimibe, gemfibrozil, Montelukast, nicardipine, Sulfinpyrazone and methoxybenzyl aminopyrimidine.

The non-limiting example of CYP2C9 inhibitor includes: amiodarone, atazanavir, Cimetidine, clopidogrel, compound Radonil, delavirdine, disulfiram, efavirenz, fenofibrate, Fluconazole, fluorouracil, Prozac, Fluvastatin, fluorine volt Sha Ming, Gemfibrozil Capsules, Imatinib, isoniazid, Itraconazole, ketoconazole, leflunomide, Lovastatin, Methoxsalen, first nitre Azoles, mexiletine, modafinil, nalidixic acid, norethindrone, Norfloxacin, Omeprazole, contraceptive, Paxil, phenylbutazone, Probenecid, Sertraline, sulfamethoxazole, sulfaphenazolum, sulfa drugs, Tacrine, Teniposide, Ticlopidine (Ticlodipine), tipranavir, troleandomycin, voriconazole, zafirlukast, Zileuton or garlic (Allium Sativum) plain (Bergamottin) extract of extract, bergamot, wire grip careless (Harpagophytum procumbens) mention Take object and fructus lycii (Lycium barbarum) extract.

The non-limiting example of CYP2C19 inhibitor includes Cimetidine, Citalopram, delavirdine, Sustiva, non- Urethane, Fluconazole, Prozac, Fluvastatin, Fluvoxamine, Indomethacin, isoniazid, ketoconazole, Lansoprazole, Mo Dafei, Omeprazole, Oxcarbazepine, probenecid, Topiramate and garlic (Allium sativum) extract and wire grip grass (Harpagophytum procumbens) extract.The non-limiting example of CYP2D6 inhibitor includes abiraterone, amine iodine Ketone, amoxapine (Asenapine), Bupropion, celecoxib, chloroquine, chlorphenamine, chlorpromazine, Cimetidine, Xi Naka Plug, Citalopram, clemastine, clomipramine, cocaine, darifenacin, desipramine, diphenhydramine, doxepin, how soft ratio Star, Duloxetine, escitalopram, Febuxostat, Prozac, fluphenazinum, halofantrine, haloperidol, hydroxychloroquine, hydroxyzine, she Imatinib, levomepromazine, methadone, metoclopramide, Mibefradil, midodrine, Moclobemide, Nefazodone, norfluoxetine, Paro Xi Ting, perphenazine, Propafenone, propoxyhene, inderal, quinacrine, quinindium, ranitidine, ranolazine, Ritonavir, Sertraline, tegaserod, Terbinafine, thioridazine, Ticlopidine (Ticlodipine), tipranavir, Tripelennamine and Galangal (Alpinia galanga) extract, common alstonia (Alstonia scholaris) extract, Herba Andrographitis (Andrographis paniculata) extract, catharanthus roseus (Catharanthus roseus) extract, rattleroot (Cimicifuga racemosa) extract, cinnamomum camphora (Cinnamomum burmannii) extract, wilsonii (Eleutherococcus senticosus) extract, Radix Glycyrrhizae (Glycyrrhiza glabra) extract, goldenseal (Hydrastis canadensis) extract, cajeputtree (Melaleuca leucadendron) extract, ginseng (Panax Ginseng) extract, American Ginseng (Panax quinquefolius) extract, pepper (Piper nigrum) extract, stone Pomegranate (Punica granatum) extract, sorrel (Rheum palmatum) extract, santal sorrel (Rheum Palmatum) extract, vomiting nut (Strychnos ligustrina) extract, cloves (Syzygium aromaticum) Extract, green packet rattan (Tinospora crispa) extract and ginger (Zingiber aromaticum) extract.

The non-limiting example of CYP2E4 inhibitor includes: that disulfiram and kawakaw (Piper methysticum) mention Take object.

The non-limiting example of CYP3A4 inhibitor includes: amiodarone, anpunave, aprepitant, atazanavir, Bo Sai Sprinkle dimension, Cimetidine, Ciprofloxacin, clarithromycin, cyclosporin, danazol, delavirdine, diltiazem, Sustiva, red Mycin, ethinylestradiol, ezetimibe, Fluconazole, Prozac, Fluvoxamine, gestodene, Imatinib, indinavir, Isoniazid, Itraconazole, ketoconazole, methylprednisolone, Mibefradil, Miconazole, mifepristone, Nefazodone, Nai Feina Wei, nicardipine, nifedipine, norethindrone, Norfloxacin, norfluoxetine, Oxiconazole, posaconazole, prednisone, quinine, Ranolazine, Ritonavir, roxithromycin, inverase, Sertraline, telavi, Ketek, troleandomycin, Wella pa Rice, voriconazole, zafirlukast, Zileuton and garlic (Allium sativum) extract, ammi visnaga (Ammi Visnaga) extract, margosa tree tree (Azadirachta indica) extract, rattleroot (Cimicifuga Racemose) extract, Harpagphytum extract, water grape (Procumbens) extract, goldenseal (Hydrastis Canadensis) extract, naringenin (Naringenin) extract, ginseng (Panax ginseng) extract, American Ginseng (Panax quinquefolius) extract, vomiting nut (Strychnos ligustrina) extract and uncaria white Mao Yang (Uncaria tomentosa) extract.

