TW201617071A - Artemisinin-based combination therapy for treating viral mediated disease - Google Patents

Abstract

The present invention describes a method of treating individuals suffering from microbial infections, including a viral infection such as Dengue Fever, using an improved Artemisinin Combination Therapy (ACT), known as Tri-ACT. The improved ACT therapy includes administering a combination of three drugs. In one embodiment of the present invention, the method includes administering to an individual a first composition comprising a therapeutically effective amount of an artemether spray sublingually. The individual is then administered a second composition, a therapeutically effective amount of artesunate. A third composition, an effective amount of berberine, or its pharmaceutically acceptable derivatives or salts is then administered to the individual.

Description

Artemisinin-based combination therapy for the treatment of viral-mediated diseases Cross-reference to related applications

According to 37 C.F.R. 1.76, the claim of priority is included in the application form for the application at the same time. Accordingly, the present invention claims priority to U.S. Patent Application Serial No. 13/542,702, filed on Jan. U.S. Patent Application Serial No. 13/542,719, the entire disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in its entirety the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire contents US Patent Application No. 12/ filed on Apr. 22, 2009, entitled "COMBINATIONS OE BERBERINE, ARTEMISININ AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA, TRAVELLERS' DIARRHEA, DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES" </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The name of the Japanese application is "ARTEMISININ-BASED COMBINATION THERAPY FOR TREATING" PARASITIC MEDIATED DISEASE, US Patent Application No. 13/542,719; and filed on February 9, 2011, entitled "COMBINATIONS OF BERBERINE, ARTEMISININ, LOPERAMIDE, AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA, TRAVELLERS' DIARRHEA, US Patent Application No. 13/024,151, to DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES, and the name of the application on February 9, 2011 are "COMBINATIONS OF BERBERINE, ARTEMISININ, LOPERAMIDE, AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA U.S. Patent Application Serial No. 13/024,161, to TRAVELLERS' DIARRHEA, DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES. The present application also claims priority to U.S. Provisional Patent Application Serial No. 61/878,848, filed on Sep. 17, 2013. The content of the above-referenced application is incorporated herein by reference in its entirety.

The present invention relates to microbial therapy, and in particular to a method for treating an individual suffering from a virus-related disease using an improved artemisinin-based therapy, and more particularly to use an improved artemisinin combination therapy (ACT) to treat a disease The method of the individual of Dengue.

Dengue fever is a virus-mediated disease that is most commonly spread by Aedes aegypti by several species of mosquitoes in the Aedes species. Dengue fever is an acute multisystem viral infection that is so dynamic that in very short periods of time, mild cases may turn into severe cases due to increased capillary permeability/vulnerability, resulting in increased plasma leakage, hypotension, Shock and death (if left untreated). According to the World Health Organization (WHO), dengue fever is the fastest growing mosquito-borne virus disease in the world. In the past 50 years, the incidence has increased by 30 times, and it has increasingly expanded geographically to new countries. It is caused by one of four similar RNA viruses of the Elaviviridae family: DEN-1, DEN-2, Den-3, and DEN-4. All four serotypes can lead to complete dengue fever. Infected dengue serotypes can produce a range of clinical conditions ranging from non-specific viral syndrome to severely fatal bleeding disorders. Symptoms of dengue include about 4 to 7 days after a bite, usually a sudden high fever in the range of 104-105 degrees. A characteristic rash similar to the rash seen in measles occurred on several days after the onset of fever. In some cases, the disease progresses to hemorrhagic dengue, resulting in bleeding, low platelet levels, plasma leakage, and dengue shock syndrome.

Dengue fever is the second most important infectious tropical disease after malaria, as more than one-third of the world's population lives in areas at risk of transmission. It is estimated that 200 million individuals are infected with dengue virus each year, 10,000,000 of whom are hospitalized for hemorrhagic dengue, of which about 5% of these cases result in death. Dengue virus infection is endemic in more than 100 tropical countries, including Asia, the Pacific, Africa, Latin America and the Caribbean. When such places tend to have unplanned and uncontrolled urbanization, as well as high poverty rates, increased air travel, lack of effective mosquito control and military deployment to risk areas may lead to outbreaks in more developed countries. In 2009, Florida residents in the United States reported that they did not travel outside the United States to contract dengue fever.

There are no known treatments or vaccines to prevent dengue virus infection. In fact, the most effective measure to prevent the disease is to avoid mosquito bites. Although protective clothing and mosquito irradiation programs theoretically provide protection, there is a need in the art for an easy method of treating individuals suffering from dengue fever.

The present invention describes a therapy for individuals suffering from viral infections based on artemisinin combination therapy (ACT). The present invention describes a method of using a combination of three drugs as compared to most ACT therapies utilizing combined dual drug therapy. In a specific embodiment of the invention, the method comprises administering to the individual a first composition. The first composition comprises a therapeutically effective amount of an artemisinin derivative or a salt thereof, such as an artemether or an artemether spray delivered sublingually. The second composition is then administered to the individual. The second composition comprises a therapeutically effective amount of a second artemisinin derivative or a salt thereof. The second artemisinin derivative is different from the first composition and is preferably artesunate. The third anti-microbial composition is administered to the individual. The third composition comprises an effective amount of berberine or a pharmaceutically acceptable derivative or salt thereof. The second and third compositions are administered to the individual for an additional period of time, such as two or three days.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease transmitted by an arthropod such as a mosquito or a tick.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease mediated by a virus of the Flaviviridae family virus.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease mediated by a virus similar to a virus in the Flaviviridae virus.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease mediated by a virus that causes hemorrhagic fever.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease mediated by a dengue virus.

In an alternate embodiment, the treatment is administered to an individual suffering from a disease mediated by dengue virus.

