WO2018063472A1

WO2018063472A1 - Compositions for treating parasitic diseases and methods thereof

Info

Publication number: WO2018063472A1
Application number: PCT/US2017/041560
Authority: WO
Inventors: Yushan ZHAO; Dezu MIAO; Shujie HOU; Jingshan HUANG; Kai Liu
Original assignee: Reyoung Corporation
Priority date: 2016-09-27
Filing date: 2017-07-11
Publication date: 2018-04-05
Also published as: CN110035763A; CN110035763B

Abstract

This disclosure is directed to pharmaceutical, compositions for treating a parasitic disease, comprising Praziquantel or its analogues aid an extract isolated from Schisandra chinensis. The parasitic disease is susceptible to treatment with Praziquantel. Also provided in the disclosure are methods for treating a parasitic disease In a subject by administering to the subject an effective amount of Praziquantel and an effective amount of extracts from Schisandra chinensis. Farther provided in the disclosure are methods of increasing biostability of Praziquantel or other CYP enzyme substrates.

Description

COMPOSITIONS FOR TREATING PARASITIC DISEASES AND

METHODS THEREOF

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 1 19(e) to U.S. Provisional Application No. 62/400,304, filed September 27, 2016, the content of which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] This disclosure relates to compositions which comprise Praziquantel (e.g., S- Praziquantel or R-Praziquantel) or its analogues in combination with extracts or compounds originally isolated from Schisandra chinensis. Also disclosed herein are methods of preventing and treating parasitic diseases. Further disclosed herein are methods of increasing the biostability of Praziquantel or other substrates of cytochromes P450 enzymes.

BACKGROUND

[0003] Schistosomiasis is one of the most prevalent parasite diseases in the tropical regions and found predominately in developing countries, e.g., some nations in Africa, Asia, the Caribbean, and South America. Currently, schistosomiasis affects approximately 200 million people worldwide with most of the affected population living in countries that lack the necessary healthcare infrastructures to combat this endemic disease. Those countries, for lack of financial resources, are facing additional challenges in implementing the large-scale preventive measures to reduce the transmission of schistosomiasis.

[0004] The blood flukes of the genus Schistosoma are the main cause of schistosomiasis. Once transmitted to a host, the parasites may lay and deposit numerous eggs in the blood vessel, intestines, and livers. The deposition of the eggs in the host can lead to serious health concerns such as lesions, fibrosis, portal hypertension, and bloody urine. Moreover, schistosomiasis may cause immunological disorders. [0005] Over the past decades, several compounds have been used for treating schistosomiasis. Among them, Praziquantel ("PZQ"), as a racemic mixture of R and S enantiomers, is the popular, almost exclusive treatment for this disease.

[0006] Despite the undeniable safety and efficacy, treatment with PZQ, due to its poor solubility, requires an extremely high dose to achieve the necessary concentrations at the target organs. Moreover, the bitter taste of PZQ often causes gagging and vomiting during administration.

[0007] Therefore, there is a need for a more effective medication or pharmaceutical composition for treating schistosomiasis or other parasitic diseases.

SUMMARY OF THE INVENTION

[0008] R-PZQ, one of the enantiomers of PZQ with R configuration, has a higher treatment efficacy against Schistosoma with a less bitter taste than S-PZQ. Meister et al.,

Antimicrobial Agents and Chemotherapy, 58(9), 5466-72 (2014); Meyer et al., PLoS. Negl. Trop. Dis., 3(1): e357 (2009). Despite its higher treatment efficacy and lower toxicity, the R- PZQ treatment is still limited by the compound's lower bioavailability or biostability due to degradations or metabolism by the enzymes in the administered subject, e.g., CYP3A4.

[0009] The extracts from Schisandra chinensis are potent substrates for CYP3A4 or other enzymes that target R-PZQ, and may act as potential competitive inhibitors of CYP3A4 or other enzymes.

[0010] With a goal to improve the bioavailability, solubility, and toxicity profiles of PZQ and/or R-PZQ, applicants demonstrated that the extracts from Schisandra chinensis can unexpectedly increase the bioavailability, biostability, and therapeutic efficacy of PZQ and/or R-PZQ in a subject. Therefore, the disclosure provides a pharmaceutical composition for treating and/or preventing a parasitic disease in a subject, which comprises PZQ and/or R- PZQ, and extracts or compounds originally isolated from Schisandra chinensis. In one embodiment, the extracts from Schisandra chinensis comprise a compound originally isolated from Schisandra chinensis. In another embodiment, the compound isolated from Schisandra chinensis includes Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or the combination thereof.

[0011] In one aspect, the parasitic disease is susceptible to being treated with PZQ and/or R-PZQ. In another embodiment, the parasitic disease is schistosomiasis. In one

embodiment, the PZQ comprises an R-PZQ and an S-PZQ. In one embodiment, the R-PZQ comprises an R-PZQ compound or its derivatives or analogues. In another embodiment, the PZQ and/or R-PZQ is between 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 1,000 mg of PZQ and/or R-PZQ per kg of a mass of the subject. In yet another embodiment, the PZQ and/or R-PZQ is at least about SO mg per kg of a mass of the subject. In one aspect, in the pharmaceutical

composition, the extracts from Schisandra chinensis is between 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 1 ,000 mg of extracts from Schisandra chinensis per kg of a mass of the subject.

[0012] In another aspect, the pharmaceutical composition is in the form of an oral suspension, a tablet, a spray, a capsule, a lotion, a gel, or a foam. In another embodiment, in the pharmaceutical composition, the mass ratio between the PZQ (or R-PZQ) and the extracts from Schisandra chinensis is 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 yet another embodiment, the mass ratio between the PZQ (or R-PZQ) and the extracts from Schisandra chinensis is 1 : 1 or 2: 1.

[0013] In one aspect, the pharmaceutical composition further comprises binding agents, flavor agents, lubricating agents, flow agents, disintegration agents, delay agents, and the combination thereof.

[0014] In another aspect, the pharmaceutical composition further comprises an antibacterial composition, an antifungal composition, an antiparasitic composition, or a combination thereof. In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In one aspect, the subject to be treated with the pharmaceutical composition is a mammal. In one embodiment, the subject is human.

[0015] The disclosure also provides methods of treating and/or preventing a parasitic disease in a subject, which comprises administering to the subject an effective amount of PZQ (or R-PZQ) and an effective amount of an extract from Schisandra chinensis. In one embodiment, the extract from Schisandra chinensis comprises a compound isolated from Schisandra chinensis. In another embodiment, the compound isolated from Schisandra chinensis includes Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol

B, and/or Schisantherin A.

[0016] In one aspect, the parasitic disease treated by the methods is susceptible to being treated with PZQ (or R-PZQ). In one embodiment, the parasitic disease is schistosomiasis. In one embodiment, the R-PZQ used in the method comprises an R-PZQ compound or its derivatives or analogues. In another embodiment, the PZQ (or R-PZQ) is between 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 1 ,000 mg per kg of a mass of the subject. In yet another embodiment, the PZQ (or R-PZQ) is at least about SO mg per kg of a mass of the subject. In one aspect, in the pharmaceutical composition, the extracts from Schisandra chinensis is between 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 1,000 mg of extracts from Schisandra chinensis per kg of a mass of the subject.

[0017] In another aspect, the method further comprises administering a composition including an antibacterial composition, an antifungal composition, an anti-parasite composition or medication, or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 shows the chemical structures of Rac-PZQ and R-PZQ.

[0019] FIG. 2 shows the chemical structures of Schisandrin A, Schisandrin B, Schisandrin

C, Schizandrol A, Schizandrol B, and Schisantherin A.

[0020] FIG. 3 shows the whole blood concentration of R-PZQ after administration of R- PZQ to rats with and without Schisandrin A, respectively.

DETAILED DESCRIPTION

[0021] After reading this description, it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, not all embodiments of the present invention are described herein. It will be understood that the embodiments presented here are presented by way of an example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth below.

[0022] Before the present invention is disclosed and described, it is to be understood that the aspects described below are not limited to specific compositions, methods of preparing such compositions, or uses thereof as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

Definitions

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0024] In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0025] The terminology used herein is for the purpose of describing particular

embodiments only and is not intended to be limiting the invention. As used herein, the singular forms "a," "an," and '"the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0026] All numerical designations, e.g., pH, temperature, time, concentration, amounts, and molecular weight, including ranges, are approximations which are varied (+) or (-) by 10%, 1%. or 0.1 %, as appropriate. It is to be understood, although not always explicitly stated, that all numerical designations may be preceded by die term "about." It is also to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0027] The term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of." when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. In one embodiment, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants or inert carriers. "Consisting of shall mean excluding more than trace amount of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.

[0028] A "composition" is also intended to encompass a combination of active agent and another carrier, e.g., compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like. In the context of this application, the active agent is the PZQ or R-PZQ, and its derivative or analog, a suitable homolog. Carriers also include pharmaceutical excipients and additive proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tctra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, es ten fled sugars, and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination l%-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative ammo acid/antibody

components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this disclosure, examples of which include, but are not limited to, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like;

polysaccharides, such as rafiinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myoinositol. [0029] A "pharmaceutical composition" is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0030] The term "pharmaceutically acceptable carrier" (or medium), which may be used interchangeably with the term biologically compatible carrier or medium, refers to reagents, cells, compounds, materials, compositions, and/or dosage forms that are not only compatible with the cells and other agents to be administered therapeutically, but also are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers suitable for use in the present disclosure include liquids, semi-solid {e.g., gels) and solid materials (e.g., cell scaffolds and matrices, tubes sheets, and other such materials as known in the art and described in greater detail herein). These semi-solid and solid materials may be designed to resist degradation within the body (non-biodegradable) or they may be designed to degrade within the body (biodegradable, bioerodible). A biodegradable material may further be bioresorbable or bioabsorbable, i.e., it may be dissolved and absorbed into bodily fluids (water-soluble implants are one example), or degraded and ultimately eliminated from the body, either by conversion into other materials or breakdown and elimination through natural pathways.

[003] J The terms "patient," "subject," "individual," and the like are used interchangeably herein, and refer to any animal, or cells thereof whether /;/ vitro or in sim, amenable to the methods described herein. In a preferred embodiment, the patient, subject, or individual is a mammal. In some embodiments, the mammal is a mouse, a rat, a guinea pig, a non-human primate, a dog, a cat, or a domesticated animal (e.g., horse, cow, pig, goat, sheep). In especially preferred embodiments, the patient, subject, or individual is a human.

[0032] The term "treating" or "treatment" refers to the treatment of a disease or disorder described herein, in a subject, such as a human. The treatment of this disclosure includes but is not limited to: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder, (iii) slowing progression of the disorder; and/Or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. For example, treatment of a parasitic disease includes, but is not limited to, elimination of a pathogen and/or the infection caused by the pathogen, remission of the infection, inhibition of the infection, reduction or elimination of at least one symptom of the infection or the parasitic disease, and the like.

[0033] The phrase "concurrently administering" refers to administration of at least two agents to a subject over a period of time. Concurrent administration includes, without limitation, separate, sequential, and simultaneous administration.

[0034] The term "separate" administration refers to an administration of at least two active ingredients at the same time or substantially the same time by different routes.

[0035] The term "sequential" administration refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients.

[0036] The term "simultaneous" administration refers to the administration of at least two ingredients by the same route and at the same time or at substantially the same time.

[0037] The term "therapeutic" as used herein means a treatment and/or prophylaxis. A therapeutic effect is obtained by suppression, remission, or eradication of a disease state.

[0038] The term "therapeutically effective amount" or "effective amount" refers to an amount of the agent that, when administered, is sufficient to cause the desired effect. For example, an effective amount of a composition may be an amount sufficient to treat, control, alleviate, or improve the conditions related to parasitic diseases. The therapeutically effective amount of the agent may vary depending on the pathogen being treated and its severity as well as the age, weight, etc., of the patient to be treated. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.

[0039] As used herein, the term "enzyme" refers to any protein that catalyzes a chemical reaction. The catalytic function of an enzyme constitutes its "activity" or "enzymatic activity." An enzyme typically is classified according to the type of catalytic function it carries out, hydrolysis of peptide bonds. For example, Cytochrome P450 is one of the enzymes that can metabolize targeted compounds in a subject.

[0040] The term "Cytochrome P450" or "CYP" refers to a family of hemoprotein enzymes capable of metabolizing xenobiotics such as drugs, carcinogens, and environmental pollutants, steroids, fatty acids, and prostaglandins. As used herein, the term "CYP" is meant to refer to CYP superfamily members of microbial, invertebrate, and vertebrate origin. Non- limiting examples of CYP enzymes include, but are not limited to, enzymes from CYP1A, CYP2B, CYP2C, CYP2D, CYP2E, CYP3A families, and additional CYP enzymes as described in U.S. Patent Nos. 5,786, 191 and 5,478,723, each of which is incorporated by reference in its entirety. In some embodiments, the CYP enzyme comprise CYP enzymes in a mammal, which include, but are 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, the mammalian CYP enzymes include, but are 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.