In another embodiment, method disclosed by the invention further includes other a effective amount of anti parasitics of application Medicine.Suitable anti-parasite medicine include but is not limited to fasigyne, metronidazole, melarsoprol, Eflornithine, rifampin, Amphotericin B, pentamidine, gluconic acid sodium succinate, meglumine antimonate, Fluconazole, Artesunate, quinine, quinindium, chlorine Quinoline, atovaquone-proguanil (atovaquone-proguanil), Artemether-benzoin alcohol, Mefloquine, fortimicin, crin are mould Element, paromomycin, Atovaquone, Nitazoxanide, azithromycin, fumidil, paromomycin, diloxan, secnidazole, nitre difficult to understand Azoles, moebiquin, diloxanide furoate, clindamycin, Atovaquone, azithromycin, diazonium phenalgin be phonetic, trypan blue, Ao Shani Quinoline is peaceful, niclosamidum, albendazole, mebendazole, thiabendazole, Pyrantel, diethylcarbamazine, ivermectin, selamectin, Duola Rhzomorph and avermectin.In another embodiment, other medicines for parasitic disease include wrapping for treating bilharzial drug Include but be not limited to nithiocyamine, arteether, Artemether, dichloroxylenol, hycanthone, Lucanthone, Meclonazepam, niridazole, Austria For pula and Oxamniquine.In another embodiment, the method also includes to subject apply a effective amount of antimicrobial component, Anti-fungal composition, anti parasitic ingredient or combinations thereof.

In one embodiment, PZQ and/or R-PZQ and Schisandra chinens P.E use respectively.In one embodiment, PZQ (including S-PZQ and R-PZQ) is administered simultaneously with Schisandra chinens P.E.In one embodiment, PZQ (including S-PZQ and R- PZQ it) is applied with Schisandra chinens P.E sequence.

The bioavilability of PZQ (including S-PZQ and R-PZQ) can mention in the presence of Schisandra chinens P.E after application It rises.In one embodiment, PZQ (and/or R-PZQ) is applied before applying Schisandra chinens P.E.In one embodiment, exist PZQ (and/or R-PZQ) is applied after application Schisandra chinens P.E.In one embodiment, application Schisandra chinens P.E it Before, simultaneously and/or later apply PZQ (and/or R-PZQ).

In some embodiments, between 1 minute to 24 hours before applying Schisandra chinens P.E, application PZQ and/ Or R-PZQ.In some embodiments, before Schisandra chinens P.E less than 1 minute, less than 2 minutes, less than 5 minutes, no By 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, less than 5 hours, less than 12 hours, less than 24 hours, less than 1 It, less than 2 days, less than 3 days, less than 4 days, less than 5 days, less than 6 days or less than 7 days, apply PZQ and/or R-PZQ.

In some embodiments, applying between 1 minute to 24 hours after Schisandra chinens P.E, application PZQ and/ Or R-PZQ.In some embodiments, after applying Schisandra chinens P.E less than 1 minute, less than 2 minutes, less than 5 minutes, Less than 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, less than 5 hours, less than 12 hours, less than 24 hours, no By 1 day, less than 2 days, less than 3 days, less than 4 days, less than 5 days, less than 6 days or less than 7 days, apply PZQ and/or R-PZQ.

In some embodiments, the amount of Schisandra chinens P.E application a period of time or application is enough to reduce or weaken enzyme pair The activity of the enzyme of PZQ (such as R-PZQ), to make Schisandra chinens P.E that there is antienzyme activity.With improve in subject PZQ and/or The bioavilability of R-PZQ.Schisandra chinens P.E includes wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, five Taste alcohol B or Schisantherin A.

In one embodiment, Schisandra chinens P.E or PZQ (such as R-PZQ) pass through intravenous, subcutaneous, oral or peritonaeum Interior application.In a preferred embodiment, Schisandra chinens P.E or PZQ (for example, R-PZQ) are by the organ of parasitic infection And/or nearside (such as near body cavity or in the identical body cavity) application of tissue.In one embodiment, Schisandra chinensis is mentioned Object or PZQ (for example, R-PZQ) is taken to be directly applied in the blood vessel for supporting infection organ and/or tissue.In one embodiment, Schisandra chinens P.E or PZQ (such as R-PZQ) are systemic administrations.In another embodiment, Schisandra chinens P.E or PZQ (such as R-PZQ) passes through microtubular, implanted device or implantation dosage form application.