When used in individuals with dengue fever, TriAct therapy has proven to be safe and effective with no death or adverse effects. TriAct therapy reduces the disease process, reduces viral antigens (NS1), and reduces the risk of bleeding. TriAct therapy results in faster standardization of blood maps and earlier regression of clinical symptoms. Individuals employing TriAct therapy showed an increase in the immune system when compared to the control group, resulting in earlier production of neutralizing antibodies.

The invention further describes an improved artemether-based supplement and/or pharmaceutical composition for administration as a sublingual spray. The supplement and/or pharmaceutical composition contains an artemisinin derivative, an allergenic minimal carrier, and a mucosal absorption enhancer. The invention further relates to a method of making an artemether-based supplement and/or pharmaceutical composition and its use for delivery to an individual in need thereof.

As used herein, the term "flavivirus" includes about 70 members having a linear, single-stranded RNA genome of positive polarity. The family includes Flavivirus, Hepatitis C virus, Hepatitis G virus and Pesvirus. The main diseases caused by the Flaviviridae include: dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, 蜱Tick-borne encephalitis, West Nile encephalitis, yellow fever, and hepatitis C virus infection.

As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" generally mean organic or inorganic materials, non-toxic, inert solids, semi-solid or liquid fillings, thinners. , encapsulating material or formulation aid, which is any type that does not react with the active ingredient. Excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethylcellulose Vitamin sodium, ethyl cellulose and cellulose acetate; powdered xanthine; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; cocoa butter and suppository wax; vegetable oil, such as peanut oil, cottonseed oil , sesame oil, olive oil, corn oil and cocoa butter; esters such as, but not limited to, ethyl oleate and ethyl laurate; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene Glycol; agar; alginic acid; buffers such as, but not limited to, magnesium hydroxide and aluminum hydroxide; pyrogen-free water; isotonic saline; and phosphate buffer solution; skimmed milk powder; Other non-toxic compatible substances in the substance. Wetting agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, flavoring agents, sweeteners, lubricants, release agents, fragrances, carriers, tableting agents, stabilizers, antioxidants and antiseptics Agents may also be present.

As used herein, "pharmaceutically acceptable salt" refers to a salt that retains biologically and otherwise desirable biological effectiveness and properties of the compound. A pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a compound derived from a variety of organic and inorganic counterions well known in the art and including, by way of example only, sodium, potassium, calcium, Magnesium, ammonium, tetraalkylammonium and the like; and when the molecule contains a basic functional group, a salt of an organic or inorganic acid such as a hydrochloride, a hydrobromide, a tartrate, a methanesulfonate or an acetate , maleic acid salt, oxalate and the like.

The term "therapeutically effective amount" as used herein generally refers to an amount of an agent sufficient to effect a treatment as defined herein when administered to an individual in need of such treatment, such as a mammal, preferably a human, for example as an active ingredient. The amount of the compound. The therapeutically effective amount of a compound, salt, analog or derivative of the invention will depend on a variety of factors including, for example, the age and weight of the individual, the precise condition and severity of the condition to be treated, the nature of the formulation, and the route of administration, and It will ultimately be judged at the discretion of the visiting physician.

As used herein, the term "treat/treating/treatment" refers to an individual who has indicated at least one symptom of a disease, in particular a mammal, more specifically a human administered therapy to obtain the desired pharmacology and physiology. Learning effect. The individual includes an individual diagnosed with a disease. The term may also include preventing the disease, that is, causing the clinical symptoms of the disease not to occur in a mammal that may be exposed to or susceptible to the disease but has not experienced or manifested the symptoms of the disease; inhibiting the disease, ie, curbing or reducing the disease or its clinical symptoms. Development; or alleviating the disease, that is, causing the disease or its clinical symptoms to subside.

As used herein, "a virus that causes hemorrhagic fever" describes an RNA virus, such as the Filoviridae, Arenaviridae, Bunyaviridae, or Flaviviridae viruses, including (but Not limited to) eboia virus, marburg virus, flexal virus, guanarito virus, jumin virus, lassa fever virus, Machupo virus, sabia virus, Crimea-congo hemorrhagic fever virus, rift valley fever virus, hantaan Virus, dengue virus, kyasanur forest disease virus, omsk hemorrhagic fever virus and yellow fever virus. In one aspect of the invention, the hemorrhagic fever virus is a dengue virus.

Accordingly, it is an object of the present invention to provide an improved artemisinin combination therapy to an individual in need thereof.

Another object of the invention is to provide an improved artemisinin-based combination therapy to an individual suffering from a viral disease.

Another object of the present invention is to suffer from diseases mediated by arthropods such as mosquitoes. Individuals with toxic diseases provide an improved artemisinin-based combination therapy.

Another object of the invention is to provide an improved artemisinin-based combination therapy to an individual suffering from a viral disease mediated by the Flaviviridae virus.

Another object of the present invention is to provide an artemisinin-based combination therapy with an improved sublingual delivery step to an individual suffering from a viral disease.

Another object of the present invention is to provide an artemisinin-based combination therapy with an improved sublingual delivery step to an individual suffering from a viral disease mediated by Flaviviridae.

Another object of the present invention is to provide an improved artemisinin-based combination therapy to individuals suffering from dengue fever, which also utilizes a sublingual spray-based delivery route to deliver artemisinin derivatives.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in an individual suffering from a viral disease.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in an individual suffering from an arthropod-mediated disease.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in an individual suffering from an arthropod-mediated disease.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever, which are safe and effective.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever, which shortens the disease process.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever, which reduces NS1 viral antigen.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever, which reduces the risk of bleeding.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route, and Oral delivery of a second independent artemisinin derivative and berberine or a derivative thereof for use in individuals suffering from dengue fever, which results in faster standardization of blood maps and earlier regression of clinical symptoms.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof for use in individuals suffering from dengue fever, which results in an enhancement of the immune system, resulting in the early production of neutralizing antibodies.

It is an object of the present invention to provide an improved artemether-based supplement and/or pharmaceutical composition for treating an individual suffering from a disease.