[0041] As used herein, the term "substrate" refers to a substance (e.g., a chemical compound) on which an enzyme performs its catalytic activity to generate a product. For example, there are a number of substrates for the CYP enzymes, e.g., CYP1 A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. [0042] Non-limiting examples of C YP3 A4 substrates include but are not limited to ciclosporin, tacrolimus, sirolimus, docetaxel, tamoxifen, Paclitaxel, cyclophosphamide, doxorubicin, Erlotinib, etoposide, ifosfamide, teniposide, vinblastine, vincristine, vindesine, imatinib, irinotecan, sorafenib, sunitinib, vemurafenib, temsirolimus, anastrozole, gefitinib, Ketoconazole, itraconazole, macrolides, clarithromycin, erythromycin, telithromycin, dapsone, tricyclic antidepressants, amitriptyline, clomipramine, imipramine, cyclobenzaprine, citalopram, norfluoxetine, sertralinesome, mirtazapine, nefazodone, reboxetine, venlafaxine, trazodone, buspirone, haloperidol, aripiprazole, risperidone, ziprasidone, pimozide, quetiapine, alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, methadone, levacety lmethadol , tramadol, benzodiazepines, alprazolam, midazolam, triazolam, diazepam, zopiclone, zaleplon, Zolpidem, donepezil, atorvastatin, lovastatin, simvastatin, cerivastatin, diltiazem, felodipine, nifedipine, verapamil, amlodipine, lercanidipine, nitrendipine, nisoldipine, amiodarone, dronedarone, quinidine, sildenafil, tadalafil, kinins, finasteride, estradiol, progesterone, ethinylestradiol, testosterone, toremifene, bicalutamide, terfenadine, astemizole, chlorphenamine, Indinavir, ritonavir, Saquinavir, nelfinavir, nevirapine, budesonide, hydrocortisone, dexamethasone, cisapride, aprepitant, caffeine, cocaine, cilostazol, dextromethorphan, domperidone, eplerenone, lidocaine, ondansetron, propranolol, salmeterol, warfarin, clopidogrel, omeprazole, nateglinide, methoxetamine, and montelukast.

[0043] Non-limiting examples of C YP2D6 substrates include atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, perphenazine, tolterodine, venlafaxine, amitriptyline, encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, and trimipramine.

[0044] Non-limiting examples of C YP2C 19 substrates include S-mephenytoin, omeprazole, diazepam, lansoprazole, rabeprazole, and voriconazole.

[0045] Non-limiting examples of CYP2C9 substrates include celecoxib, glimepiride, phenytoin, tolbutamide, and warfarin.

[0046] Non-limiting examples of CYP2C8 substrates include repaglinide, montelukast, pioglitazone, and rosiglitazone.

[0047] Non-limiting examples of CYP2B6 substrates include bupropion and efavirenz. [0048] Non-limiting examples of C YP 1 A2 substrates include alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidine, clozapine, pirfenidone, and ramosetron.

[0049] The term "inhibitor" refers to a substance that blocks, reduces, inhibits, or suppresses the activity of an enzyme. For this disclosure, an inhibitor includes but is not limited to a reversible, irreversible, competitive, or noncompetitive inhibitor. In one embodiment, the inhibitor is a CYP inhibitor, which includes, but is not limited to, a

CYP1 A2 inhibitor, a CYP2B6 inhibitor, a CYP2C8 inhibitor, a CYP2C9 inhibitor, a

CYP2C19 inhibitor, a CYP2D6 inhibitor, a CYP2E1 inhibitor, and a CYP3A4 inhibitor.

[0050] Non-limiting examples of CYP 1 A2 inhibitors include Amiodarone, Atazanavir, Cimetidine, Ciprofloxacin, Citalopram, Clarithromycin, Diltiazem, Enoxacin, Erythromycin, Estradiol, Fluvoxamine, Interferon, Isoniazid Ketoconazole, Methoxsalen, Mibefradil, Tegaserod. Non-limiting examples of CYP2B6 inhibitors include Thiotepa and Ticlopidine. Non-limiting examples of CYP2C8 inhibitors include Anastrozole, Ezetimibe, Gemfibrozil, Montclukast, Nicardipine, Sulfinpyrazone, and Trimethoprim.

[0051] Non-limiting examples of CYP2C9 inhibitors include Amiodarone, Atazanavir, Cimetidine, Clopidogrel, Cotrimoxazole, Delavirdine, Disulfiram, Efavirenz, Fenofibrate, Fluconazole, Fluorouracil. Fluoxetine, Fluvastatin, Fluvoxamine, Gemfibrozil, Imatinib, Isoniazid, Itraconazole, Ketoconazole, Leflunomide, Lovastatin, Methoxsalen,

Metronidazole, Mexiletine, Modafmil, nalidixic acid, Norethindrone, Norfloxacin,

Omeprazole, Contraceptives, Paroxetine, Phenylbutazone, Probenecid, Sertraline,

Sulfamethoxazole, Sulfaphenazole, Sulfonamides, Tacrine, Teniposide, Ticlodipine, Tipranavir, Troleandomycin, Voriconazole, Zafirlukast, Zileutin, or extracts from Allium sativum, Bergamottin, Harpagophylum procumbens, and Lycium barbanim.

[0052] Non-limiting examples of CYP2C 19 inhibitors include Cimetidine, Citalopram, Delavirdine, Efavirenz, Felbamate, Fluconazole, Fluoxetine, Fluvastatin, Fluvoxamine, Indomethacin, Isoniazid, Ketoconazole, Lansoprazole, Modafmil, Omperazole,

Oxcarbazepine, Probenecid, Ticlodipine, Topiramate and extracts from Allium sativum, and Harpagophylum procumbens. Non-limiting examples of CYP2D6 inhibitors include Abiraterone. Amiodarone. Asenapine, Buproprion, Celecoxib, Chloroquine,

Chlorpheniramine, Chlorpromazine, Cimetidine, Cinacalcet, Citalopram, Clemastine, Clomipramine, Cocaine, Darifenacin, Desipramine, Diphenhydramine, Doxepin,

Doxorubicin, Duloxetine, Escitalopram, Febuxostat, Fluoxetine, Fluphenazine, Halofantrine, Haloperidol, Hydroxychloroquine, Hydroxyzine, lmatinib, Levomepromazine, Methadone, Metoclopramide, Mibefiradil, Midodrine, Moclobemide, Nefazodone, Norfluoxetine,

Paroxetine, Peφhenazine, Propafenone, Propoxyphene, Propranolol, Quinacrine, Quinidine, Ranitidine, Ranolazine, Ritonavir, Sertraline, Tegaserod, Terbinafine, Thioridazine,

Ticlodipine, Tipranavir, Tripelennamine, and extracts from Alpinia galanga, Alstonia scholaris. Andrograph is paniculate, Catharanthus rosetis, Cimicifiiga racemosa,

Cinnamomum burmannii, Eleutherococcus senticosus, Gfycyrrhiza glabra, Hydrastis canadensis, Melaleuca leucadendrtm, Panax ginseng, Panax quinquefolius. Piper nigrum, Punica granutum. Rheum palmalum, Suntulum album, Strychnos ligustrinu, Syzygium aromaticum, Tinospora crispa, and Zingiber aromaticum.

[0053] Non-limiting examples of CYP2E1 inhibitors include disulfiram and extracts from Piper methysticum.

[0054] Non-limiting examples of C YP3A4 inhibitors include Amiodarone, Amprenavir, Aprepitant, Atazanavir, Boceprevir, Cimetidine, Ciprofloxacin, Clarithromycin,

Cyclosporine, Danazol, Delavirdine, Diltiazem, Kfavirenz, Erythromycin, Ethinyl Estradiol, Ezetimibe, Fluconazole, Fluoxetine, Fluvoxamine, Gestodene, lmatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Methylprednisolone, Mibefradil, Miconazole, Mifepristone, Nefazodone, Nelfinavir, Nicardipine, Nifedipine, Norethindrone, Norfloxacin, Norfluoxetine, Oxiconazole, Posaconazole, Prednisone, Quinine, Ranolazine, Ritonavir, Roxithromycin, Saquinavir, Sertraline, Telaprevir, Telithromycin, Troleandomycin, Verapamil, Voriconazole, Zafirlukast, Zileutin, and extracts from Allium sativum, Ammi visnaga, Azadirachta indica, Cimicifiiga racemosa, Harpagophylum prtKumbens, Hydrastis canadensis, Naringenin, Panax ginseng, Panax quinquefolius, Strychnos ligtistrina, and Uncaria tomentosa.

[0055] The term "Praziquantel" or "PZQ" refers to a Praziquantel compound, a

Praziquantel derivative or analog, a suitable homolog, or a portion thereof, capable of promoting at least one of the biological responses normally associated with Praziquantel. In one embodiment, PZQ includes, but is not limited to, its salts, esters, solvates, derivatives, polymorphs, or hydrates.

[0056] As used herein, the term "R-Praziquantel" or "R-PZQ" refers to a R-Praziquantel compound, an R-Praziquantel derivative or analog, a suitable homolog. or a portion thereof, capable of promoting at least one of the biological responses normally associated with R- Praziquantel. In one embodiment, R-PZQ includes, but is not limited to, its salts, esters, solvates, derivatives, polymorphs, or hydrates.

[0057] As used herein, the term "biostability" refers to a stability of a substance (e.g., a chemical, a protein, a lipid, a DNA, a peptide, a polymorph) in circulating blood, plasmas and serums, various living body tissues, and various tissue homogenates. Methods or parameters to measure biostability are well known in the art. For example, C_mx is used to evaluate the biostability by measuring the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose. An elimination half-life in blood can also be used, which is the time required to decrease the concentration of the substance to a half of the maximum concentration of the substance.

[0058] The term "therapeutic efficacy" refers to the amount of an agent effective to achieve beneficial or clinical results. In one embodiment, the therapeutically efficacy relates to reducing the number of cancer cells, treating parasitic diseases, or ameliorating at least part of one or more symptoms associated with a disease.

[0059] The term "disease" refers to an impairment of the normal state of a living organism (e.g., a plant, a mammal, and human) or any of its components that interrupt or modify the performance or the function of the organisms. The "parasitic disease" refers to a disease caused or transmitted by a parasite. Examples or parasitic diseases include toxoplasmosis, malaria, African trypanosomiasis. Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, as can as is, trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis and cestodiasis. [0060] In another embodiment, the parasitic disease is a human parasite disease, which includes, but is not limited to, Tapeworm - Tapeworm infection, Diphyllobothriasis - tapeworm, Echinococcosis - tapeworm, Hymenolepiasis, Beef tapeworm, Cysticercosis-Pork tapeworm, Bertielliasis, Sparganosis, Clonorchiasis, Lancet liver fluke. Liver fluke - Fasciolosis, Fasciolopsiasis - intestinal fluke, Metagonimiasis - intestinal fluke,

Metorchiasis, Chinese liver fluke. Paragonimiasis, lung fluke, Schistosomiasis - bilharzia, bilharziosis or snail fever (all types), intestinal schistosomiasis, urinary schistosomiasis.

Schistosomiasis by Schistosoma japonicum, Asian intestinal schistosomiasis, Swimmer's itch, Ancyiostomiasis/Hookworm, Angiostrongyliasis, Anisakiasis, Roundworm - Parasitic pneumonia. Roundworm— Baylisascariasis. Roundworm-lymphatic filariasis, Dioctophyme renal is infection, Guinea worm - Dracunculiasis, Pinworm-Enterobiasis, Gnathostomiasis, Halicephalobiasis, Loa loa filariasis, Calabar swellings, Mansonelliasis, filariasis, River blindness, onchocerciasis, Strongyloidiasis-Parasitic pneumonia, Thelaziasis, Toxocariasis, Trichinosis, Whipworm, Elephantiasis - Lymphatic filariasis, Acanthocephaliasis, Halzoun syndrome, Myiasis, Screwworm, Cochliomyia, Chigoe flea. Bedbug, Human botfly, Head louse-Pediculosis, Body louse— Pediculosis, Crab louse— Pediculosis, Demodex-Demodicosis, Scabies, "Chiggers" (TrombiculidaeV-Trombiculosis, Flea, Siphonaptera, Tick,

Granulomatous amoebic encephalitis (eye infection), Acanthamoeba keratitis. Granulomatous amoebic encephalitis (skin infection), Babesiosis, Balantidiasis, Blastocystosis,

Cryptosporidiosis, Cyclosporiasis, Dientamoebiasis, Amoebiasis, Giardiasis, Isosporiasis, Leishmaniasis, Primary amoebic meningoencephalitis (PAM), malaria, rhinosporidiosis, Sarcocystosis, Toxoplasmosis (Acute and Latent), Trichomoniasis, sleeping sickness, and Chagas disease.

[0061] In one embodiment, the parasitic disease is schistosomiasis. In another

embodiment, the parasitic disease is caused by blood fluke.