In one embodiment, Schisandra chinens P.E or PZQ (such as R-PZQ) continuous administration whithin a period of time.Another In one embodiment, Schisandra chinens P.E or PZQ (such as R-PZQ) are applied in a pulsed fashion.For example, Schisandra chinens P.E can be with Interval is applied whithin a period of time.

The parasitic disease sensitive to compositions described herein and method include but is not limited to dysentery, diarrhea Giardiasis, Diarrhea, Cryptosporidiosis, trichomoniasis, malaria, toxoplasmosis, pneumonia, South American trypanosomiasis, difussa, kala-azar, corynebacterium diphtheriae It is disease, hydatidoma, taeniasis, cysticercosis, snail fever, clonorchiasis, paragonimiasis, hookworm disease, roundworm disease, very little white Insect infection, strongyloidosis, trichinosis, trichuriasis, drachunculiasis, loaiasis (loiasis), disk tailfiber Parasitosis, filariasis, the migration of internal organ larva, louse disease, fly-blown, scabies, tick paralysis and spider bites.In one embodiment, Parasitic disease includes echinococcosis, cysticercosis, snail fever, clonorchiasis, paragonimiasis or fasciolopsiasis.

In some embodiments, the parasitic disease include the alimentary infection as caused by tapeworm, including Taenia elliptica or Band-like cysticercus.In another embodiment, the parasitic disease includes snail fever.

The method for improving biological stability or therapeutic effect

On the other hand, the present invention relates to improve PZQ in subject's vivo biodistribution stability or the method for therapeutic effect. As described above, it improves the biological stability of PZq (or R-PZQ) or the pharmaceutical composition comprising PZQ can be enhanced in bulk concentration Therapeutic effect.In one embodiment, the bulk concentration of PZQ includes blood or tissue concentration.PZQ is improved in subject's body Biological stability or therapeutic effect method include to subject apply effective dose the combination comprising Schisandra chinens P.E Object.In one embodiment, Schisandra chinens P.E includes the compound separated from Schisandra chinensis.In another embodiment, five Taste seed extract include wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B or Schisantherin A or A combination thereof.

PZQ can be used to treat the disease as caused by helminth or infection as a kind of pest repellant.Such as snail fever, Clonorchiasis, opisthorchiasis, cestode infection, cysticercosis, echinococcosis and other fluke infections.But in the present invention In, the therapeutic effect of PZQ is not limited to treatment parasitic disease.It is surprising that Schisandra chinens P.E can improve after application The bioavilability, level, concentration or other pharmacokinetic parameters of PZQ in subject's body.Therefore the present invention provides raisings The method of the therapeutical uses or drug effect of PZQ (or R-PZQ) comprising treatment parasitic disease.

Schisandra chinens P.E is provided to the inhibiting effect of CYP enzyme, the disclosure of invention, which additionally provides, inhibits CYP enzyme Enzymatic activity improves the bioavilability of CYP zymolyte or the method or composition of therapeutic effect.Pass through the drug generation of CYP system Thank and have become the important determinant that several drugs-drug interaction occur, this cause drug toxicity, pharmacological action reduce and Adverse drug reaction.The effect of drug can be significantly affected by its metabolism in vivo.For the medicine of tachymetabolism Object, it may be difficult to maintain its dose therapeutically effective in vivo, drug is made to generally have to more frequently, higher doses apply And/or it is applied with extended release preparation.

In various types of CYP enzymes, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are in drug There is especially significant effect in metabolism.The inactivation of a large amount of application drugs is the extensive generation due to CYP3A4 isodynamic enzyme in the gastrointestinal tract It thanks.Therefore, by inhibiting the bioavilability or enzymatic activity of CYP, the present invention also provides the medicines improved as CYP enzyme object The therapeutic effect or method horizontal in vivo of object, protein or any bioactivator.This method includes having to subject's application The composition comprising Schisandra chinens P.E of effect amount.Application can prevent the drop of CYP substrate comprising the composition of Schisandra chinens P.E It solves, and promotes the pharmacokinetic property of substrate when it serves as therapeutic agent.