Another object of the present invention is to provide an improved artemisinin-based combination therapy which delivers artemisinin derivatives using a sublingual spray-based delivery route and oral delivery of a second independent artemisinin derivative. And berberine or a derivative thereof, for use in an individual suffering from a disease, wherein the artemether-based supplement and/or pharmaceutical composition can be delivered in the form of a sublingual spray for an individual suffering from a disease and has a risk of causing an allergic reaction Minimized carrier.

Another object of the present invention is to provide an artemether supplement and/or pharmaceutical composition which can be delivered in the form of a sublingual spray for treating an individual suffering from a disease and which contains a carrier which promotes mucosal absorption.

Another object of the present invention is to provide an artemether supplement and/or pharmaceutical composition which can be delivered in the form of a sublingual spray for treating an individual suffering from a disease and which contains a carrier which minimizes the risk of allergic reactions and promotes mucosal absorption. .

The other objects and advantages of the invention will be apparent from the description and accompanying drawings. Any of the figures contained herein form part of this specification and include an illustration of the invention Specific examples and descriptions of various objects and features.

Figure 1 is a graphical representation of an individual diagnosed with dengue and treated with TriAct therapy versus an individual diagnosed with dengue and treated with a standard care regimen for duration of fever; Figure 2 is a diagnosis of dengue fever with TriAct therapy A graphical representation comparing the individual treated with dengue fever and treated with a standard care regimen for the number of days of abdominal pain; Figure 3 is an illustration of an individual diagnosed with dengue and treated with TriAct therapy and diagnosed with dengue fever and used Individuals treated with standard care regimens are compared for the number of days of abdominal tenderness; Figure 4 is for individuals diagnosed with dengue and treated with TriAct therapy and individuals diagnosed with dengue and treated with standard care regimens for NS1 A graphical representation comparing the days before the antigen test was negative; Figure 5 is the number of days in which an individual diagnosed with dengue and treated with TriAct therapy and an individual diagnosed with dengue and treated with a standard care regimen standardized the absolute platelet count. Graphical comparison; Figure 6 is a diagnosis of dengue fever and treatment with TriAct therapy Individuals who were diagnosed with dengue fever and treated with standard care regimens were compared for the number of days that IgM became positive; Figure 7 is an individual diagnosed with dengue fever and treated with TriAct therapy and diagnosed with dengue fever Individuals treated with the standard care regimen are graphically compared for the number of days the IgG becomes positive.

While the invention has been described in terms of the preferred embodiments of the embodiments of the present invention The invention is limited to the specific embodiments illustrated.

The present invention describes a novel combination therapy for treating a microbial infection, such as a viral infection. As an illustrative example, the invention has been found to be useful for treating diseases mediated by arthropods and/or from Flaviviridae, such as viral infections that cause dengue. The combination therapy according to the invention is based on artemisinin combination therapy (ACT). The present invention uses a triple therapy regimen using a unique combination of three compositions: artemether, artesunate, and berberine. Novel combination therapies can be generally referred to as TriACt therapy for the three components that make up the combination therapy.

Artemisinin and artemisinin derivatives

Artemisinin has 3 R , 5a S , 6 R , 8a S , 9 R , 12 S , 12a R )-octahydro-3,6,9-trimethyl-3,12-epoxy-12 H - The IUPAC name of piperido[4,3- j ]1,2-benzodioxan-10( 3H )-one, also known as Qinhaosu, is a Chinese herb derived from known antiviral activity. For natural products of Artemisia annua L., see Efferth et al. The Antiviral Activities of Artemisinin and Artesunate. Clin. Inf. Dis. 2008: 47:804-11. It has the following chemical structure:

Artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. It is believed that this peroxide is responsible for the mechanism of action of the drug. Very few other natural compounds with this peroxide bridge are known; see Artemisinin and a new generation of antimalarial drugs". Education in Chemistry. July 2006. http://www.rsc.org/Education/EiC/issues/ 2006July/Artemisinin.asp. It is widely used for the treatment of malaria, especially with other drugs such as mefloquine (ASMQ), benzoquinol (such as sold under the trade name Coartem), aminophenolquine (such as sold under the trade name Camoquin, Flavoquine, ASAQ), piperaquine. (such as sold under the trade name Duo-Cotecxin), artemisinin and pyronaridine (such as sold under the trade name Pyramax). Artemisinin derivatives are typically used as prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage in which the parasite is located inside the red blood cells. The mechanism by which the salty artemisinin derivative kills the parasite acts by disturbing the redox stability in the malaria parasite. Thus, such compositions may include free radical production in parasite food bubbles and inhibition of parasite calcium ATPase. The key advantage of artemisinin is the rapid effect of parasites relative to all red blood cell stages including propagating gametocytes, resulting in rapid clinical benefit and reduced malaria transmission; see Rosenthal, Artesunate for Treatment of Severe Falciparum Malaria, N. Engl J Med 2008, 358: 1829-1836.