[0062] In some embodiments, the parasitic diseases include any conditions caused by a parasite. The parasite includes, but is not limited to, endoparasites and ectoparasites. Non- limiting examples of parasites include Rafflesia, Cuscuta, Acanthocephala, Ascariasis (roundworms), Cestoda (tapeworms) including: Taenia saginata (human beef tapeworm), Taenia solium (human pork tapeworm), Diphyllohuthrium latum (fish tapeworm) and Echinococcosis (hydatid tapeworm), Clonarchis sinensis (the Chinese liver fluke), Dracunculus medinensis (Guinea worm), Enterobius vermicularis (pinworm), Filariasis, Hookworm, Loa loa, Onchocerciasis (river blindness), Schistosomiasis, Strongyloides stercoral is. Tapeworm, Toxocara canis (dog roundworm), Trichinella, Whipworm,

Entamoeba histolytica, Entamoeba coli, Acanthamoeba, Halamuthia mandril laris, Giardia, Cyc/ospora cayelanensis, Cryptosporidium, Toxoplasma gondii, Leishmania (/,. tropica, /.. donovani, and L. Mexicana), Plasmodium, Babesia, Gymnosporangium and other rusts, Pyrenophora teres, Cordyceps, Arthropoda, Acari, Varroa destructor, Cymothoa exigua. Bed bugs, Culicidae (mosquitoes), Calyptra (vampire moths), Hippoboscoidea, Tsetse fly, Lipoptena, Mefophagus ovinus (sheep keds) and relatives, Oestridae (bot flies), Human botfly, Phlcbotominae (sand flies), Phthiraptera (Lice), Body louse, Crab louse. Head louse, Siphonaptera (fleas), Tabanidae (horse flies), Tanlulocarida, Triatominae, Pea crab,

Sacctt/ina, Annelids, Hirudinea (some leeches), Monogeneans, Calydiscoides euzeti,

Lethacotyle vera, Protocotyle euzetmaillardi, Pseudorhabdosynochus spp., Mollusks, Cancellaria cooper ii, Olochidium, Pyramidellidae, Chordates, Cookiecutter shark, Candiru (vampire fish of Brazil, a facultative parasite). Lampreys, Deep sea anglers, False cleanerfish, Hood mockingbird. Ox peckers, Snubnosed eel. Vampire bat, Vampire finch, Mistletoe, certain orchids. Com smut, and certain mushrooms.

[0063] In some embodiments, the parasite is a tapeworm, which is a flat, segmented worm that lives in the intestines of mammals. During infection, live tapeworm larvae are grouped in cysts. Once inside the digestive tract, a larva can grow into a very large adult tapeworm, which causes symptoms in the host. Tapeworms can cause gastrointestinal infections. For example, cysticercosis is one disease involving larval tapeworms in the human body. The tapeworm comprises Taenia solium, Taenia saginata, Hymenolepis nana, Dipylidium caninum, and Taenia laeniaeformis.

[0064] The term "administering" or "administration" of an agent to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or topically. Administration includes self-administration and the administration by another. [0065] The term "extract" can be used to refer to a powder form of the compounds of interest, a liquid form of the compounds of interest, or any one or any combination of the compounds of interest in powder or liquid form. One of skill will appreciate that the term "extract" can be used to refer to the compounds of interest before, during, or after their isolation.

[0066] An extract from a plant or an organism includes but is not limited to a compound that is isolated from the plant or the organism. Instead, the extract from a plant also includes molecules or chemicals that have same or similar functions or structures with the compounds that are isolated from the plant or the organism. In one embodiment, the compounds originally isolated from Schisandra chinensis include but are not limited to the compounds that are extracted directly from Schiscmdra chinensis, and chemicals or molecules that have same or similar functions or structures with the compounds that are isolated directly from Schisandru chinensis. The chemicals or molecules can be synthesized or extracted from a different source. For example, schisandrin A, a compound originally isolated from

Schisandra chinensis, can be synthesized, purchased commercially, or isolated from a different source.

[0067] The terms "isolated" and "purified" can be used interchangeably. In some embodiments, the term "isolated" can be used to refer to the extract being removed from the natural chemical environment.

[0068] The term "analogue" refers to a compound in which one or more individual atoms or functional groups have been replaced, either with a different atom or a different functional, generally giving rise to a compound with similar properties.

[0069] The term "derivative" refers to a compound that is formed from a similar, beginning compound by attaching another molecule or atom to the beginning compound. Further, derivatives, according to the invention, encompass one or more compounds formed from a precursor compound through addition of one or more atoms or molecules or through combining two or more precursor compounds. [0070] The term "pharmaceutically acceptable carrier" refers to a carrier that is conventionally used in the art to facilitate the storage, administration, and/or healing effect of a biologically active agent.

PZQ andR-PZQ

[0071] Praziquantel ("PZQ"), or 2-(cyclohexylcarbonyl)- 1 ,2,3,6,7, 1 lb-hexahydro-4H- pyrazino[2,l-a]isoquinolin-4-one, acts as an antihelminthic agent. Studies indicate that PZQ increases the permeability of parasitic cell membranes to calcium ions, thereby inducing contraction of the parasites. PZQ may further cause vacuolization and disintegration of the parasite tegument.

[0072] PZQ, also known as Bay-8440 or MSC- 1028703 A, corresponding with C₁₉H24N2O2, is a racemic mixture ("Rac-PZQ") composed of R-PZQ and S-PZQ. Rac-PZQ and R-PZQ have the chemical structures shown in Figure 1.

[0073] The preparation of PZQ is described in US 4362875 and other synthetic method is described in CN102093346, US 2013289275, CN103570710, CN103638884, CN

103739601, CN105237532, and CN 105294679, which are incorporated by references. PZQ can control the growth of parasites by disrupting calcium ion channels, which facilitates subsequent immunological attack and later clearance of the parasite. Thus, PZQ is used to treat diseases caused by infection with several types of internal/gastrointestinal, and external parasites, including hydatid disease, cysticercosis. schistosomiasis, clonorchasis,

paragonimiasis, and fasciolopsiasis. PZQ is a common treatment for schistosomiasis with some drawbacks, e.g., the high dose requirement and the bitter taste.

[0074] Currently. PZQ is the primary drug compound of choice in treating a number of parasitic diseases, including, but not limited to, hydatid disease, cysticercosis,

schistosomiasis, clonorchiasis, paragonimiasis, or fasciolopsiasis, or the gastrointestinal infection caused by tapeworms, including Dipylidium caninum or Taenia taeniaeformis. In one embodiment, the parasitic disease is schistosomiasis. In particular, PZQ has been used for treating infections caused by the species of Schistosoma, e.g., Schistosoma mefcongi, Schistosoma japonicum. Schistosoma mansoiii and Schistosoma hematobhim, and infections due to the liver flukes, Clonorchis sinensislOpisthorchis viverrini. PZQ is currently in clinical trials for the treatment of cysticercosis, neurocysticercosis (NCC), and malaria. PZQ is also useful for the treatment of health conditions that may be treated with anthelmintics, antischistosomals, and antitrematodes. Further, PZQ is used in veterinary medicine, for example, in dogs for the removal of tapeworm, and for the removal of hookworms, roundworms, and whipworms in combination with pyrantel pamoate and febantel. Moreover, PZQ is useful in cats for the removal of tapeworm, and also in combination with pyrantel pamoate for the removal of various types of hookworms and roundworms. PZQ may eliminate tapeworms in humans, ferrets, birds, chinchillas, mice, rats, hamsters, gerbils, and guinea pigs, and for removing tapeworms and flukes in reptiles.

[0075] Administration of PZQ is often accompanied with mild and transient adverse events, which include severity, malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature, and urticaria. Some of the symptoms, in fact, may result from the parasitic infection itself. Because PZQ is a substrate of drug metabolizing liver enzymes, e.g.. Cytochrome P4S0. concomitant administration of a compound or a reagent that enhances the activities of the enzymes can reduce plasma levels of PZQ.

[0076] The reagents that enhance the activities of the metabolizing liver enzyme include, but are not limited to, antiepileptic drugs (e.g., phenytoin, phenobarbital, and carbamazepine) and dexamethasone. On the other hand, reagents that decrease the activity of drug

metabolizing liver enzymes (Cytochrome P 450) can increase the plasma levels of PZQ. The reagents that can decrease the metabolizing liver enzymes include, but are not limited to, cimetidine, ketoconazole, itraconazole, and erythromycin.

[0077] When administered alone, only half of the administered PZQ remains its activity against schistosomiasis. Without being bound by a theory, the efficacy of PZQ in treating schistosomiasis is undermined by its low bioavailability in the patients. Meyer T, et al., PLoS Negl Trap Dis 3(1 ): e357 (2009). Moreover, PZQ's well-documented bitter taste, which affects its usage among child patients, cannot be masked by traditional methods, e.g., encapsulation and coating. DEI 02005062270.

[0078] R-PZQ is one enantiomer of PZQ and the schistosomicidal component as

determined by X-ray crystoUogrphy. Meyer T, et al., PLoS Negl Trop Dis 3( 1 ): e357 (2009). Because of its lower bitterness, R-PZQ is a suitable candidate for young patients, or school- age patients, against schistosomiasis. R-PZQ has both in vitro and in vivo higher treating efficacies against Schistosoma, with a less bitter taste than S-PZQ. Meister et al.,

Antimicrobial Agents and Chemotherapy, 58(9), 5466-72 (2014); Meyer et al., PI.oS. Negl. Trap. Dot., 3( 1 ): e357 (2009). Furthermore, R-PZQ is less toxic than S-PZQ and clinical studies have already shown that treatment with R-PZQ resulted in less adverse events than the standard treatment. Sun et al.. Drug Des. Devef. Then, 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 US 4362875, each of which is incorporated here by reference in its entirety.

[0079] Similar with PZQ, R-PZQ is also limited by its low bioavailability, due to the quickly stereo-selective metabolism into the inactive monohydroxylated metabolite R-trans- 4-OH-PZQ by CYP3A. Wang et al., Biochem. Pharmacol., 15. 90,166-178 (2014); Meister et al., Antimicrobial Agents and Chemotherapy, 58(9), 5466-72 (2014). One study shows that the Cm«x in the healthy volunteers is 0.16 pg/ml after 2.67 hours of an oral dose of 23.3 mg/Kg R-PZQ and the AUCo— / is 0.87 pg*h/ml per hour. Lima et al., Br. J. Clin.

Pharmacol., 201 1, 71 : 528 535.

[0080] Another study with Opisthorchis viverini-infected patients shows that the dux is 0.2 pg/ml after 7 hours of an oral dose with 25 mg/Kg of R-PZQ and the AUCo— 24h is 1.1 ug*h/ml per hour. Meister et al., PLoSNegl. Trop. Dis., 2016, 10(5): e0004700.

[0081] Without being bound by a theory, limiting the enzymatic activity against the R-PZQ can increase the bioavailability of R-PZQ in the patients. Competitive inhibition is one way to prevent or limit the enzymatic activity against R-PZQ.

[0082] In the competitive inhibition, the inhibitor and the targeted substrate compete for the active site of an enzyme. When the inhibitor binds to the active site, it blocks the binding of the enzyme with the substrate, and thus inhibits the enzymatic digestion of the substrate. Therefore, administration of a substrate for the R-PZQ-targeting enzymes, which functions as a competitive inhibitor, may promote the bioavailability of R-PZQ within the host. Extracts from Schisandra chinensis

/0083/ Schisandra sphenanthera, a native plant in China, has long been used as an ingredient in oriental medicine for treating viral and drug-induced hepatitis. Hancke JL et al., Fitoterapia, 70:451-471 (1999). The extracts from Schisandra sphenanthera, including gomisin A, can be hydroxylated by CYP3A, thereby serving as a potent substrate for this enzyme. Wu et al., AAPS. J., 18(1), 134-45 (2016); CN 104892563A; Wu et al., Drug Metah /Hsptts, 42, 94-104 (2014). Further, the extracts from Schisandra sphenanthera can also increases the blood concentration of Tacrolimus (FK506), which is metabolized by CYP3A4, by inhibiting the enzymatic activity of CYP3 A4. Iwata et al., Drug Metah Dispos, 32, 1351- 1358 (2004); Qin et al. Drug Metah Disptjs. 32. 193-199 (2014).

[0084] Applicant unexpectedly discovered that the extracts of Schisandra chinensis can inhibit the activities of Cytochrome P450 (CYP) enzymes, which induce metabolism of chemical compounds, including R-PZQ. In one embodiment, the extracts from Schisandra chinensis comprise a compound isolated from Schisandra chinensis. In another embodiment, the compound originally isolated from Schisandra chinensis includes Schisandrin A,

Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or the combination thereof. The structures of the above compounds are shown in Figure 2.

[0085] CYP is a family of enzymes, which targets both exogenous and endogenous compounds as substrates in enzymatic reactions. In one aspect of this disclosure, the extracts from Schisandra chinensis inhibit the activity of CYP enzymes.

[0086] Any means of inhibiting CYP is embodied herein for the therapeutic purposes herein. CYP enzymes include CYP supcrfamily members of microbial, invertebrate, and vertebrate origin. Examples of CYP enzymes include, but are not limited to, enzymes from CYP1A, CYP2B, CYP2C, CYP2D, CYP2E, CYP3A families, and additional CYP enzymes as described in U.S. Patent Nos. 5,786,191 and 5,478,723, each of which is incorporated by reference in its entirety. In some embodiments, the CYP enzymes comprise CYP enzymes in a mammal, which include, but are 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, the mammalian CYP enzymes include, but are 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, CYP4A1 1, 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.