The non-limiting example of CYP3A4 substrate includes but is not limited to: cyclosporin, tacrolimus, sirolimus, mostly west His match, tamoxifen, taxol, cyclophosphamide, adriamycin, Tarceva, Etoposide, ifosfamide, Teniposide, length Spring alkali, eldisine, Imatinib, Irinotecan, Sorafenib, Sutent, Wei Mofeini, replaces Xi Luomo at vincristine Department, Anastrozole, Gefitinib, ketoconazole, Itraconazole, macrolides, clarithromycin, erythromycin, Ketek, phenalgin Sulfone, tricyclic antidepressant, amitriptyline, clomipramine, imipramine, cyclobenzaprine, Citalopram, norfluoxetine, Sertraline Group, Mirtazapine, Nefazodone, Reboxetine, Venlafaxine, Trazodone, buspirone, haloperidol, Aripiprazole, Li Pei Ketone, Ziprasidone, Pimozide, Quetiapine, alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, methadone, Ah Method dimepheptanol, C16H25NO2, Benzodiazepines, alprazolam, midazolam, triazolam, diazepam, zopiclone, Zaleplon, Zolpidem, donepezil, Atorvastatin, Lovastatin, Simvastatin, cerivastatin, diltiazem, felodipine, nitre Benzene Horizon, Verapamil, Amlodipine, Lercanidipine, nitrendipine, Nisoldipine, amiodarone, dronedarone, quinindium, west Ground that non-, Tadalafei, kassinin kinin, Finasteride, estradiol, progesterone, ethinyloestradiol, testosterone, Toremifene, Bicalutamide, spy Fei Nading, astemizole, chlorphenamine, indinavir, Ritonavir, inverase, Nai Feinawei, nevirapine, cloth how Moral, hydrocortisone, dexamethasone, Cisapride, aprepitant, caffeine, cocaine, Cilostazol, dextromethorphan, dopan Vertical ketone, eplerenone, lidocaine, Ondansetron, Propranolol, salmeterol, warfarin, clopidogrel, Omeprazole, that Ge Lienai, methoxy Xi Ting and montelukast.

The non-limiting example of CYP2D6 substrate includes: atomoxetine, desipramine, dextromethorphan, Yi Ligelusita (Eliglustat), nebivolol, nortriptyline, perphenazine, Tolterodine, Venlafaxine, amitriptyline, encainide, the third miaow Piperazine, metoprolol, Propafenone, Propranolol, C16H25NO2 and trimipramine.

The non-limiting example of CYP2C19 substrate includes S- mephenytoin, Omeprazole, stable, Lansoprazole, Lei Beila Azoles and voriconazole.

The non-limiting example of CYP2C9 substrate includes celecoxib, Glimepiride, phenytoinum naticum, orinase and Hua Fa Woods.

The non-limiting example of CYP2C8 substrate includes Repaglinide, montelukast, Pioglitazone and Rosiglitazone.

The non-limiting example of CYP2B6 substrate includes Bupropion and Sustiva.

Non-limiting example Alosetron, caffeine, Duloxetine, epiphysin, the Rameau ketone, Ta Ximo of CYP1A2 substrate Ketone, theophylline, Tizanidine, Clozapine, pirfenidone and ramosetron.

In one embodiment, the PZQ and the Schisandra chinens P.E are distinguished, are simultaneously and/or sequentially applied.Another In embodiment, the Schisandra chinens P.E is applied prior to, concurrently with, or after applying PZQ.In another embodiment, described Schisandra chinens P.E after applying PZQ less than 1 minute, less than 2 minutes, less than 5 minutes, less than 10 minutes, less than 30 minutes, no To 1 hour, less than 2 hours, less than 5 hours, less than 12 hours, less than 24 hours, less than 1 day, less than 2 days, less than 3 days, no It is applied by 4 days, less than 5 days, less than 6 days or less than 7 days.In another embodiment, the Schisandra chinens P.E is in application PZQ Before less than 1 minute, less than 2 minutes, less than 5 minutes, less than 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, Less than 5 hours, less than 12 hours, less than 24 hours, less than 1 day, less than 2 days, less than 3 days, less than 4 days, less than 5 days, less than 6 It was applied less than 7 days.

In one embodiment, the substrate of the CYP enzyme and the Schisandra chinens P.E are respectively, simultaneously and/or sequentially Application.In another embodiment, the Schisandra chinens P.E is applied prior to, concurrently with, or after applying substrate.At another In embodiment, the Schisandra chinens P.E is after applying substrate less than 1 minute, less than 2 minutes, less than 5 minutes, less than 10 points Clock, less than 30 minutes, less than 1 hour, less than 2 hours, less than 5 hours, less than 12 hours, less than 24 hours, less than 1 day, no It is applied by 2 days, less than 3 days, less than 4 days, less than 5 days, less than 6 days or less than 7 days.In another embodiment, the five tastes Seed extract after applying substrate less than 1 minute, less than 2 minutes, less than 5 minutes, less than 10 minutes, less than 30 minutes, no To 1 hour, less than 2 hours, less than 5 hours, less than 12 hours, less than 24 hours, less than 1 day, less than 2 days, less than 3 days, no It is applied by 4 days, less than 5 days, less than 6 days or less than 7 days.