One of the disadvantages of artemisinin is its poor physical properties, resulting in poor bioavailability, which limits its effectiveness. For example, the compound is sparingly soluble in water or oil and therefore cannot be readily absorbed by the gastrointestinal tract. Therefore, many semi-synthetic derivatives have been developed, including artesunate (water-soluble: orally, rectally, intramuscularly or intravenously), artemether (fat-soluble: oral, rectal or intramuscular) Use) dihydroartemisinin, arteniphonic acid, artenimol and arteether. As used in the present invention, artemisinin derivatives include, but are not limited to, artesunate, dihydroartemisinin, dihydroartemisinin semi-succinate, dihydroartemisinin succinate, artemisia acumin Stable form of sodium, artesunate, stable form of artesunate, dihydroartemisene dimer as described in U.S. Patent No. 7,098,242, amine functionalization 1, 2 as described in U.S. Patent 7,071,226 , 4-three Artemisinin-peripheral as described in U.S. Patent No. 6,984,640, and the snail and snail 1,2,4-trioxolane anti-malarial drug as described in U.S. Patent No. 6,906,205, the disclosure of which is incorporated herein by reference. The mixed steroids 1, 2, 4, 5 - 4 Compounds, such as those described in U.S. Patent No. 6,750,356, the replacement of 1,2,4-three as described in U.S. Patent No. 6,737,438. Artemisia annua extract, as described in U.S. Patent No. 6,685,972, artemether as described in U.S. Patent No. 6,683,193, and Artemisinin III, as described in U.S. Patent No. 6,649,647. a derivative, such as the one described in USRE 38,117 A dimeric compound, such as the conjugate of artemether, as described in U.S. Patent No. 6,461,603, the artemisinin from dihydroartemisinin, as described in U.S. Patent No. 6,346,631, which is incorporated herein by reference. Or artemisinin derivative, C-10 carbon as described in U.S. Patent No. 6,160,004, substituted for artemisinin-like three a compound, such as the water soluble three described in U.S. Patent No. 6,136,847 Artemisinin dimers as described in U.S. Patent No. 6,127,405, the artemisinin dimers described in U.S. Patent No. 5,856,,,,,,,,,,,,,,,, Analogs of artemisinin and 10-substituted ether derivatives of dihydroartemisinin as described in U.S. Patent 5,225,427, and salts or other derivatives thereof, are known to those skilled in the art.

Artemether is a methyl-ether derivative of dihydroartemisinin derived from artemisinin. It has (+)-(3-α,5a-β,6-β,8a-β,9-α,12-β,12aR)-decahydro-10-methoxy-3,6,9-three The IUPAC chemical name of methyl-3,12-epoxy-12H-piperazino(4,3-j)-1,2-benzodioxan with the following chemical formula:

Artemether is known to be effective against several blood schizophage causing malaria parasites and is used as an ACT drug.

Artesunate, also known as dihydroartemisinin hemisuccinate and its salt, has 3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl The chemical name of IUPAUC, a 3-, 12-epoxy-12H-piperaco(4,3-j)-1,2 benzodioxan-10-ol hydrosuccinate, having the following chemical formula:

Artesunate is mainly used for the treatment of malaria.

Dosage of artemisinin, artemisinin salt and derivatives.

Oral dosages of artemisinin, artemisinin salts and derivatives range from about 1 mg to about 1,500 mg per dose, administered one to three times a day. More preferably, if administered one to three times a day, the oral dosage of artemisinin, artemisinin salt and derivatives ranges from about 20 mg to about 250 mg per dose. Optimally, the oral dose of artemisinin, artemisinin salt and derivatives ranges from about 40 mg per dose. Between approximately 100 mg, take one to three times a day.

Berberine, its salts and berberine derivatives.

Berberine is a quaternary ammonium salt of the original berberine group derived from isoquinoline alkaloids. It has the IUPAC name of (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxol[5,6-a]quinolizine) With the following chemical formula:

It is found in various plant species of the genus Euphorbia (such as Berberis aquifolium (Oregon), Berberis vulgaris/Barberry, and Berberis aristata (Tree turmeric)), and Other plant families, including but not limited to, Hydrastis canadensis/Goldenseal, Phellodendron amurense/Amur Cork Tree/Huang Bai/Huang Po/Po Mu, and Coptis chinensis/Chinese Goldthread/Huang-Lian/ Huang-Lien) and Tinospora cordifolia, and to a lesser extent, Argemone mexicana/Prickly Poppy and Eschsoholzia californica/Californian Poppy, Rhizoma coptidis Huanglian Jiedu decoction), San-Huang-Xie-Xin-Tang, Xietianwu, Gegen Quinlian and Shizhu. Berberine is mainly isolated from roots, rhizomes, stems and bark. Berberine has been used in medical applications in Ayurvedic medicine and Chinese medicine in India, and has recently been targeted at antibacterial activity in diarrhea, prostate cancer and diabetes. Use for testing. It is generally considered to be non-toxic and does not exhibit genotoxic activity.

According to the present invention, the berberine, berberine derivative or a salt thereof may include, but is not limited to, berberine alkaloid, berberine base, berberine hydrochloride, berberine ( berberine), berberine red base (berberrubine), heterogeneous bicuculline (coreximine), tetrahydropalmatine (tetrahydropalmatine), jatrorrhizine (jatrorrhizine), 13- hydroxy berberine chloride (13-hydroxyberberine chloride), Corynene, methoxycainine, 7,8-dihydro-13-methylberberine, berberine acetone, 13-allyl berberine, palmatine , 13-benzyl berberine, tetrahydroberberine, tetrahydroprotoberberine 8-cyanodihydroberberine, dimerized protoberberine alkaloid, demethylated protoberberine Alkali, quaternary protoberberine alkaloid, protoberberine and protoberberine alkaloid, berberine salt, including berberine hydrochloride, berberine chloride, berberine sulfate, small tannic acid Scopolamine and other salts known to those skilled in the art.

Dosage range of berberine, its salts and derivatives.

The oral dose of berberine ranges from about 50 mg to about 1,500 mg, administered in a single dose of two to three times per day, no more than 4,500 mg per day. More preferably, the dose of berberine is a single human dose of from about 100 mg to about 1,000 mg, no more than 3,000 mg per day, delivered one to three times a day. The optimal dosage range for a single dose of berberine is from about 200 mg to about 500 mg, taken one to three times a day.

The invention is further described by the following non-limiting examples. The following examples illustrate specific examples of the route of administration and the form of the composition, but are preferred embodiments. Although preferred forms and/or routes are described, other forms such as, but not limited to, tablets, capsules, sachets, pills, caplets, dragees, dispersions, suspensions, solutions, syrups, granules, beads Percutaneous Patches, gels, powders, pellets, emulsions, buccal tablets, creams, pastes, plasters, lotions, trays, suppositories; liquid sprays for nasal or oral administration, for inhalation A dry powder or aerosolized formulation, a composition for intravesical administration, and a formulation. Compositions may also be developed for inhalation, oral, rectal, transvaginal, parenteral, topical, transdermal, transpulmonary, intranasal, buccal, transocular, intrathecal, intravenous or any route of administration. .