[0087] Compounds embodied herein— e.g., extracts of Schisandra chinensis— can inhibit the CYP enzymes of this disclosure. In one embodiment, the compounds are more selective in inhibiting one CYP enzyme than another. The term "selectivity" means the compound the ICso of the compound for inhibiting one CYP is a smaller value than that of another CYP enzyme.

[0088] The term "IC50," as used herein, refers to the concentration of an inhibitor (e.g.. an antibody or antibody fragment) that inhibits a response in an assay half way between the maximal response and the baseline. In one embodiment, the IC50 means the concentration of a CYP inhibitor that reduces, suppresses, or inhibits the enzymatic activities of a CYP enzyme by 50%. In one embodiment, the IC₅0 means the concentration of an extract from Schisandra chinensis that reduces, suppresses, or inhibits the enzymatic activities of a CYP enzyme (e.g., CYP3A4) by 50%. In one embodiment, a compound of the invention is at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, or 1,000-fold more selective at inhibiting one CYP enzyme than another CYP enzyme. In one embodiment, a compound of the invention is at least 5-fold more selective at inhibiting one CYP enzyme than another CYP.

[0089] The ICsu for an extract from Schisandra chinensis is between 0.01 mg and about 200 mg, about 200 mg and about 400 mg, about 400 mg and about 600 mg, about 600 mg and about 800 mg, or about 800 mg and about 1 ,000 mg per kg of a mass of the subject. In another embodiment, the IC50 for an extract from Schisandra chinensis is at least 0.01 mg, 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 1,000 mg, 2,000 mg, 5,000 mg, or 10,000 mg per kg of the mass of the subject. [0090] Compounds embodied herein, e.g., extracts ofSchixandra chinensis. can be used in combination with another CYP enzyme inhibitor, which may be a reversible, irreversible, competitive, or noncompetitive inhibitor. The CYP enzyme inhibitor includes, but is not limited to, a CYP1 A2 inhibitor, a CYP2B6 inhibitor, a CYP2C8 inhibitor, a CYP2C9 inhibitor, a CYP2CI9 inhibitor, a CYP2D6 inhibitor, a CYP2E1 inhibitor, and a CYP3A4 inhibitor.

[0091] Non-limiting examples of CYP1 A2 inhibitors include Amiodarone, Atazanavir, Cimetidine, Ciprofloxacin, Citalopram, Clarithromycin, Diltiazem, Enoxacin, Erythromycin, Estradiol, Fluvoxamine, Interferon, Isoniazid Ketoconazole, Methoxsalen, Mibefradil, and Tegaserod.

[0092] Non-limiting examples of CYP2B6 inhibitors include Thiopeta and Ticlodipine. Non-limiting examples of CYP2C8 inhibitors include Anastrozole, Ezetimibe, Gemfibrozil, Montelukast, Nicardipine, Sulfinpyrazone, and Trimethoprim.

[0093] Non-limiting examples of C YP2C9 inhibitors include Amiodarone, Atazanavir, Cimetidine, Clopidogrel, Cotrimoxazole, Delavirdine, Disulfiram, Efavirenz, Fenofibrate, Fluconazole, Fluorouracil, Fluoxetine, Fluvastatin, Fluvoxamine, Gemfibrozil, Imatinib, Isoniazid, Itraconazole, Ketoconazole, Leflunomide, Lovastatin, Methoxsalen,

Metronidazole, Mcxilctinc, Modafinil, Nalidixic acid, Norcthindronc, Norfloxacin,

Omeprazole, Contraceptives, Paroxetine, Phenylbutazone, Probenecid, Sertraline,

Sulfamethoxazole, Sulfaphenazole, Sulfonamides, Tacrine, Teniposide, Ticlodipine, Tipranavir, Troleandomycin, Voriconazole, Zafirlukast, Zileutin, or extracts from Allium sativum. Hergamottin, Harpagophylum procumhens, and I.ycium barharum.

[0094] Non-limiting examples of C YP2C 19 inhibitors include Cimetidine, Citalopram, Delavirdine, Efavirenz, Felbamate, Fluconazole, Fluoxetine, Fluvastatin, Fluvoxamine, Indomethacin, Isoniazid, Ketoconazole, Lansoprazole, Modafinil. Omperazole,

Oxcarbazepine, Probenecid, Ticlodipine, Topiramate, and extracts from Allium sativum and Harpagophylum procumhens.

[0095] Non-limiting examples of CYP2D6 inhibitors include Abiraterone, Amiodarone, Asenapine, Buproprion, Celecoxib, Chloroquine, Chloφheniramine, Chloφromazine, Cimetidine, Cinacalcet, Citalopram. Clemastine. Clomipramine, Cocaine, Darifenacin, Desipramine, Diphenhydramine, Doxepin, Doxorubicin, Duloxetine, Escitalopram,

Febuxostat, Fluoxetine, Fluphenazine, Halofantrine, Haloperidol, Hydroxychloroquine, Hydroxyzine, Imatinib, Levomepromazine, Methadone, Metoclopramide, Mibefradil, Midodrine, Moclobemide, Nefazodone, Norfluoxetine, Paroxetine, Perphenazine,

Propafenone, Propoxyphene, Propranolol, Quinacrine, Quinidine, Ranitidine, Ranolazine, Ritonavir, Sertraline, Tegaserod, Terbinafine, Thioridazine, Ticlodipine, Tipranavir,

Tripelennamine, and extracts from Alpinia glanga, Alstotiia scholaris, Andrographis paniculata, Calharanthus roseus, Cimicifuga racemose, Cimiamomum burmannii,

Eleutherococcus senticoccus, Gycyrrhiza glabra, Hydrastis canadensis, Melaleuca leucadcndron, Panax ginseng, Panax quinqucfolius. Piper nigrum, Punica granaium, Rheum pa/matum, San/alum album, Strychnas ligustrina, Syzygium aromaticum, Tmospora crispa, and Zingiber aromaticum.

[0096] Non-limiting examples of CYP2E1 inhibitors include Disulfiram and extracts from Piper Methysticum.

[0097] Non-limiting examples of C YP3 A4 inhibitors include Amiodarone, Amprenavir, Aprepitant, Atazanavir, Boceprevir, Cimetidine, Ciprofloxacin, Clarithromycin,

Cyclosporine, Danazol, Delavirdine, Diltiazem, Efavirenz, Erythromycin, Ethinyl Estradiol, Ezetimibe, Fluconazole, Fluoxetine, Fluvoxamine, Gestodene, Imatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Methylprednisolone, Mibefradil, Miconazole, Mifepristone, Nefazodone, Nelfinavir, Nicardipine, Nifedipine, Norethindrone, Norfloxacin, Norfluoxetine, Oxiconazole, Posaconazole, Prednisone, Quinine, Ranolazine, Ritonavir, Roxithromycin, Saquinavir, Sertraline, Telaprevir, Telithromycin, Troleandomycin, Verapamil, Voriconazole, Zafirlukast, Zileutin, and extracts from Allium sativum, Ammi visnaga, Azadirachta indica, Cimicifuga racemose, Harpagphytum, Procumhens, Hydrastis canadensis, Naringenin, Panax ginseng, Panax quinqucfolius, Strychnos ligustrina, and Uncaria tnmentasa.

Pharmaceutical Compositions

[0098] In another aspect, the disclosure relates to a pharmaceutical composition for treating and/or preventing a parasitic disease in a subject, comprising PZQ (e.g., R-PZQ) and extracts from Sehisandra chinensis or compounds originally from Schiscmdra chinensis. In one embodiment, the extracts from Sehisandra chinensis comprise a compound isolated from Sehisandra chinensis. In another embodiment, Sehisandra chinensis extracts comprise Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, or Schisantherin A. In a further embodiment, the composition comprises an effective amount of the extracts from Sehisandra chinensis to reduce or inhibit the enzymatic activity against PZQ and/or R- PZQ.

[0099] The pharmaceutical composition or composition of the disclosure may exist in various forms of solid foods or liquid foods such as tablets, effervescent granules or powder, effervescent tablets, liquids, dispersible and/or soluble tablets, dispersible powder, suspensions, sachets, premix syrups, jellies, glycerites, chewable tablets, granules or capsules (e.g., hard capsules), liquid beverages and foods such as soups, juices, tea drinks, milk drinks, fermented milk drinks, soy milk, cocoa drinks and jellied drinks, semi-solid foods such as pudding or yogurt, breads, noodles such as udon, confections such as cookies, chocolate, candy or crackers, and spreads such as rice seasonings, butter or jam, and the like. In addition, the pharmaceutical composition or composition can also be in the form of a health food or therapeutic food. There are no particular limitations on the form thereof, and preferable examples include a form that enables continuous ingestion, such as tablets, chewable tablets, granules or capsules (e.g., hard capsules), as well as confections, soups, beverages, and liquid foods.

[0100] The parasitic disease is susceptible to being treated by the composition or pharmaceutical composition of this disclosure. In one embodiment, the parasitic disease comprises hydatid disease, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, or fasciolopsiasis. In another embodiment, the parasitic disease is schistosomiasis. In a further embodiment, the parasitic disease comprises the gastrointestinal infections caused by tapeworms, including lYipylidium caninnm or Taenia laeniaefarmis.

[0101] The composition or pharmaceutical composition comprises a PZQ, R-PZQ or its analogues. As is generally known, the effective dosage for active compounds in the pharmaceutical composition depends on the intended route of administration and other factors such as age and weight of the patient, as generally known to a physician. The dosage also depends on the illness to be treated. For example, the dosage depends on the particular parasitic disease targeted by the pharmaceutical composition of the disclosure.

[0102] In one embodiment, the composition or pharmaceutical composition comprises 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 1,000 mg of PZQ or R-PZQ per kg of a mass of the subject. Tn another embodiment, the composition comprises about 1 to about 1,000, about 10 to about 500. about 20 to about 250, about 30 to about 200, or about 40 to about 100 mg of PZQ or R- PZQ per kg of a mass of the subject. In yet another embodiment, the dosage for the PZQ or R-PZQ is at least about 50 mg per kg of a mass of the subject. In another embodiment, the composition or pharmaceutical composition comprises PZQ or R-PZQ at a dosage less than 10,000. 100, 80, 60, 50, 30, 20, 10, 5, or 1 mg per kg of a mass of the subject.

[0103] The composition or pharmaceutical composition comprises the extracts from Schisandra chinemis. At noted above, the dosage of the extracts from Schisandra chinensis in the composition depends on the intended route of administration and other factors such as age and weight of the patient and the amount of PZQ or R-PZQ in the composition. In one embodiment, the dosage of Schisandra chinensis extract is at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject. In some embodiments, the dosage of Schisandra chinensis is between about 1 and about 200, about 200 and about 400, about 400 and about 600, about 600 and about 800, or about 800 and about 1,000 mg of Schisandra chinensis extracts per kg of a mass of the subject.

[0104] The Schisandra chinensis extract comprises Schisandrin A, Schisandrin B,

Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A. Thus, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A at a dosage at least 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 1,000 mg, 2,000 mg, 5,000 mg, or 10,000 mg per kg of the mass of the subject. In another embodiment, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A at a dosage between about 1 nig and about 200 mg, about 200 mg and about 400 mg, about 400 mg and about 600 mg, about 600 mg and about 800 mg, or about 800 mg and about 1 ,000 mg per kg of a mass of the subject. In some embodiments, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A,

Schizandrol B, and/or Schisantherin A at a dosage between about I mg and about 10,000 mg, about 10 mg and about 7,000 mg, about 100 mg and about 5,000 mg, about 200 mg and about 3,000 mg, about 500 mg and about 2,000 mg, and about 700 mg and about 1,500 mg per kg of a mass of the subject.

[0105] Tn one aspect, the pharmaceutical composition is in the form of an oral suspension, a tablet, a spray, or a capsule, a lotion, a gel, or a foam.

[0106] In another aspect, the mass ratio between the PZQ (e.g., S-PZQ or R-PZQ) and the extracts from Schisandra chinensis is at least 1:10,000, 1:1,000, 1:100, 1: 10, 1:5, 1:3, 1 :2, 1: 1 , 2: 1, 3: 1, 5: 1, 10: 1, 100:1 , 1, 000; 1, or 10,000:1. In one embodiment, the mass ratio between the PZQ and the extracts from Schisandra chinensis is 1 : 1 or 2: 1. In another embodiment, the mass ratio between the PZQ and the extracts from Schisandra chinensis is at least 1:3. 1:5, 1:10, or 1:100.