The extract of the Schisandra chinensis can be applied in various ways.In one embodiment, the Schisandra chinens P.E By intravenous, subcutaneously, oral or intraperitoneal application.In one embodiment, the Schisandra chinens P.E includes schizandrin A, wuweizisu B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B or Schisantherin A or combinations thereof.In another embodiment In, the Schisandra chinens P.E dosage be subject's mass 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg, 10mg/kg, 20mg/kg、30mg/kg、50mg/kg、70mg/kg、100mg/kg、150mg/kg、200mg/kg、250mg/kg、500mg/kg、 1000mg/kg, 2000mg/kg or 5000mg/kg.

Kit of parts

On the one hand, the present invention relates to the kits for treating parasitic disease, and it includes PZQ (such as R-PZQ) and the five tastes Seed extract.

The kit for treating patient's parasitic disease is provided in one embodiment, and it includes therapeutically effective amounts The Schisandra chinens P.E of PZQ (such as R-PZQ) and therapeutically effective amount.

In one embodiment, the Schisandra chinens P.E includes the compound separated from Schisandra chinensis.In another implementation In scheme, it is described isolated from Schisandra chinensis compound include wuweizisu A, wuweizisu B, schisandrin C, wuweizi alcohol A, Wuweizi alcohol B and Schisantherin A.

In one embodiment, the parasitic disease is to PZQ (such as R-PZQ) sensitivity.In another embodiment, described to post Infested disease includes echinococcosis, cysticercosis, snail fever, clonorchiasis, paragonimiasis and fasciolopsiasis.Further real It applies in scheme, the parasitic disease includes the infection of the intestines and stomach as caused by tapeworm.In one embodiment, the tapeworm includes pig Tapeworm, teniarhynchosis, Diplacanthus nanus, Taenia elliptica and band-like cysticercus.

In one embodiment, the kit further comprises the directions for use for treating parasitic disease.Another In one embodiment, the kit contains the explanation for illustrating and/or applying pharmaceutical composition of the invention for dosage.

Working example

The following example purpose for illustrative purposes only, should not be construed as the limitation of claimed invention.Those skilled in the art Various substitute technologies and method can be used in member, also allows for being successfully executed expected invention.

Embodiment

Animal:

Male Sprague-Dawley rat (200-250g) is placed in 22-24 DEG C of interior, Dark-light cycle is that 12-12 is small When (the subsequent 12 hours dark of illumination in 12 hours) and 55%-60% relative humidity.Rat can be arbitrarily dynamic using standard sawtooth Object food and clean tap water.Before experiment, by animal fasting 10-14 hours.Animal Procedures are according to the People's Republic of China (PRC) " the management of laboratory animal regulations " of Ministry of Science and Technology's publication carry out (http://www.most.gov.cn).

Drug

Freshly prepd R-PZQ (99.6%) and wuweizisu A (95%) 3% sodium cellulose glycolate (CMC-Na, In 300-800), it to be used in vivo studies.

In order to study internal effect of the wuweizisu A to R-PZQ pharmacokinetics, by rat fasting 10- first before experiment 14 hours, 8 groups (the 1st groups, the 2nd group, the 3rd group, the 4th group, the 5th group, the 6th group, the 7th group and the 8th group) are then randomly divided into, Every group of 6 rats.Wuweizisu A is applied to Oral Administration in Rats, dosage is respectively 0,10,20,40,80,100,160 and 200mg/ kg.It applies wuweizisu A after five minutes, gives all Oral Administration in Rats R-PZQ with the dosage of 31mg/kg.Pass through neck using test tube of hepari pipe Vein was received at 5 minutes, 15 minutes, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours respectively Collect blood sample, and be centrifuged 6 minutes under 4 DEG C and 8,000g, is then stored at -80 DEG C for subsequent analysis.

R-PZQ is quantified using LC-MS/MS

By the blood plasma homogenate from rat with the methanol pretreatment containing 200ng/mL orinase of 5 times of volumes with heavy Shallow lake protein is centrifuged 5 minutes under 14000g then at 4 DEG C.The supernatant for being centrifuged blood plasma injection LC-MS/MS is analyzed. Use TQ5500 mass spectrograph (Applied Biosystems) and ACQUITY UPLC system (Waters).It is modified using mobile phase Agent (mobile phase A: 99.9% water and 0.1% formic acid, Mobile phase B: 99.9% acetonitrile and 0.1% formic acid) is from ACQUITY UPLC R-PZQ and orinase (internal standard, IS) are eluted on 1.7 μm of BEH C18 (50mm × 2.10mm) columns.Flow velocity is 0.5mL/ min.Pharmacokinetic parameter passes through1.6.2 software (AppliedBiosystems) calculates.All results all tables It is shown as average ± S.D.