Dosage forms of the invention may include immediate release or controlled release forms. Each of the compositions can be formulated and manufactured by procedures known to those skilled in the art, and can include a 100% composition or a mixture of one or more pharmaceutically acceptable excipients or pharmaceutically acceptable carriers. For sublingual sprays, liquid artemether can be prepared in a spray form using, for example, a microfluidization process as described in U.S. Patent No. 6,861,066.

The present invention further describes an alternative sublingual spray artemether-based supplement and/or pharmaceutical composition, a method of making an improved artemether-based supplement and/or pharmaceutical composition, and for delivery to The use of the individual in need. The supplement and/or pharmaceutical composition contains an active compound such as an artemisinin derivative, a pharmaceutically non-allergenic acceptable carrier and a mucosal absorption enhancer which reduce the risk of allergic reactions when administered to an individual. In a preferred embodiment, the sublingual spray supplement and/or pharmaceutical composition comprises artemether; a pharmaceutically non-allergenic acceptable carrier, such as a neutral oil, including, for example, olive oil (obtained from olive oil ( Olea europaea ) is a neutral oil; and a quaternary ammonium salt such as benzalkonium chloride, which acts as a mucosal absorption enhancer.

The present invention includes an improved artemether supplement and/or pharmaceutical composition for use in reducing the risk of an allergic reaction to a subject susceptible to food-based allergy. Although artemisinin and artemisinin derivatives for treating diseases are known in the art, these compositions are prepared using arachis/peanut oil. Use of this oil for delivery in the mouth Any supplement or pharmacological route of administration causes problems, such as the mouth, whereby the active ingredient needs to diffuse through the tissue under the tongue into the circulatory system. As a common trigger for individuals with food-induced allergic reactions, the use of peanut oil as a carrier for sublingual spray increases the risk of serious injury and even death.

In order to minimize the risk of potential allergic reactions, the supplements and/or pharmaceutical compositions according to the invention use olive oil as a carrier for artemether, since there is no known allergy to olive oil when taken by mouth. The situation.

Mucosal absorption enhancer:

The quaternary ammonium salt can be used to form supplements and/or pharmaceutical compositions. Such quaternary ammonium salts include those quaternary ammonium salts which are commonly used and which are considered safe for human use. The compounds are typically tetrasubstituted ammonium salts wherein the substituent is preferably a hydrocarbon compound bonded to the nitrogen via an N-C bond and is selected from the group consisting of substituted and unsubstituted, saturated and unsaturated. , aliphatic and aromatic and branched and positive chain groups. In all cases, the nitrogen atom is pentavalent and is in the positively charged portion of the molecule, so the quaternary ammonium salt is a cationic electrolyte.

Preferably, the mucosal absorption enhancer of the present invention is benzalkonium chloride, also known as alkyl dimethyl benzyl ammonium chloride, alkyl dimethyl (phenyl methyl), quaternary ammonium chloride, Ammonyx and Roccal. Benzalkonium chloride has the following chemical formula:

Benzalkonium chloride is commercially available in a suitable form from a variety of sources including Sigma Aldrich Chemical company. Benzalkonium chloride is used in an amount effective to act as a film enhancer and a preservative. The benzalkonium chloride may be between about 0.001% by weight and about 0.1% by weight, and preferably between about 0.005% and about 0.05% by weight of the composition, and more preferably 0.007% or about 0.007 by weight of the composition. The final concentration of % is used.

Tables 1-5 illustrate examples of spray artemether supplements and/or pharmaceutical compositions in accordance with the present invention.

EXAMPLES: Preparation of sublingual artemether spray, single dose 80 mg method

To prepare a sublingual spray of artemether, powdered artemether was obtained. In preparing a single spray dose, 700 mL of extra virgin olive oil was heated to 130 degrees in a one liter beaker. Cool the olive oil to 70 degrees. Once at 70 degrees, add 80 grams of artemether powder. 80 grams of artemether powder was slowly added to the cooled olive oil with continuous stirring until the powder dissolved to form a clear solution. 0.7 ml of 10% benzalkonium chloride was added to the solution of artemether under continuous stirring. The artemether solution was allowed to cool to room temperature. The concentration of artemether was verified using HPLC.

Preferably, the above described artemether solution is packaged in a single-dose delivery system, such as an atomized jet pump as described in U.S. Patent No. 6,126,038, wherein the patient can only spray the composition to the desired placement. , that is, under the tongue, until the bottle is completely empty.

Method of treating an individual

Example 1: Method of treating an individual afflicted with a disease mediated by a Flaviviridae virus.

A method of treating an individual afflicted with a disease mediated by a Flaviviridae virus comprises the steps of: (1) administering to a mammal, preferably a human, a first composition comprising a therapeutically effective amount of an artemisinin derivative Preferably, 50-80 mg, preferably 60 mg of artemether per dose; (2) administering to the mammal a second composition comprising a therapeutically effective amount of a second artemisinin derivative, second green The artemisinin derivative is different from the first composition, and is preferably artesunate or a pharmaceutically acceptable derivative thereof, in an amount of from 1 mg to 1,500 mg per dose, preferably from about 20 mg to about 250 mg per dose, three times a day. And preferably from about 40 mg to about 100 mg per dose, three times a day; and (3) administering to the mammal a third composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable derivative thereof , about 1 mg to about 1,500 mg per dose, specifically about every dose From 100 mg to about 1,000 mg three times a day, and more specifically from about 200 mg to about 400 mg per dose, two to three times per day.

An illustrative, but preferred, delivery therapy schedule is described below:

Day 1: Delivery of artemether - single dose.