[0107] The pharmaceutical composition of this disclosure comprises additional antiparasitic drugs or medications that are effective for treatment of parasitic diseases, including, but not limited to, toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis. trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis, and cestodiasis. In one embodiment, additional anti-parasitic drugs or medications are effective for treatment of parasitic diseases including Tapeworm - Tapeworm infection, Diphylloboihriasis— tapeworm, Echinococcosis - tapeworm, Hymenolepiasis, Beef tapeworm, Cysticercosis-Poik tapeworm, Berlie/liasis, Sparganosis, Clonorchiasis, Lancet liver fluke, Liver fluke - Fusciulosis, Fasciolopsiasis - intestinal fluke, Mclagonimiasis - intestinal fluke,

Metorchiasis, Chinese liver fluke. Paragonimiasis, lung fluke. Schistosomiasis— bilharzia, bilharziosis or snail fever (all types), intestinal schistosomiasis, urinary schistosomiasis, Schistosomiasis by Schistosoma japonicum, Asian intestinal schistosomiasis, Swimmer's itch, Ancylostomiasis/Hookworm, Angiostrongyliasis, Anisakiasis. Roundworm - Parasitic pneumonia. Roundworm - Baylisascariasis, Roundworm-lymphatic filariasis, Dioctophyme renalis infection, Guinea worm - Dracunculiasis, Pinworm-Enterobiasis, Gnathostomiasis, Ilalicephalohiasis, Loa loa filariasis. Calabar swellings, Mansonelliasis, filariasis. River blindness, onchocerciasis, Strongyloidiasis-Parasitic pneumonia, Thelaziasis, Toxocariasis, Trichinosis, Whipworm, Elephantiasis - Lymphatic filariasis, Acanlhocephaliasis, Halzoun syndrome. Myiasis, Screwworm, Coch/iomyia, Chigoe flea. Bedbug, Human botfly. Head louse-Pediculosis, Body louse-Pediculosis, Crab louse-Pediculosis, Oemodex-Demodicosis, Scabies, "Chiggers" (Trombiculidaey-Trombiculosis, Flea, Siphonaptera, Tick,

Granulomatous amoebic encephalitis (eye infection), Acanthamoeba keratitis.

Granulomatous amoebic encephalitis (skin infection), Babesiosis, Balantidiasis,

Blastocystosis, Cryptosporidiosis, Cyclosporiasis, Dientamoebiasis, Amoehiasis, Giardiasis, Isospttriusis, leishmaniasis. Primary amoebic meningoencephalitis (PAM), Malaria,

Rhinosporidiosis, Sarcocystosis, Toxoplasmosis (Acute and Latent), Trichomoniasis,

Sleeping sickness, and Chagas disease.

[0108] The additional suitable anti-parasitic medications for the composition or

pharmaceutical composition of this disclosure include tinidazole, metronidazole, melarsoprol, eflornithine, rifampin, amphotericin B, pentamidine, sodium stibogluconate, meglumine antimoniate, fluconazole, artesunate, quinine, quinidine, chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, doxycycline, clindamycin, paromomycin, atovaquone, nitazoxanide, azithromycin, fumagillin, paromomycin, diloxanide, secnidazole, ornidazole, iodoquinol, diloxanide furoate, clindamycin, atovaquone, azithromycin, diminazen, trypan blue, oxamniquinine, niclosamide, albendazole, mebendazole, thiabendazole, pyrantel, diethylcarbamazine, ivermectin, selamectin, doramectin, and abamectin. In another embodiment, the additional anti-parasitic medications comprise a drug for treating

schistomiasis, including, but not limited to, amoscanate, arteether, artemether, chloroxylenol, hycanthone, lucanthone, meclonazepam, niridazole, oltipraz, and oxamniquine.

[0109] As discussed above, the enzymatic activity of CYP may be one contributing factor for the low bioavailability of PZQ (including both S-PZQ and R-PZQ), once administered. Thus, the composition or pharmaceutical composition of this disclosure further comprises a CYP inhibitor, which includes CYP1 A2 inhibitor, a CYP2B6 inhibitor, a CYP2C8 inhibitor, a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor, a CYP2E1 inhibitor, or a CYP3A4 inhibitor. Non-limiting examples of CYP1 A2 inhibitors includes Amiodarone, Atazanavir, Cimetidine, Ciprofloxacin, Citalopram, Clarithromycin, Diltiazem, Enoxacin, Erythromycin, Estradiol, Fluvoxamine, Interferon, Isoniazid Ketoconazole, Methoxsalen, Mibefradil, Tegaserod. Non-limiting examples of CYP2B6 inhibitors include Thiopeta and Ticlodipine. Non-limiting examples of CYP2C8 inhibitors include Anastrozole, Ezetimibe, Gemfibrozil, Montelukast, Nicardipine, Sulfinpyrazone, and Trimethoprim. Non-limiting examples of C YP2C9 inhibitors include Amiodarone, Atazanavir, Cimetidine, Clopidogrel, Cotrimoxazole, Delavirdine, Disulfiram, Efavirenz, Fenofibrate, Fluconazole. Fluorouracil, Fluoxetine, Fluvastatin, Fluvoxamine, Gemfibrozil, Imatinib, Isoniazid, Itraconazole, Ketoconazole, Lefiunomide, Lovastatin, Methoxsalen, Metronidazole, Mexiletine, Modafinil, Nalidixic acid. Norethindrone, Norfloxacin, Omeprazole, Contraceptives, Paroxetine, Phenylbutazone, Probenecid, Sertraline, Sulfamethoxazole, Sulfaphenazole, Sulfonamides, Tacrine, Teniposide, Ticlodipine, Tipranavir, Troleandomycin, Voriconazole, Zaflrlukast, Zileutin, or extracts from Allium sativum, Rergamotthi, Harpagnphytum prttcumhens, and Lycium harhartim. Non-limiting examples of CYP2C19 inhibitors include Cimetidine, Citalopram, Delavirdine, Efavirenz, Felbamate, Fluconazole, Fluoxetine, Fluvastatin, Fluvoxamine, Indomethacin, Isoniazid, Ketoconazole, Lansoprazole, Modafinil, Omperazole, Oxcarbazepine, Probenecid, Ticlodipine, Topiramate and extracts from Allium sativum, and Harpagophytum prttcumhens. Non-limiting examples of CYP2D6 inhibitors include

Abiraterone. Amiodarone, Asenapine, Buproprion, Celecoxib, Chloroquine,

Doxorubicin, Duloxetine, Escitalopram, Febuxostat, Fluoxetine, Fluphenazine, Halofantrine, Haloperidol, Hydroxychloroquine, Hydroxyzine, Imatinib, Levomepromazine, Methadone, Metoclopramide, Mibefradil, Midodrine, Moclobemide, Nefazodone, Norfluoxetine,

Paroxetine, Perphenazine, Propafenone, Propoxyphene, Propranolol, Quinacrine, Quinidine, Ranitidine, Ranolazine, Ritonavir, Sertraline, Tegaserod, Terbinafine, Thioridazine,

Ticlodipine, Tipranavir, Tripelennamine, and extracts from Alpinia glanga, Alstonia scholar is, Andrographis panicuiata, Catharanthus rosetis, Cimicifitga racemose. Cinnamamum hurmannii, Eleutherocaccus senticoccus, Gycyrrhiza glabra, Hydrastis canadensis, Melaleuca leucadendron, Panax ginseng, Panax quinquefolhis. Piper nigrum, Punica granatum, Rheum palmatum, Santalum album, Sfrychnos ligustrina, Syzygium aromaticum, Tinospora crispa, and Zingiber aroma ticum. Non-limiting examples of 0ΎΡ2Ε1 inhibitors include Disulfiram and extracts from Piper methysticum. Non-limiting examples of CYP3A4 inhibitors include Amiodarone, Amprenavir, Aprepitant, Atazanavir, Boceprevir, Cimetidine, Ciprofloxacin, Clarithromycin, Cyclosporine, Danazol, Delavirdine, Diltiazem, Efavirenz, Erythromycin, Ethinyl Estradiol, Ezetimibe, Fluconazole, Fluoxetine, Fluvoxamine, Gestodene, Imatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Methylprednisolone, Mibefradil, Miconazole, Mifepristone, Nefazodone, Nelfinavir.

Nicardipine, Nifedipine, Norethindrone, Norfloxacin, Norfluoxetine, Oxiconazole,

Posaconazole, Prednisone, Quinine, Ranolazine, Ritonavir, Roxithromycin, Saquinavir, Sertraline, Telaprevir, Telithromycin, Troleandomycin, Verapamil, Voriconazole,

Zafirlukast, Zileutin, and extracts from Allium sativum, Ammi visnaga, Azadirachta indica, Cimicifiiga racemose, Harpagphytum, Procumbens, Hydrastis canadensis, Naringenin, Panax ginseng, Panax uuinquefitlius, Sfrychnos ligustrinu, and llncuria tomentosa.

[0110] In one aspect, the pharmaceutical composition comprises one agent selected from a group consisting of binding agents, flavor agents, lubricating agents, flow agents,

disintegration agents, delay agents, and combinations thereof. In one embodiment, the binding agent comprises starch, modified starch, cellulose, modified cellulose, brewer's yeast, sucrose, dextrose, whey, dicalcium phosphate, or a combination thereof. In another embodiment, the flavoring agent comprises dried liver, liver extract, cheese, cheese products, natural flavors, artificial flavors, milk flavored products, soybean flavored products, brewer's yeast, or the combinations thereof. In a further embodiment, the lubricating agent comprises magnesium stearate, stearic acid, starch, modified starch, modified cellulose, or a

combination thereof. In yet another embodiment, the flow agent comprises silica dioxide, modified silica, fumed silica, talc, or a combination thereof. In a different embodiment, the disintegration agent comprises croscarmellose sodium, sodium starch glycolate, starch, modified starch, or a combination thereof. In some embodiments, the delay agent comprises stearic acid, stearic acid salts, magnesium stearate, polyethylene glycols, starch, modified starch, methacrylate polymers, or a combination thereof. [0111] It will be readily understood by those skilled in the art that any suitable pharmaceutically acceptable liposome may be used as a vehicle for the composition of the present invention. Such liposomal compositions have activity against many microorganisms similar to the activity of other compositions of this invention discussed in more detail above. Additionally, these compositions may be administered in a variety of conventional and well- known ways as is also discussed in greater detail above.

[0112] In another aspect, the pharmaceutical composition further comprises an antibacterial composition, an antifungal composition, an antiparasitic composition, or a combination thereof. In one aspect, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0113] Pharmaceutically acceptable carrier preparations for administration comprise, or alternatively consist essentially of, or yet further consist of sterile or aqueous or non-aqueous solutions, suspensions, and emulsions. Non-limiting examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleatc. Non-limiting examples of aqueous carriers include water, alcoholic/aqueous solutions, emulsions, or suspensions, including saline and buffered media. Non-limiting examples of parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. An active agent or therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Non-limiting examples of suitable excipients include water, saline, dextrose, glycerol, and ethanol, or combinations thereof. Intravenous vehicles include, but are not limited to, fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.

[0114] In one aspect, the subject is a mammal. In one embodiment, the subject is a human.

[0115] In one embodiment, the pharmaceutical composition is formulated for injection.

[0116] In one embodiment, the composition comprises a pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed composition. Such excipient may be any solid, liquid, semi-solid or gaseous excipient that is generally available to one of skill in the art.

[0117] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt. rice, flour, chalk, silica gel. magnesium stearate. sodium stearate. glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil. soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Other suitable pharmaceutical excipients and their formulations are described in Remington 's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

Dose and Administration

[0118] The pharmaceutical compositions, as described herein, are administered in effective amounts. The effective amount will depend upon the mode of administration, the particular condition being treated and the desired outcome. It will also depend upon the stage of the condition, the age and physical condition of the subject, the nature of concurrent therapy, if any, and like factors well known to the medical practitioner. For therapeutic applications, it is that amount sufficient to achieve a medically desirable result.

[0119] In addition, the dose or concentration of PZQ (or R-PZQ) or the Schisandra chinensis extracts in the pharmaceutical composition depends on absorption, inactivation and excretion rates of the extract as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The composition may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. In some embodiments, a mode of administration of the pharmaceutical composition is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

[0120] The dosage of PZQ or R-PZQ depends on the species of the subject, the health condition, the temperature, or any physical and/or physiological conditions. Generally, the dose of the PZQ or R-PZQ of the present invention is between about 1 mg/kg to about 200 mg/kg, about 200 mg/kg to about 400 mg/kg, about 400 mg/kg to about 600 mg/kg, about 600 mg/kg to about 800 mg/kg. or about 800 mg/kg to about 1.000 mg/kg body weight of the subject per day, inclusive of all values and ranges therebetween, including endpoints. In one embodiment, the dose is from about 10 mg/kg to about 200 mg/kg per day. In one embodiment, the dose is from about 200 mg/kg to about 400 mg/kg per day.

[0121] In one embodiment, the dosage of PZQ or R-PZQ does not exceed about 1 ,000 mg/kg per day. In yet another embodiment, the PZQ or R-PZQ is at least about 50 mg per kg of a mass of the subject. In another embodiment, the composition or pharmaceutical composition comprises PZQ or R-PZQ at a dosage less man 100, 80, 60, SO, 30, 20, 10, 5, or 1 mg per kg of a mass of the subject. In some embodiment, the composition or

pharmaceutical composition comprises PZQ or R-PZQ at a dosage from about 20 to about 60 mg per kg of a mass of the subject.

[0122] The dosage of Schisandra chinensis extract is at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg'kg of the mass of the subject. In some embodiments, the dosage of Schisandra chinensis is between about 1 and about 200, about 200 and about 400, about 400 and about 600, about 600 and about 800, or about 800 and about 1,000 mg of Schisandra chinensis extracts per kg of a mass of the subject.

[0123] In one aspect of the invention, administration of the pharmaceutical composition as described herein is pulsatile. In one embodiment, the composition or the pharmaceutical composition is administered every 1 hour to every 24 hours, for example, every 1 hour, 2 hours, 3 hours, 4 hours, S hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, IS hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In one embodiment, the composition or the pharmaceutical composition is administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days.