After Fig. 3 shows the R-PZQ that oral administration contains or not contain wuweizisu A (schisandrin A), average R- The curve of PZQ haemoconcentration and time.The main pharmacokinetic parameter of R-PZQ is listed in table 1, display, with no Schisandra chinensis The group of plain A is compared, and after the oral co-administration rat of the wuweizisu A of various dose, the full blood concentration (AUC) of R-PZQ is increased 160%, and the maximal plasma concentration (C of R-PZQ_max) increase 68%.Meanwhile wuweizisu A is co-administered by oral The clearance rate for reducing R-PZQ improves 43% proof by mean residence time (MRT).

Table 1: after single oral dose R-PZQ (31mg/kg), application and the wuweizisu A rat for not applying various dose The medicine kinetic parameter of R-PZQ

Abbreviation: T_maxIt is the time for reaching maximum concentration, C_maxIt is maximal plasma concentration, T_1/2It is half-life period；AUC_0→tBe from The plasma concentration v. time area under a curve in sampling time to the end zero-time, MRT_0→∞It is from zero-time to infinity Plasma concentration v. time area under a curve；MRT_0→tBe from the mean residence time in sampling time to the end zero-time, MRT_0→∞It is from the zero-time to infinitely great mean residence time.

The content of present invention of illustratively described herein can lack any element or limitation not specifically disclosed herein In the case where be appropriately carried out.Thus, for example, term " includes ", "comprising" and " containing " should be understood broadly without by Limitation.In addition, the term that terms and expressions used herein are only described rather than limit, and be not intended to use these terms and table It reaches to exclude any equivalent or part thereof of shown and described feature, and will be appreciated that at it in model claimed Various modifications can be carried out in enclosing.

It will thus be appreciated that although disclosing the present invention, this field by preferred embodiment and optional feature Technical staff can use modification, the improvements and changes of disclosure herein, and these modifications, improvements and changes are considered It is in range disclosed by the invention.Material, method and embodiment provided herein are the representatives of preferred embodiment, are only shown Example property, and be not intended to limit the scope of the present disclosure.

The present invention herein by extensively and generally describe.Fall into each of scope of the invention relatively narrow aspect and subgenus It is also a part of the invention.This includes times that general description of the invention, collateral condition or negative limitation are excluded from the category What theme, regardless of whether the material of removal has been described in detail herein.

In addition, ability is according to ground technical staff in the case where describing features or aspect of the invention according to Ma Kushi group It will be recognized that therefore the present invention is also described in the form of any single member of marlcush group or member's subgroup.

Publication mentioned by this paper, patent application, patent and other bibliography all pass through reference entirety clearly simultaneously Enter herein, range is individually recited identical with it.As with clash herein if with this specification, including subject to definition.

Claims (62)

1. a kind of for treating the pharmaceutical composition of parasitic disease, it includes pyridone (" PZQ ") and Schisandra chinensis (Schisandra Chinensis) extract.

2. pharmaceutical composition as described in claim 1, the Schisandra chinens P.E includes wuweizisu A, wuweizisu B, five Taste element C, wuweizi alcohol A, wuweizi alcohol B, Schisantherin A, or combinations thereof.

3. pharmaceutical composition as claimed in claim 1 or 2, wherein the PZQ includes R-PZQ or S-PZQ.

4. pharmaceutical composition as claimed in claim 3, wherein R-PZQ includes R-PZQ compound or derivatives thereof or the like.

5. pharmaceutical composition according to any one of claims 1-4, wherein described pharmaceutical composition is to be administered according to every kilogram Subject's mass of pharmaceutical composition include 1mg to about 1000mg, about 10mg to about 500mg, about 20mg to about 250mg, about The PZQ of 30mg to about 200mg and about 40mg to about 100mg.

6. pharmaceutical composition as claimed in claim 3, wherein described pharmaceutical composition is according to every kilogram of pharmaceutical composition to be administered Subject's mass of object includes 1mg to about 1000mg, about 10mg to about 500mg, about 20mg to about 250mg, about 30mg to about The R-PZQ of 200mg and about 40mg to about 100mg.

7. pharmaceutical composition as claimed in claim 6, wherein described pharmaceutical composition includes according to every kg of body's mass About 40 to 100mg R-PZQ.