Artesunate and berberine lozenges are delivered at doses every eight hours depending on the age and/or weight of the user.

Day 2: Delivery of artesunate and berberine tablets at doses every eight hours depending on the age and/or weight of the user.

Day 3: Delivery of artesunate and berberine lozenges at doses every eight hours depending on the age and/or weight of the user.

Example 2: Treatment of more than 165 pounds (75 Kg) of adults infected with viral infection using sublingually delivered artemether solution: dengue fever.

A method for treating an individual suffering from dengue fever, comprising the steps of: (1) administering to a mammal, preferably a human, a first composition, the first composition comprising a therapeutically effective amount of artemether; (2) to adulthood The mammal is administered a second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable derivative thereof; and (3) administering a third composition to the adult mammal, third The composition comprises a therapeutically effective amount of berberine or a pharmaceutically acceptable derivative thereof.

Adults over 165 pounds (75 Kg) begin the method according to the invention by administering the first starting dose of artemether. Artemether is preferably delivered to the individual using a single dose sublingual spray bottle containing preferably 60 mg of artemether solution per vial. Using a spray provides the advantage over an injectable form: providing a medical professional (such as a doctor or care) that is easy to administer and does not require training And avoid problems associated with needles, such as fear of spreading diseases such as HIV or hepatitis C and methods of delivery that are properly disposed of. In addition, sublingual drug delivery, in particular a spray, increases the absorption of the active ingredient and enhances bioavailability.

In use, the user simply removes the bottle from the shipping/delivery package and replaces any security features, such as any tamper proof outer package that is secured to the bottle. After removing the sealed portion from the spray bottle, the adult individual lifts its tongue and pumps the spray bottle with the artemether solution into the mouth so the solution is delivered to the sublingual area. The bottle is held in this position until the contents of the bottle are fully delivered to the sublingual area. The liquid is preferably maintained under the tongue for a predetermined period of time, preferably 30 seconds. Any liquid remaining in the mouth of the user is then swallowed. After waiting for a predetermined period of time, such as from 1 minute to 1 hour and more preferably 30 minutes, the user is administered a second composition comprising a dose of artesunate, such as 2 x 50 mg tablets, 3 doses per day (300 mg per day) , or every 8 hours for 2 days. The user administers a third composition comprising a dose of berberine, such as 2 x 400 mg tablets, 3 doses per day (2,400 mg), or every 8 hours. Alternatively, the second and third compositions can be administered simultaneously with the first composition.

Example 3: Treatment of a virus-infected adult with a sublingually delivered artemether solution 66 lbs (30 kg) - 165 lbs (75 Kg): dengue.

An adult weighing 66 pounds (30 kg) to 165 pounds (75 kg) begins the method according to the invention by administering a first starting dose of artemether. Artemether is preferably delivered to the individual using a single dose sublingual spray bottle containing preferably 60 mg of artemether solution per vial. The user simply removes the bottle from the shipping/delivery package and replaces any security features, such as an external package that is fixed to the bottle indicating tampering. After removing the sealed portion from the spray bottle, the adult individual lifts its tongue and pumps the spray bottle with the artemether solution into the mouth so the solution is delivered to the sublingual area. The bottle remains in this position Place until the contents of the bottle are fully delivered to the sublingual area. The liquid is preferably maintained under the tongue for a predetermined period of time, preferably 30 seconds. Any liquid remaining in the mouth of the user is then swallowed. After waiting for a predetermined period of time, such as from 1 minute to 1 hour and more preferably 30 minutes, the user is administered a second composition comprising a dose of artesunate, such as 1 x 50 mg of a tablet, 3 doses per day (150 mg), Or every 8 hours for 2 days. The user administers a third composition comprising a dose of berberine, such as 1 x 400 mg of lozenge, 3 doses per day (1200 mg), or every 8 hours. Alternatively, the second and third compositions can be administered simultaneously with the first composition.

Example 4: Treatment of 33 lbs (15 kg) to 66 lbs (30 Kg) of human children with viral infection using sublingually delivered artemether solution: dengue fever.

The treatment is the same as described in Example 3 for children or individuals in the range between 33 lbs (15 kg) and 66 lbs (30 Kg).

Example 5: Treatment of 33 pounds (under 15 kg) infants and young children up to 3 years old with viral infection using a sublingually delivered artemether solution: dengue fever.

The treatment was similar to that of Example 1 for infants and young children up to 33 years old (under 15 kg). The dose delivered to the user includes preferably a single dose sublingual spray containing preferably 60 mg of the artemether solution per bottle to the individual artemether, 25 mg of artesunate per dose, 3 doses per day (75 mg total daily) ), or every 8 hours for 2 days, and 200 mg of berberine per dose, 3 doses per day (600 mg total daily), or every 8 hours. For infants and young children, the lozenge can be ground and mixed with liquids that are allowed to be delivered to the user, such as milk, juice, and syrup.

Example 6: Treatment of an individual infected with a viral infection using an injectable delivery of artemether solution: dengue fever.

A method of treating an individual suffering from dengue fever comprising the steps of: (1) administering to a mammal, preferably a human, a first composition comprising a therapeutically effective amount of artemether; (2) to a mammal Administering a second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable derivative thereof; and (3) administering to the mammal a third composition, the third composition comprising A therapeutically effective amount of berberine or a pharmaceutically acceptable derivative thereof.

In a preferred embodiment, the method of treatment can be facilitated by the use of a kit comprising an extractable worm in the form of a single dosage unit contained in an ampoule, an injectable vial or in the form of a single single preloaded syringe having a needle. a methyl ether solution, a first package containing artesunate tablets, and a second package containing berberine tablets. Individual users begin the method according to the invention by administering a first starting dose of artemether. Artemether is delivered to the subject as an injection via an intravenous or intramuscular administration mode. The second and third compositions are delivered as previously described in Examples 2 through 4, depending on the weight and age of the individual user.