[0124] The Schisandra chinettsis extract comprises Schisandrin A, Schisandrin B,

Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A. Thus, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A at a dosage at least 0.1 mg, I mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, SO mg, 70 mg, 100 mg, ISO mg, 200 mg, 2S0 mg, 500 mg, 1,000 mg, 2,000 mg, 5,000 mg, or 10,000 mg per kg of the mass of the subject.

[0125] In another embodiment, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and/or

Schisantherin A at a dosage between about 1 mg and about 200 mg, about 200 mg and about 400 mg, about 400 mg and about 600 mg, about 600 mg and about 800 mg, or about 800 mg and about 1 ,000 mg per kg of a mass of the subject. In some embodiments, the composition or pharmaceutical composition comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and/or Schisantherin A at a dosage between about 1 mg and about 10,000 mg, about 10 mgand about 7,000 mg, about 100 mg and about 5,000 mg, about 200 mg and about 3,000 mg, about 500 mg and about 2,000 mg, or about 700 mg and about 1 ,500 mg per kg of a mass of the subject.

[0126] In one aspect of the invention, doses of the pharmaceutical composition are administered in a pulsatile manner for a period of time sufficient to have an anti-parasitic effect (e.g., to reduce or inhibit the disease caused by parasite). In one embodiment, the period of time is between about 1 day and about 10 days. For example, the period of time may be I day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days.

[0127] A variety of administration routes are available. The pharmaceutical composition of the invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active ingredients without causing clinically unacceptable adverse effects.

[0128] Modes of administration include oral, rectal, topical, nasal, intradermal, or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous or intramuscular routes are not particularly suitable for long-term therapy and prophylaxis. They could, however, be preferred in emergency situations. Oral administration will be preferred for prophylactic treatment because of the convenience to the patient as well as the dosing schedule.

[0129] Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active agent(s). Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir, or emulsion.

[0130] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions, or suspensions, including saline, and buffered media. Parenteral vehicles include sodium chloride solution. Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. Lower doses will result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.

[0131] Other delivery systems can include time-release, delayed release, or sustained release delivery systems. Such systems can avoid repeated administrations of the

pharmaceutical composition of this invention, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly (lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non- polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di-„ and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.

[0132] In one embodiment, the pharmaceutical composition is administered in a time- release, delayed release or sustained release delivery system. In one embodiment, the time- release, delayed release, or sustained release delivery system comprising the pharmaceutical composition of the invention is inserted directly into the tumor.

[0133] When administered, the pharmaceutical preparations of the invention are applied in pharmaccutically-acccptablc amounts and in pharmaccutically-acccptably compositions. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and, optionally, other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutical ly-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts.

Methods of Treatment

[0134] The invention also provides a method for treating and/or preventing a parasitic disease in a subject, comprising administering to the subject an effective amount of PZQ or R-PZQ and an effective amount of an extract from Schisandra chinensis. In one

embodiment, the extract from Schisandra chinensis comprises a compound isolated from Schisandra chinensis. In another embodiment, the compound originally isolated from

Schisandra chinensis comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or the combination thereof.

[0135] The parasite diseases that are susceptible to the methods of this disclosure include, but are not limited to, hydatid disease, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, fasciolopsiasis, or the gastrointestinal infection caused by tapeworms, including Pipy/idium caniinim or Taenia taeniaeformis. In another embodiment, the parasitic disease comprises toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis. lymphatic filariasis, onchocerciasis, dracunculiasis.

ascariasis, trichuriasis, stronglyoidiasis, trichostrongyliasts, trichomoniasis, cestodiasis, or the combination thereof. In another embodiment, the parasite disease is a human parasite disease, which includes, hut is not limited to, tapeworm-tapeworm infection,

diphyllobothriasis - tapeworm. Echinococcosis - tapeworm, Hymenolepiasis, Beef tapeworm, C ysticercosis-Poik tapeworm, Bertielliasis, Sparganosis, C 'lonorchiasis. Lancet liver fluke, Liver fluke— Fasciolosis, Fasciolopsiasis— intestinal fluke, Metagonimiasis— intestinal fluke, Metorchiasis, Chinese liver fluke, Paragonimiasis, lung fluke,

Schistosomiasis bilharzia, bilharziosis or snail fever (all types), intestinal schistosomiasis, urinary schistosomiasis. Schistosomiasis by Schistosoma japonicnm, Asian intestinal schistosomiasis. Swimmer's itch, Ancylosiomiasis/Hookworm, Angiostrongyliasis,

Anisakiasis, Roundworm— Parasitic pneumonia, Roundworm— Baylisascariasis,

Roundworm-lymphatic filariasis, Dioctophyme renalis infection, Guinea worm—

Dracunculiasis, Pinworm— /i/j terohiasis, Gnathosiomiasis, Halicephalohiasis, Loa loa filariasis, Calabar swellings, Mansonelliasis, filariasis, River blindness, onchocerciasis, Slrongy/oidiasis-Parssitic pneumonia, Thelaziasis, Toxocariasis, Trichinosis, Whipworm, Klephuntiasis - Lymphatic filariasis, Acunihocephuliasis, Halzoun syndrome. Myiasis, Screwworm, Cochliomyia, Chigoe flea. Bedbug, Human botfly. Head louse-Pediculosis, Body louse-Pedictdosis, Crab louse-Pediculosis, OemodeK-Demodicosis, Scabies,

"Chiggers" (Tromhiculidaey-Tromhiculosis, Flea, Siphonaptera, Tick, Granulomatous amoebic encephalitis (eye infection), Acanihamoeha keratitis. Granulomatous amoebic encephalitis (skin infection). Babesiosis, Balantidiasis, Blastocystosis, C 'ryptosporidiosis, Cyclosporiasis, Dientamoehiasis, Amochiasis, Giardiasis, Isosporiasis, Leishmaniasis, Primary amoebic meningoencephalitis (PAM), Malaria, Rhinosporidiosis, Sarcocystosis, Toxoplasmosis (Acute and Latent), Trichomoniasis, Sleeping sickness, and Chagas disease.

[0136] In one embodiment, the parasitic disease is schistosomiasis. In another

embodiment, the parasitic disease is caused by blood fluke.

[0137] In another embodiment, the parasitic diseases include any conditions caused by parasites. The parasites include, but are not limited to, endoparasites and ectoparasites. Non- limiting examples of parasites include Rafflesia, Cuscuta, Acanthocephala, Ascariasis (roundworms), Cestoda (tapeworms) including: Taenia saginata (human beef tapeworm), Taenia solium (human pork tapeworm). Diphyllobothrium latum (fish tapeworm) and

Echinococcosis (hydatid tapeworm), Clonorchis sinensis (the Chinese liver fluke),

Dracunculus medinensis (Guinea worm), Enterobhts vermicidaris (pinworm), Filariasis, Hookworm, Loa loa, Onchocerciasis (river blindness), Schistosomiasis, Sirongyloides stercorulis. Tapeworm, Toxocara can is (dog roundworm), Trichinella, Whipworm,

Entamoeba histolytica. Entamoeba coli, Acanthamoeba, Balamuthia mandrillaris, Giardia, Cyc/ospora cayetanensis, Cryptosporidium, Toxoplasma gondii, Leishmania (L. tropica, L. donovani, and L. Mexicana), Plasmodium, Babesia, Gymnosporangium and other rusts, Pyrenophora teres, Cordyceps, Arthropoda, Acari, Varroa destructor, Cymothoa exigua, Bed bugs, C 'nlicidae (mosquitoes), ( 'alyptra (vampire moths), Hippoboscoidea, Tsetse fly, IJpoptena, Melophagus ovinus (sheep keds) and relatives, Oestridae (bot flies), Human botfly, Phlebotominae (sand flies), Phthiraptera (Lice), Body louse, Crab louse. Head louse, Siphonaptera (fleas), Tabanidae (horse flies), Tantulocarida, Triatominae, Pea crab,

Sacculina, Annelids, Hirudinea (some leeches), Monogeneans, Calydiscoides euzetl,

Lethacotyle vera, Protocotyle euzetmaillardi, Pseudorhabdosynochtis spp., Mollusks.

Cancel laria cooper ii, Glochidium, Pyramidellidae, Chordates, Cookiecutter shark, Candiru (vampire fish of Brazil, a facultative parasite), lampreys, Deep sea anglers. False cleanerfish, Hood mockingbird, Oxpeckers, Snubnosed eel, Vampire bat, Vampire finch, Mistletoe, certain orchids. Com smut, and certain mushrooms.

[0138] Given the enzymatic activity of CYP against PZQ, the methods of this disclosure further comprise administering to a subject an effective amount of a CYP inhibitor. A CYP inhibitor includes but is not limited to a CYP I A2 inhibitor, a CYP2B6 inhibitor, a CYP2C8 inhibitor, a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor, a CYP2E1 inhibitor, or a CYP3A4 inhibitor.

[0139] Non-limiting examples of CYP 1 A2 inhibitors includes Amiodarone. Atazanavir. Cimetidine, Ciprofloxacin, Citalopram, Clarithromycin, Diltiazem, Enoxacin, Erythromycin, Estradiol, Fluvoxamine, Interferon, Isoniazid Ketoconazole, Methoxsalen, Mibefradil, Tegaserod.

[0140] Non-limiting examples of CYP2B6 inhibitors include Thiopeta and Ticlodipine.

[0141] Non-limiting examples of CYP2C8 inhibitors include Anastrozole, Ezetimibe, Gemfibrozil, Montelukast, Nicardipine, Sulfinpyrazone, and Trimethoprim.

[0142] Non-limiting examples of CYP2C9 inhibitors include Amiodarone, Atazanavir, Cimetidine, Clopidogrel, Cotrimoxazole, Delavirdine, Disulfiram, Efavirenz, Fenofibrate, Fluconazole, Fluorouracil, Fluoxetine, Fluvastatin, Fluvoxamine, Gemfibrozil, Imatinib, Isoniazid, Itraconazole, Ketoconazole, Leflunomide, Lovastatin, Methoxsalen,

Metronidazole, Mexiletine, Modafinil, Nalidixic acid, Norethindrone, Norfloxacin,

Omeprazole, Contraceptives, Paroxetine, Phenylbutazone, Probenecid, Sertraline,

Sulfamethoxazole, Sulfaphenazole, Sulfonamides, Tacrine, Teniposide, Ticlodipine, Tipranavir, Troleandomycin, Voriconazole, Zafirlukast, Zileutin, or extracts from Allium sativum, Bergamottin, Harpagophytum procumbens, and Lycium barbarum.

[0143] Non-limiting examples of CYP2C 19 inhibitors include Cimetidine, Citalopram, Delavirdine, Efavirenz, Felbamate, Fluconazole, Fluoxetine, Fluvastatin, Fluvoxamine, Indomethacin, Isoniazid, Ketoconazole. Lansoprazole, Modafinil. Omperazole,

Oxcarbazepine, Probenecid, Ticlodipine, Topiramate, and extracts from Allium sativum and Harpagophytum pracumheiis.

[0144] Non-limiting examples of CYP2D6 inhibitors include Abiraterone, Amiodarone, Asenapine, Buproprion, Celecoxib, Chloroquine, Chlorpheniramine, Chlorpromazine, Cimetidine, Cinacalcet, Citalopram. Clemastine, Clomipramine, Cocaine, Darifenacin, Desipramine, Diphenhydramine, Doxepin, Doxorubicin, Duloxetine, Escitalopram, Febuxostat, Fluoxetine, Fluphenazine, Halofantrine. Haloperidol, Hydroxychloroquine, Hydroxyzine, Imatinib, Levomepromazine, Methadone, Metoclopramide, Mibefradil, Midodrine, Moclobemide, Nefazodone, Norfluoxetine, Paroxetine, Perphenazine,

Tripelennamine, and extracts from Alpinia glanga, Alstonia scholaris, Andrttgraphis paniculata, Calharanthus roseus, Cimicifuga racemose, Cinnamomum burmannii,

Eleutherococcus senticoccus, Gycyrrhiza glabra, Hydrastis Canadensis, Melaleuca leucadendron, Panax ginseng, Panax quinquefolius. Piper nigrum, Punica granalum, Rheum palmatum, San/alum album, Sirychnos ligustrina, Syzygium aromaticum, Tinospora crispa, and Zingiber aromaticum.

[0145] Non-limiting examples of CYP2E1 inhibitors include Disulfiram and extracts from Piper methysticum.

[0146] Non-limiting examples of CYP3A4 inhibitors include Amiodarone, Amprenavir, Aprcpitant, Atazanavir, Boccprcvir, Cimctidinc, Ciprofloxacin, Clarithromycin,

Cyclosporine, Danazol, Delavirdine, Diltiazem, Efaviienz, Erythromycin, Ethinyl Estradiol, Ezetimibe, Fluconazole, Fluoxetine, Fluvoxamine, Gestodene, Imatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Methylprednisolone, Mibefradil, Miconazole, Mifepristone, Nefazodone, Nelfinavir, Nicardipine, Nifedipine, Norethindrone, Norfloxacin, Norfluoxetine, Oxiconazole, Posaconazole, Prednisone, Quinine, Ranolazine, Ritonavir, Roxithromycin, Saquinavir, Sertraline, Telaprevir, Telithromycin, Troleandomycin, Verapamil, Voriconazole, Zafirlukast, Zileutin, and extracts from Allium sativum, Ammi visnaga, Azadirachta indica, Cimicifuga racemose, Harpagphytum. procumbens, Hydrastis canadensis, Naringenin, Panax ginseng, Panax quinquefolius, Sirychnos ligustrina, and Uncaria tomentosa.