8. such as the described in any item pharmaceutical compositions of claim 1-7, wherein the Schisandra chinens P.E is every kg of body Quality at least 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, 50mg/kg, 70mg/ Kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or 5000mg/ kg。

9. such as the described in any item pharmaceutical compositions of claim 1-8, wherein described pharmaceutical composition includes wuweizisu A, It is at least 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/ according to every kg of body's mass kg、50mg/kg、70mg/kg、100mg/kg、150mg/kg、200mg/kg、250mg/kg、500mg/kg、1000mg/kg、 2000mg/kg or 5000mg/kg.

10. such as the described in any item pharmaceutical compositions of claim 1-9, the wuweizisu A that wherein described pharmaceutical composition includes, It is at least 200mg/kg according to every kg of body's mass.

11. such as the described in any item pharmaceutical compositions of claim 1-10, wherein the matter of the PZQ and the Schisandra chinens P.E Amount than is at least 1:10000,1:1000,1:100,1:10,1:5,1:3,1:2,1:1,2:1,3:1,5:1,10:1,100:1, 1000:1 or 10000:1.

12. such as the described in any item pharmaceutical compositions of claim 1-11, wherein the mass ratio is at least 1:3,1:5,1:10 Or 1:100.

13. such as the described in any item pharmaceutical compositions of claim 1-12, wherein the parasitic disease includes echinococcosis, cysticercus Disease, snail fever, clonorchiasis, paragonimiasis, fasciolopsiasis or combinations thereof.

14. such as the described in any item pharmaceutical compositions of claim 1-13, wherein the parasitic disease is snail fever.

15. such as the described in any item pharmaceutical compositions of claim 1-14, further include an antimicrobial component, one it is antimycotic at Point, an anti parasitic ingredient or combinations thereof.

16. further including a Cytochrome P450 (CYP) enzyme such as the described in any item pharmaceutical compositions of claim 1-15 Inhibitor.

17. further including the carrier pharmaceutically received such as such as described in any item pharmaceutical compositions of claim 1-16.

18. -17 described in any item pharmaceutical compositions according to claim 1, described pharmaceutical composition is oral outstanding suspension, piece Agent, spray, the form of capsule, lotion, gel or foam.

19. further including an adhesive, a flavoring agent, one such as the described in any item pharmaceutical compositions of claim 1-18 Lubricant, a flowable, a disintegrating agent, a delayed-action activator or combinations thereof.

20. a kind of method for treating subject's parasitic disease, it includes apply a effective amount of PZQ and a effective amount of five to subject Taste seed extract.

21. method as claimed in claim 20, wherein the PZQ includes R-PZQ or S-PZQ.

22. method as claimed in claim 21, wherein the R-PZQ includes R-PZQ compound or derivatives thereof or its is similar Object.

23. such as the described in any item methods of claim 20-22, wherein the Schisandra chinens P.E includes wuweizisu A, the five tastes Sub- element B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B, Schisantherin A, or combinations thereof.

24. such as the described in any item methods of claim 20-23, wherein the parasitic disease is easy to be treated by PZQ.

25. such as the described in any item methods of claim 20-24, wherein the parasitic disease is easy to be treated by R-PZQ.

26. such as the described in any item methods of claim 20-25, wherein the parasitic disease includes echinococcosis, cysticercosis, blood Fluke disease, clonorchiasis, paragonimiasis, fasciolopsiasis, or combinations thereof.

27. such as the described in any item methods of claim 20-26, wherein the parasitic disease is the intestines and stomach sense as caused by tapeworm Dye, the tapeworm includes Taenia elliptica (Dipylidium caninum) or band-like cysticercus (Taenia taeniaeformis).

28. such as the described in any item methods of claim 20-27, wherein the parasitic disease is snail fever.

29. such as the described in any item methods of claim 20-28, wherein the PZQ with about 1mg to about 1000mg, about 10mg extremely About 500mg, about 20mg to about 250mg, about 30mg every kg of body's mass to about 200mg and about 40mg to about 100mg agent Amount application.

30. such as the described in any item methods of claim 21-29, wherein the R-PZQ is with about 1mg to about 1000mg, about 10mg Every kg of body's mass to about 500mg, about 20mg to about 250mg, about 30mg to about 200mg and about 40mg to about 100mg Dosage application.

31. method as claimed in claim 30, wherein the R-PZQ is with about 40 to about 100mg every kg of body's mass Dosage application.

32. such as the described in any item methods of claim 20-31, wherein the Schisandra chinens P.E at least 0.1mg/kg, 1mg/kg、2mg/kg、5mg/kg、10mg/kg、20mg/kg、30mg/kg、50mg/kg、70mg/kg、100mg/kg、150mg/ The every kg of body's mass of kg, 200mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or 5000mg/kg Dosage application.