As described in the above examples, the components of the present invention can be supplied to a kit to help deliver and use the method according to the present invention for treatment in areas that are not readily accessible or establish a distribution channel and/or medical community. According to the present invention, the kit may comprise a secure delivery package in the form of a self-sealing blister pack, a zipper pack, a stand-up pouch, a foil pouch comprising a single use spray bottle and artesunate and berberine one day, two days , three days, four days, five days or more packaging. If an injectable artemether is used, it may include a needle, a syringe, an injection bottle or a preloaded syringe with a capping needle. The kit preferably contains instructions for proper use and storage of the kit components and/or any other instructions.

And the use of a modified modified artemisinin-based combination therapy for delivering an artemisinin derivative using a sublingual spray-based delivery route

Two hundred eighty-eight (288) evaluable individuals were initially randomly grouped into two groups: A, receive standard care plus TriAct therapy, and group B, only receive standard care. Standard care programs include bed rest and liquids. Individuals were analyzed using the World Health Organization (WHO) classification (denture fever without warning signal (IA/IB), dengue fever with warning signs (IIA/IIB), and severe dengue fever (IIIA/IIIB) based on the presented symptoms.

All study participants used NS1 antigen as a surrogate for viral load to confirm dengue cases and compared all clinical and laboratory parameters in both groups. Group A showed: 1) faster elimination of viral antigens in serum, which is further disease Progress has been the chief culprit in serious forms such as plasma leaks and severe bleeding; 2) rapid regression of clinical signs and symptoms of dengue; 3) faster standardization of laboratory parameters such as white blood cells (WBC) and platelet counts. These observations were not observed in the control group (group B).

Upon completion of the clinical study, statistics confirmed that the modified and improved artemisinin-based combination therapy regimen was demonstrated to be safe and effective with no death or adverse effects. Modified modified artemisinin-based combination therapy for shortening the disease process, reducing viral antigens (NS1), reducing the risk of bleeding, standardizing blood patterns, early resolution of clinical symptoms, and strengthening the immune system, resulting in earlier development And antibodies.

Materials and methods:

The study was a prospective, open-label randomized, controlled, single-center study enrolling 300 individuals divided into two treatment groups: Group A, WHO standard care plus TriAct therapy, and Group B, WHO standard care only . Individuals, including individuals between the ages of 5 and 65 who are admitted to be dengue cases, are screened for caution by adhering to the discretionary medical history and physical examination of the inclusion criteria. All individuals were positive for dengue NS1 and/or dengue IgM/IgG. All individuals are informed and voluntarily signed a consent form (consent/assent form). WHO/DOH revised dengue guide (WHO/DOH Revised The Dengue Guidelines are used to guide the study. Individuals in groups A and B were further divided into dengue fever (dengue/DHF I) without warning signals, dengue fever (DHF II) with warning signs, and severe dengue fever (DHF III/IV). Individuals were monitored at least 30 days after the last dose of the test particles.

A test drug combination using a starting dose of artemether (60 mg solution, sublingual nano spray), 50 mg of artesunate per spindle, and 400 mg of berberine per tablet was used. Instructions and dosages for age groups and body weights are based on Table VI.

Package A = Artesunate

Packet B = berberine

All individuals performed daily CBC by actual platelet count assessment. The NS1 assay was performed daily until the result became negative. Dengue IgM/IgG was also measured daily until the patient was discharged. Other laboratory tests, such as prothrombin time (PT), partial prothrombin time (PTT), aspartate transaminase (AST), and alanine transaminase (ALT), are also performed after registration. Test and urine test and repeat at least on the 7th day of the disease. Chest X-rays and abdominal ultrasound were performed on all individuals during the first 24 hours of fever. Chest X-rays were repeated at least after 72 hours. Abdominal ultrasound is repeated for individuals with abnormal findings.

Daily assessment of all individuals. Statistical analysis was performed using independent sample T-test and Chi Square test to test for independence using SPSS 11.5.

RESULTS: Of the 300 confirmed individuals enrolled, 288 were eligible for assessment and the remaining individuals were unable to complete the required data set. Perform daily assessments of clinical and laboratory parameters. Differences between group A and group B are shown for the following parameters: disease days, p=0.038, Cramer's V=0.201; days of fever in patients, p<0.001, Cramer's V=0.516; days with headache, p<0.001 Cramer's V=0.389; days with physical discomfort, p<0.001, Cramer's V=0.389; days with joint pain, p=0.012, Cramer's V=0.210, days with nausea/vomiting, p=0.001, Cramer's V=0.265; days with abdominal pain, p<0.001, Cramer's V=0.540; days with abdominal tenderness, p<0.001, Cramer's V=0.586; days of standardized white blood cell count, p<0.001, Cramer's V=0.545 Days of standardized hemoglobin, p<0.001, Cramer's V=0.311; days of normalized blood volume ratio, p<0.001, Cramer's V=0.360; days of normalized absolute platelet count, p<0.001, Cramer's V=0.610; The number of days before becoming negative, p < 0.001, Cramer's V = 0.589; the number of days before IgM became positive, p < 0.001, Cramer's V = 0.343; the number of days before IgG became positive, p < 0.001, Cramer's V=0.293; based on NS1 of disease days, p<0.001, Cramer's V=0.638.

For clinical parameters, study drug group A showed a rapid recovery and regression of clinical signs and symptoms.

Group A reached an antipyretic one day earlier than control group B (p < 0.001), see Figure 1.

Compared with group B, all individuals in group A had physical discomfort and regression of post-surgical pain during the 3-day period. The above symptoms in group B continued until day 5 (p<0.001 and p=0.511, respectively). .

The majority (98.6%) of the individuals in Group A had regression of joint pain over a 2-day period compared to Group B (p=0.012).

The most significant observations between the 2 groups were found in differences in abdominal pain and abdominal tenderness (including nausea and vomiting), with almost all individuals in group A compared to group B with regression on days 6 and 4 (98.6%, 98.6%, and 99.3%, respectively) had regression on day 3 (p<0.001, p<0.001, and p=0.001, respectively), see Figures 2 and 3.