[0147] In another embodiment, the methods of this disclosure further comprise

administering an effective amount of additional anti-parasite medications. The suitable anti- parasite medications include, but are not limited to, tinidazole, metronidazole, melarsoprol, cflomithinc, rifampin, amphotericin B, pentamidine, sodium stibogluconate, meglumine antimoniate, fluconazole, artesunate, quinine, quinidine, chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, doxycycline, clindamycin, paromomycin, atovaquone, nitazoxanide, azithromycin, fumagillin, paromomycin, diloxanide, secnidazole, omidazole. iodoquinol, diloxanide furoate, clindamycin, atovaquone, azithromycin, diminazen, trypan blue, oxamniquinine, niclosamide, albendazole, mebendazole, thiabendazole, pyrantel, diethylcarbamazine, ivermectin, selamectin, doramectin, and abamectin. In another embodiment, the additional anti-parasitic medications comprise a drug for treating schistomiasis, including, but not limited to, amoscanate, arteether, artemether, chloroxylenol, hycanthone, lucanthone, meclonazepam, niridazole, oltipraz, and oxamniquine. In another embodiment, the methods further comprise administering to the subject an effective amount of an antibacterial composition, an antifungal composition, an antiparasitic composition, or a combination thereof.

[0148] In one embodiment, PZQ and/or R-PZQ and the extract from Schisandra chinensis are administered separately. In one embodiment, PZQ (including S-PZQ and R-PZQ) and the extract from Schisandra chinensis are administered simultaneously. In one embodiment. PZQ (including S-PZQ and R-PZQ) and the extract from Schisandra chinensis are administered sequentially.

[0149] The bioavailability of PZQ (including S-PZQ and R-PZQ) after administration can be increased in presence of the extract of Schisandra chinensis. In one embodiment, PZQ (and/or R-PZQ) is administered prior to administration of the extract from Schisandra chinensis. In one embodiment, the PZQ (and/or R-PZQ) is administered after administration of the extract from Schisandra chinensis. In one embodiment, PZQ (and/or R-PZQ) is administered before, during, and/or after administration of the extract from Schisandra chinensis.

[0150] In some embodiments, the PZQ and/or R-PZQ is administered between one minute and 24 hours prior to administration of the extract of Schisandra chinensis. In some embodiments, the PZQ and/or R-PZQ is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the extract of Schisandra chinensis.

[0151] In some embodiments, the PZQ and/or R-PZQ is administered between one minute and 24 hours after administration of the extract of Schisandra chinensis. In some embodiments, the PZQ and/or R-PZQ is administered less than 1 min, 2 min. S min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the extract of Schisandra chinensis.

[0152] In some embodiments, the extract of Schisandra chinensis is administered for a period of time or in an amount sufficient to reduce or attenuate the enzymatic activity of the enzyme against PZQ (e.g., R-PZQ) such that the extract of Schisandra chinensis has an anti- enzymatic activity to increase the bioavailability of PZQ and/or R-PZQ in the subject.

Schisandra chinensis extracts comprise Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, or Schisantherin A.

[0153] In one embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered intravenously, subcutaneously, orally, or intraperitoneally. In a preferred embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered proximal to (e.g., near or within the same body cavity as) the organ(s) and/or tissue(s) infected by parasites. In one embodiment, the Schisandra chinensis extract or PZQ (e.g., R- PZQ) is administered directly into a blood vessel feeding the infected organ(s) and/or tissue(s). In one embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered systemically. In a further embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered by microcatheter, an implanted device, or an implanted dosage form.

[0154] In one embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered in a continuous manner for a defined period. In another embodiment, the extract of Schisandra chinensis or PZQ (e.g., R-PZQ) is administered in a pulsatile manner. For example, the extract of Schisandra chinensis may be administered intermittently over a period of time.

[0155] The parasitic diseases that are susceptible to the treatment of the compositions and methods described herein include, but not limited to: dysentery, Diarrhea Giardiasis, diarrhea, cryptosporidiosis, trichomoniasis, malaria, toxoplasmosis, Pneumonia, Chagas disease, sleeping sickness, kala-azar, diphyllobothriasis, hydatid cyst, taeniasis, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, hookworm, ascariasis, pinworm infection. strongyloidiasis, trichinosis, whipworm, dracunculiasis, loiasis, onchocerciasis, filariasis. visceral larva migrans, pediculosis, myiasis, scabies, tick paralysis, and spider bites. In one embodiment, the parasitic disease comprises hydatid disease, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, or fasciolopsiasis.

[0156] In some embodiment, the parasitic disease comprises the gastrointestinal infections caused by tapeworms, including Dipylidium caninum or Taenia taeniaeformis. In another embodiment, the parasitic disease comprises schistosomiasis.

Methods of increasing biostability or therapeutic efficacy

[0157] In another aspect, the invention relates to methods of increasing the biostability or therapeutic efficacy of PZQ in a subject. As noted above, increased the biostability or in vivo concentration of PZQ (<?.#., R-PZQ) can enhance the therapeutic efficacy of a pharmaceutical composition comprising PZQ. In one embodiment, the in vivo concentration of PZQ comprises a blood or tissues concentration. The method of increasing the biostability or therapeutic efficacy of PZQ in a subject comprises administering to the subject an effective amount of a composition comprising an extract from Schisandra chinettsis. In one

embodiment, the extracts from Schisandra chinemis comprise a compound isolated from Schisandra chinemis. In another embodiment, the compound isolated from Schisandra chinemis includes Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or the combination thereof.

[0158] PZQ, known as an antihelmintic, can be used for treating diseases or infection caused by parasites, e.g., schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, hydatid disease, and other fluke infections. In this disclosure, however, the therapeutic efficacy of PZQ is not limited to treating parasitic diseases. Unexpectedly, the Schisandra chinemis extract can increase the bioavailability, level, concentration, or other pharmacokinetic parameters of PZQ in a subject once administered. Thus, the present disclosure provides a method of enhancing the therapeutic use or medical efficacy of PZQ (or R-PZQ), which includes treating parasitic diseases.

[0159] Also given the inhibitory function of Schisandra chinemis extract against CYP enzymes, this disclosure also provides a method or a composition of inhibiting enzymatic activity of CYP enzyme or increasing the bioavailability or therapeutic efficacy of a substrate of the CYP enzyme. Drug metabolism via the CYP system has emerged as an important determinant in the occurrence of several drug-drug interactions, which results in drug toxicities, reduced pharmacological effect, and adverse drug reactions. The efficacy of a drug can be dramatically affected by its metabolism in the body. For drugs that are rapidly metabolized it can be difficult to maintain an effective therapeutic dose in the body, and the drug often must be given more frequently, in higher dose, and/or be administered in a sustained release formulation.

[0160] Among various types of CYP enzymes, CYP1 A2, CYP2C 19, CYP2C9, CYP2D6, CYP2E I , and CYP3 A4 have particularly notable roles in drug metabolism. Inactivation of a significant number of administered drugs is due to extensive metabolism by the CYP3A4 isozyme in the gastrointestinal tract. Thus, by inhibiting the bioavailability or enzymatic activity of CYP. the present disclosure also provides a method of increasing the therapeutic efficacy or in-vivn level of a drug, protein, or any bioactive agent that is a subject of CYP enzymes. The method comprises administering to the subject an effective amount of a composition comprising an extract from Schisaudra chinensis. Administration of the composition comprising the extract from Schisaudra chinensis prevents the degradation of the CYP substrate and promotes pharmacokinetic properties of the substrate when it acts as a therapeutic agent.

[0161] Non-limiting examples of CYP3A4 substrates include, but are not limited to, ciclosporin, tacrolimus, sirolimus, docetaxel, tamoxifen, Paclitaxel, cyclophosphamide, doxorubicin, Erlotinib, etoposide, ifosfamide, teniposide, vinblastine, vincristine, vindesine, imatinib, irinotecan, sorafenib, sunitinib, vemurafenib, temsirolimus, anastrozole, gefitinib, Ketoconazole, itraconazole, macrolides, clarithromycin, erythromycin, telithromycin, dapsone, tricyclic antidepressants, amitriptyline, clomipramine, imipramine, cyclobenzaprine, citalopram, norfluoxetine, sertralinesome, mirtazapine, nefazodone, reboxetine, venlafaxine, trazodone, buspirone, haloperidol, aripiprazole, risperidone, ziprasidone, pimozide, quetiapine, alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, methadone, levacetylmethadol, tramadol, benzodiazepines, alprazolam, midazolam, triazolam, diazepam, zopiclone, zaleplon, Zolpidem, donepezil, atorvastatin, lovastatin, simvastatin, cerivastalin, diltiazem. felodipine, nifedipine, verapamil, amlodipine, lercanidipine, nitrendipine, nisoldipine, amiodarone, dronedarone, quinidine, sildenafil, tadalafil, kinins, finasteride, estradiol, progesterone, ethinylestradiol, testosterone, toremifene, bicalutamide, terfenadine, astemizole, chlorphenamine. Indinavir, ritonavir. Saquinavir, nelfinavir, nevirapine, budesonide, hydrocortisone, dexamethasone, cisapride, aprepitant, catTeine, cocaine, cilostazol, dextromethorphan, domperidone, eplerenone, lidocaine, ondansetron, propranolol, salmeterol, warfarin, clopidogrel, omeprazole, nateglinide, methoxetamine, and montelukast.

[0162] Non-limiting examples of CYP2D6 substrates include atomoxetine, desipramine, dextromethoφhan , eliglustat, nebivolol, nortriptyline, perphenazine, tolterodine, venlafaxine, amitriptyline, encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, and trimipramine.

[0163] Non-limiting examples of C YP2C 19 substrates include S-mephenytoin, omeprazole, diazepam, lansoprazole, rabeprazole, and voriconazole.

[0164] Non-limiting examples of CYP2C9 substrates include celecoxib, glimepiride, phcnytoin, tolbutamide, and warfarin.

[0165] Non-limiting examples of CYP2C8 substrates include repaglinide, montelukast, pioglitazone, and rosiglitazone.

[0166] Non-limiting examples of CYP2B6 substrates include bupropion and efavirenz.

[0167] Non-limiting examples of CYP 1 A2 substrates include alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidine, clozapine,

pirfenidone, and ramosetron.

[0168] Additional information about CYP enzyme substrates that are applicable to this invention can be found at PCT/US2009/057183, which incorporated by reference in its entirety.

[0169] In one embodiment, the PZQ and the extract from Schisandra chinensis are administered separately, simultaneously, and/or sequentially. In another embodiment, the extract from Schisandra chinensis is administered before, during, or after administration of the PZQ. In another embodiment, the extract from Schisandra chinensis is administered less than 1 min, 2 min, S min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the PZQ. In another embodiment, the extract from Schisandra chhiensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, I hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the PZQ.

[0170] In one embodiment, the substrate of a CYP enzyme and the extract from Schisandra chinensis are administered separately, simultaneously, and/or sequentially. In another embodiment, the extract from Schisandra chinensis is administered before, during, or after administration of the substrate. In another embodiment, the extract from Schisandra chinensis is administered less than 1 min, 2 min. 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, I day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the substrate. In another embodiment, the extract from Schisandra chinensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the substrate.

[0171] The extract from Schisandra chinensis can be administered in various methods. In one embodiment, the extract of Schisandra chinensis is administered intravenously, subcutaneously, orally, or intraperitoneally. In another embodiment, the extract from

Schisandra chinensis comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or a combination thereof. In another embodiment, the extract from Schisandra chinensis comprises Schisandrin A. In another embodiment, the extract from Schisandra chinensis is at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, 5,000 mg/kg of the mass of the subject.

Kit of Parts

[0172] In one aspect, this invention relates to a kit of parts for treatment of a parasitic disease, the kit comprising PZQ (e.g., R-PZQ) and the extracts from Schisandra chinensis. [0173] In one embodiment is provided a kit of parts for treatment of a parasitic disease in a patient, the kit comprising a therapeutically effective amount of PZQ (e.g., R-PZQ) and a therapeutically effective amount of the extracts from Schisandra chinensis.

[0174] In one embodiment, the extracts from Schisandra chinensis comprise a compound isolated from Schisandra chinensis. In another embodiment, the compound isolated from Schisandra chinensis comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, and Schisantherin A.

|0I7S| In one embodiment, the parasitic disease is susceptible to being treated with PZQ (e.g., R-PZQ). In another embodiment, the parasitic disease comprises hydatid disease, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, or fasciolopsiasis. In a further embodiment, the parasitic disease comprises the gastrointestinal infections caused by a tapeworm. In one embodiment, the tapeworm comprises Taenia solium, Taenia saginaia, Hymenolepis nana, Dipylidium caninum, and Taenia laeniaeformis. In another embodiment, the tapeworm comprises Dipylidium caninum or Taenia laeniaeformis.