33. method as claimed in claim 23, wherein the wuweizisu A at least 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg、10mg/kg、20mg/kg、30mg/kg、50mg/kg、70mg/kg、100mg/kg、150mg/kg、200mg/kg、 The dosage of the every kg of body's mass of 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or 5000mg/kg is applied.

34. method as claimed in claim 33, wherein the wuweizisu A is with the every kg of body's mass of at least 200mg/kg Dosage application.

35. such as the described in any item methods of claim 20-34, wherein the PZQ and the Schisandra chinens P.E are applied respectively.

36. such as the described in any item methods of claim 20-34, wherein the PZQ and the Schisandra chinens P.E are administered simultaneously.

37. such as the described in any item methods of claim 20-34, wherein the PZQ and Schisandra chinens P.E sequence are applied.

38. such as the described in any item methods of claim 20-34, wherein before applying the Schisandra chinens P.E, simultaneously or Later, the PZQ is applied.

39. such as the described in any item methods of claim 20-34, wherein 1 minute, 2 after applying the Schisandra chinens P.E Minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, apply the PZQ.

40. such as the described in any item methods of claim 20-34, wherein 1 point before applying the Schisandra chinens P.E application Clock, 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, apply the PZQ.

41. such as the described in any item methods of claim 20-40, wherein the Schisandra chinens P.E and/or the PZQ pass through it is quiet Arteries and veins application.

42. such as the described in any item methods of claim 20-40, wherein the Schisandra chinens P.E and/or the PZQ pass through skin Lower application.

43. such as the described in any item methods of claim 20-40, wherein the Schisandra chinens P.E and/or the PZQ pass through mouth Clothes application.

44. such as the described in any item methods of claim 20-40, wherein the Schisandra chinens P.E and/or the PZQ pass through abdomen Intracavitary application.

45. such as the described in any item methods of claim 20-44, further include to the subject apply an antibacterial at Point, an anti-fungal composition, an anti parasitic ingredient or drug, or combinations thereof.

46. further including to subject such as the described in any item methods of claim 20-45 and applying a CYP enzyme inhibitor.

47. such as the described in any item methods of claim 20-46, wherein the subject is mammal.

48. wherein described, subject is a human such as the described in any item methods of claim 20-47.

49. a kind of method for improving the biological stability or therapeutic effect of PZQ in subject's body comprising have to subject's application The composition comprising Schisandra chinens P.E of effect amount.

50. method as claimed in claim 49, wherein the PZQ and the Schisandra chinens P.E are distinguished, simultaneously and/or sequentially Application.

51. the method as described in claim 49 or 50, wherein the Schisandra chinens P.E before applying PZQ, simultaneously or it After apply.

52. such as the described in any item methods of claim 49-51, wherein 1 minute after the application of PZQ, 2 minutes, 5 minutes, It 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, applies With the Schisandra chinens P.E.

53. such as the described in any item methods of claim 49-52, wherein 1 minute before the application of PZQ, 2 minutes, 5 minutes, It 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, applies With the application of the Schisandra chinens P.E.

54. a kind of method for improving the biological stability or therapeutic effect of CYP zymolyte in subject's body comprising to subject Apply a effective amount of one composition containing Schisandra chinens P.E.

55. method as claimed in claim 54, wherein the substrate and the Schisandra chinens P.E are distinguished, are simultaneously and/or suitable Sequence application.

56. the method as described in claim 54 or 55, wherein the Schisandra chinens P.E before applying the substrate, simultaneously Or it applies later.

57. such as the described in any item methods of claim 54-56, wherein 1 minute, 2 minutes, 5 points after substrate application Clock, 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 It, applies the Schisandra chinens P.E.

58. such as the described in any item methods of claim 54-57, wherein 1 minute, 2 minutes, 5 before the application of the substrate Minute, 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 It, applies the Schisandra chinens P.E.

59. such as the described in any item methods of claim 49-58, wherein the Schisandra chinens P.E passes through intravenous, subcutaneous, mouth Clothes or intraperitoneal application.

60. such as the described in any item methods of claim 49-59, wherein the Schisandra chinens P.E includes wuweizisu A, the five tastes Sub- element B, schisandrin C, wuweizi alcohol A, wuweizi alcohol B, Schisantherin A, or combinations thereof.

61. such as the described in any item methods of claim 49-60, wherein the Schisandra chinens P.E includes wuweizisu A.

62. such as the described in any item methods of claim 49-61, wherein the extract of the Schisandra chinensis is every kg of body's matter Measure at least 0.1mg/kg, 1mg/kg, 2mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, 50mg/kg, 70mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg, 2000mg/kg or 5000mg/kg.