[0176] In one embodiment, the kit further comprises instructions for treating the parasitic disease. In one embodiment, the kit of parts comprises instructions for dosing and/or administration of the pharmaceutic composition of this invention.

WORKING EXAMPLES

[0177] The following examples are for illustrative purposes only and should not be interpreted as limitations of the claimed invention. There are a variety of alternative techniques and procedures available to those of skill in the art which would similarly permit one to successfully perform the intended invention.

Examples

Animals:

[0178] Male Sprague-Dawley rats (200-250 g) were kept in a room at 22-24 °C with a light-dark cycle of 12/12 hours ( 12-hour light followed by 12-hour dark) and 55%-60% relative humidity. The rats had free access to standard rodent chow and clean tap water. Before the experiments, the animals were fasted for 10-14 hours. The animal procedures were done in accordance with the Regulations of Experimental Animal Administration issued by the Ministry of Science and Technology of the People's Republic of China

(http://www.most.gov.cnV

Drugs

[0179] The solutions of R-PZQ (99.6%) and Schisandrin A (95%), freshly made, were prepared in 3% sodium carboxymethyl cellulose (CMC-Na, 300-800) for the in-vivo study.

[0180] To study the in vivu effects of Schisandrin A on the pharmacokinetics of R-PZQ, the rats were first deprived of food for 10-14 hours before the experiment, and were randomly divided into eight groups (group 1, group 2, group 3, group 4, group 5, group 6, group 7, and group 8) with 6 rats in each group. The rats were administered orally with Schisandrin A with a dose of 0, 10, 20, 40, 80, 100, 160, and 200 mg/kg respectively. 5 min after the administration of Schisandrin A, all rats were given orally R-PZQ at the dose of 31 mg/kg. Blood sample were collected using heparinized tubes through the jugular vein at 5 min, IS min, 0.S h, I h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h respectively and centrifuged at 4 °C and 8,000 g for 6 minutes, and were then stored at -80 °C for later analysis.

Quantification of R-PZQ by LC-MS/MS

[0181] Plasma homogenates from the rats were pretreated with 5-fold volume of methanol containing 200 ng/ml tolbutamide to precipitate proteins, and were then centrifuged at 4 °C, 14,000 g for 5 min. The supernatant from the centrifuged plasma was injected into LC- MS/MS for analysis. A TQ5500 mass spectrometer (Applied Biosystems) and ACQUITY UPLC system (Waters) were used. R-PZQ and tolbutamide (internal standard, IS) were eluted from an ACQUITY UPLC BEH C 18 1.7μιπ (SO mm*2.10 mm) column using a mobile phase modifier (mobile-phase A: 99.9% water with 0.1% formic acid, mobile-phase B:

99.9% acetonitrile with 0.1% formic acid). Flow rate was 0.5 ml/min. Pharmacokinetic parameters were calculated using Analyst® 1.6.2 Software (Applied Biosystems). All results were expressed as mean ± S.D. [0182] Fig. 3 shows the mean R-PZQ blood concentrations versus time curves after oral administration of R-PZQ with or without Schisandrin A. The major pharmacokinetic parameters of R-PZQ are listed in Table 1, which shows that, after the oral co-administration of different doses of Schisandrin A to rats, the whole blood concentrations (AUC) of R-PZQ increased by 160% and the maximum plasma concentration (Cam) R-PZQ increased by 68% compared to the group without Schisandrin A. Meanwhile, the clearance of R-PZQ was reduced by the oral co-administration of Schisandrin A, which was evidenced by increasing the mean residence time (MRT) by 43%.

Table 1. Pharmacokinetic parameters of R-PZQ after a single oral dose of R-PZQ (31 mg/kg) to rats with and without a different dose of Schisandrin A.

[0183] The disclosure illustratively described herein can suitably be practiced in the absence of any element or elements, or limitation or limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," and "containing," shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

[0184] Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement, and variation of the disclosure embodied therein herein disclosed can be resorted to by those skilled in the art, and that such modifications, improvements, and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

[0185] The disclosure has been described broadly and genetically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0186] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0187] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

Claims

WHAT IS CLAIMED IS:

1. Λ pharmaceutical composition for treating a parasitic disease, comprising

Praziquantel ("PZQ") and an extract from Schisandra chinensis.

2. The pharmaceutical composition of claim 1 , the extract from Schisanc/ra chinensis comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A, Schizandrol B, Schisantherin A, or a combination thereof.

3. The pharmaceutical composition of claim 1 or 2. wherein the PZQ comprises an R-PZQ or an S-PZQ.

4. The pharmaceutical composition of claim 3, wherein the R-PZQ comprises an R- PZQ compound or its derivative or analogue.

5. The pharmaceutical composition of any one of claims 1-4, wherein the

pharmaceutical composition comprises about 1 to about 1,000, about 10 to about 500, about 20 to about 250. about 30 to about 200, or about 40 to about 100 mg of PZQ per kg of a mass of a subject to be administered with the pharmaceutical composition.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition comprises about 1 to about 1,000, about 10 to about 500, about 20 to about 250, about 30 to about 200, or about 40 to about 100 mg of R-PZQ per kg of a mass of a subject to be administered with the pharmaceutical composition.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises about 40 to about 100 mg of R-PZQ per kg of the mass of the subject.

8. The pharmaceutical composition of any one of claims 1-7, wherein the extract from Schisandra chinensis is at least 0.1 mg/kg, I mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject.

9. The pharmaceutical composition of any one of claims 1-8, wherein the

pharmaceutical composition comprises Schisandrin A at a dosage of at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject.

10. The pharmaceutical composition of any one of claims 1-9. wherein the

pharmaceutical composition comprises Schisandrin A at a dosage of at least 200 mg/kg of the mass of the subject.

1 1. The pharmaceutical composition of any one of claims 1-10, the mass ratio between the PZQ and the extract from Schisandra chinensis is at least 1 : 10,000, 1 : 1 ,000, 1: 100, 1 : 10, 1 :5, 1 :3, 1:2, 1 :1, 2: 1, 3: 1, 5: 1, 10:1, 100:1, 1, 000; 1, or 10,000:1.

12. The pharmaceutical composition of any one of claims 1-11, the mass ratio is at least 1 :3; 1 :5, 1 : 10, or 1 : 100.

13. The pharmaceutical composition of any one of claims 1-12, wherein the parasitic disease comprises hydatid disease, cysticercosis, schistosomiasis, clonorchiasis,

paragonimiasis, fasciolopsiasis, or combination thereof.

14. The pharmaceutical composition of any one of claims 1-13, wherein the parasitic disease is schistosomiasis.

15. The pharmaceutical composition of any one of claims 1-14, further comprises an antibacterial composition, an antifungal composition, an anti-parasite composition or medication, or a combination thereof.

16. The pharmaceutical composition of any one of claims 1-15. further comprises a Cytochrome P450 (CYP) enzyme inhibitor.

17. The pharmaceutical composition of any one of claims 1-16, further comprising a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of any one of claims 1-17, where the

pharmaceutical composition is in the form of an oral suspension, a tablet, a spray, or a capsule, a lotion, a gel, or a foam.

19. The pharmaceutical composition of any one of claims 1-18. further comprising a binding agent, a flavor agent, a lubricating agent, a flow agent, a disintegration agent, a delay agent, and combinations thereof.

20. A method of treating a parasitic disease in a subject, comprising administering to the subject an effective amount of a PZQ and an effective amount of an extract from

Schisandra chinensis.

21. The method of claim 20, wherein the PZQ comprises an R-PZQ or an S-PZQ.

22. The method of claim 21 , wherein the R-PZQ comprises an R-PZQ compound or its derivative or analogue.

23. The method of any one of claims 20-22, wherein the extract from Schisandra chinensis comprises Schisandrin A, Schisandrin B, Schisandrin C, Schizandrol A,

Schizandrol B, Schisantherin A, or a combination thereof.

24. The method of any one of claims 20-23, wherein the parasitic disease is susceptible to being treated with PZQ.

25. The method of any one of claims 20-24, wherein the parasitic disease is susceptible to being treated with R-PZQ.

26. The method of any one of claims 20-25, wherein the parasitic disease comprises hydatid disease, cysticercosis, schistosomiasis, clonorchiasis, paragonimiasis, fasciolopsiasis, or a combination thereof

27. The method of any one of claims 20-26, wherein the parasitic disease is a gastrointestinal infection caused by a tapeworm, said tapeworm comprising Dipylidium canimtm or Taenia laeniaeformis.

28. The method of any one of claims 20-27, wherein the parasitic disease is schistosomiasis.

29. The method of any one of claims 20-28, wherein the PZQ is administered at a dosage of about 1 mg to about 1 ,000 mg, about 10 mg to about 500 mg, about 20 mg to about 250 mg, about 30 mg to about 200 mg, or about 40 mg to about 100 mg per kg of a mass of the subject.

30. The method of any one of claims 21 -29, wherein the R-PZQ is administered at a dosage of about 1 mg to about 1,000 mg, about 10 mg to about 500 mg. about 20 mg to about 250 mg, about 30 mg to about 200 mg, or about 40 mg to about 100 mg per kg of the mass of the subject.

31. The method of claim 30, wherein the R-PZQ is administered at a dosage of about 40 and about 100 mg per kg of the mass of the subject.

32. The method of any one of claims 20-31, wherein the extract from Schisandra chinensis is administered at a dosage of at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject.

33. The method of claim 23, wherein the Schisandrin A is administered at a dosage of least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject.

34. The method of claim 33, wherein the Schisandrin A is administered at a dosage of at least 200 mg/kg of the mass of the subject.

35. The method of any one of claims 20-34, wherein the PZQ and the extract from Schisandra chinensis are administered separately.

36. The method of any one of claims 20-34, wherein the PZQ and the extract from Schisandra chinensis are administered simultaneously.

37. The method of any one of claims 20-34, wherein the PZQ and the extract from Schisandra chinensis arc administered sequentially.

38. The method of any one of claims 20-34, wherein the PZQ is administered before, during, or after administration of the extract from Schisandra chinensis.

39. The method of any one of claims 20-34, wherein the PZQ is administered less than 1 min, 2 min, S min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the extract of Schisandra chinensis.

40. The method of any one of claims 20-34, wherein the PZQ is administered less than 1 min, 2 min, S min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the extract of Schisandra chinensis.

41. The method of any one of claims 20-40, the extract of Schisandra chinensis and/or the PZQ is administered intravenously.

42. The method of any one of claims 20-40, the extract of Schisandra chinensis and/or the PZQ is administered subcutaneously.

43. The method of any one of claims 20-40, the extract of Schisandra chinensis and/or the PZQ is administered orally.

44. The method of any one of claims 20-40, the extract of Schisandra chinensis and/or the PZQ is administered intraperitoneally.

45. The method of any one of claims 20-44, further comprising administering to the subject an antibacterial composition, an antifungal composition, an anti-parasite composition or medication, or a combination thereof.

46. The method of any one of claims 20-45, further comprising administering to the subject a CYP enzyme inhibitor.

47. The method of any one of claims 20-46, wherein the subject is a mammal.

48. The method of any one of claims 20-47, wherein the subject is a human.

49. A method of increasing biostability or therapeutic efficacy of PZQ in a subject, comprising administering to the subject an effective amount of a composition comprising an extract from Schisandra chinensis.

50. The method of claim 49, wherein the PZQ and the extract from Schisandra chinensis are administered separately, simultaneously, and/or sequentially.

51. The method of claim 49 or 50, wherein the extract from Schisandra chinensis is administered before, during, or after administration of the PZQ.

52. The method of any one of claims 49-51, wherein the extract from Schisandra chinensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the PZQ.

53. The method of any one of claims 49-52, wherein the extract from Schisandra chinensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the PZQ.

54. A method of increasing biostability or therapeutic efficacy of a substrate of a CYP enzyme in a subject, comprising administering to the subject an effective amount of a composition comprising an extract from Schisandra chinensis.

55. The method of claim 54, wherein the substrate and the extract from Schisandra chinensis are administered separately, simultaneously, and/or sequentially.

56. The method of claim 54 or 55, wherein the extract from Schisandra chinensis is administered before, during, or after administration of the substrate.

57. The method of any one of claims 54-56, wherein the extract from Schisandra chinensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the substrate.

58. The method of any one of claims 54-57, wherein the extract from Schisandra chinensis is administered less than 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 5 hr, 12 hr, 24 hr, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to administration of the substrate.

59. The method of any one of claims 49-58, the extract of Schisandra chinensis is administered intravenously, subcutaneously, orally, or intraperitoneally.

60. The method of any one of claims 49-59, the extract from Schisandra chinensis comprises Schisandrin A. Schisandrin B. Schisandrin C. Schizandrol A, Schizandrol B. Schisantherin A, or a combination thereof.

61. The method of any one of claims 49-60, the extract from Schisandra chinensis comprises Schisandrin A.

62. The method of any one of claims 49-61 , wherein the extract from Schisandra chinensis is at least 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 500 mg/kg, 1,000 mg/kg, 2,000 mg/kg, or 5,000 mg/kg of the mass of the subject.