As in the laboratory parameters of WBC and absolute platelet count, the standardized control group (see Figure 5) was obtained in 7 days (p < 0.001) and 6 days (p < 0.001), respectively. All individuals showed normalization within 4 days of treatment.

Individuals in Group A maintained hemoglobin and hematocrit stability throughout the course of the study compared to the control group in which 2.7% (p < 0.001) and 4.1% (p < 0.001) remained unstable until day 5, respectively. However, we anticipate that there will be no significant differences in the percentage increase in blood volume ratio due to standard care administered to both treatment groups.

The study further showed that early specific antibody production was present in Group A (on day 3, IgM 96.5%) compared to control group B (IgM 77.9%) with a p value of <0.001, see Figure 6. Xianxin's early specific antibody production helps to quickly eliminate viruses in the body and reduce the chance of forming antigen-antibody complexes, thereby preventing possible plasma leaks. Figure 7 illustrates the number of days before IgG became positive for Group A and Control Group B.

Disintegration of the NS1 antigen was observed relatively quickly in Group A, and all individuals were negative on Day 4. This finding differed for control group B, which took up to 8 days to make some, but not all individuals became negative (p < 0.001), see Figure 4.

It is hypothesized that the NS1 antigen may be essential for dengue virus replication, so the earlier disintegration of the NS1 antigen means that viral replication has ceased, which may be the mechanism of action of TriAct therapy.

Number of individuals showing higher serum glutamate acetic acid transaminase (SGOT) The decrease means that there is no further invasion of liver cells in group A (38/84) compared to control group B (51/84) (p value = 0.044). However, both groups exhibited higher serum pyruvate transaminase (SGPT). Compared to group B, 51/84 (60.7%) (p=0.071), there was a continuous increase in SGPT in group A, 62/84 (73.8%).

The present invention demonstrates the use of TriACt therapy as an effective combination therapy for the effective treatment of dengue. Studies have shown that TriACt therapy is safe because there are no adverse events recorded in the treatment group. TriACt therapy was found to provide several unexpected benefits as a therapeutic procedure. As documented by the disappearance of NS1, TriAct therapy eliminates 50% (50%) of the virus faster. In those patients treated with TriAct therapy, the number of disease days was significantly reduced by at least fifty percent (50%), which was unexpected. Among their patients treated with TriAct therapy, TriAct therapy reduced the number of incompetent days by at least fifty percent (50%). The TriAct therapy group recovered faster from fever. Abdominal pain and abdominal tenderness were significantly reduced in this treatment group, which was a surprise for the investigator. Treatment resulted in complete recovery of pain after the frame. The use of TriAct therapy results in rapid standardization of white blood cell and platelet counts. Bleeding discontinuation is a crucial finding in this study. Individuals within the TriAct therapy group also showed a significant reduction in physical discomfort and joint pain. An earlier discontinuation of nausea/vomiting was obtained in the TriAct therapy group.

All patents and publications referred to in this specification are indicative of the skill of those skilled in the art. All patents and publications are hereby incorporated by reference in their entirety to the extent of the extent of the disclosure of the disclosures

It will be understood that, although a certain form of the invention is described, it is not limited to the specific forms or configurations described and illustrated herein. It will be apparent to those skilled in the art that various changes can be made without departing from the scope of the invention and the invention should not be construed as The content shown and described in any of the drawings/drawings included in the drawings.

Those skilled in the art will readily appreciate that the present invention is well adapted to carry out the <RTIgt; The specific examples, methods, procedures, and techniques described herein are illustrative of the preferred embodiments and are intended to be illustrative and not restrictive. Variations and other uses that are within the spirit of the invention and are defined by the scope of the appended claims are contemplated by those skilled in the art. Although the present invention has been described in connection with the specific preferred embodiments, it should be understood that the invention In fact, it is apparent to those skilled in the art that various modifications of the described modes of carrying out the invention are intended to be within the scope of the following claims.

Claims (29)

A method of treating an individual afflicted with an arthropod-mediated disease, comprising the steps of: administering to a subject a first composition comprising a therapeutically effective amount of an artemisinin derivative; administering to the individual a second composition comprising a therapeutically effective amount of a second artemisinin derivative, the second artemisinin derivative being different from the first composition; administering to the individual an effective amount of a small amount a third component of a base or a pharmaceutically acceptable derivative thereof. A method of treating an individual suffering from an arthropod-mediated disease as claimed in claim 1 wherein the arthropod is a mosquito. A method of treating an individual suffering from an arthropod-mediated disease as claimed in claim 1 wherein the first component is administered sublingually. A method of treating an individual suffering from an arthropod-mediated disease, as in claim 3, wherein the sublingual delivery is via a spray. A method of treating an individual suffering from an arthropod-mediated disease as claimed in claim 1 wherein the first composition is administered to the individual via injection. A method of treating an individual suffering from an arthropod-mediated disease as claimed in claim 1 wherein the second and third compositions are delivered via the oral route. A method of treating an individual suffering from an arthropod-mediated disease as claimed in claim 6 wherein the second and third compositions are in the form of pills or capsules. A method of treating an individual suffering from an arthropod-mediated disease, as in claim 6, further comprising administering to the individual an additional dose of the second and third components The steps to renew the scheduled time. A method of treating an individual suffering from an arthropod-mediated disease, as claimed in claim 1, wherein the individual has dengue fever. A method of treating an individual afflicted with a disease mediated by a flavivirus (Flaviviridae) virus, comprising the steps of: administering to a subject a first composition comprising a therapeutically effective amount of an artemisinin derivative; Administering to the individual a second composition comprising a therapeutically effective amount of a second artemisinin derivative, the second artemisinin derivative being different from the first composition; administering to the individual A third composition comprising an effective amount of berberine or a pharmaceutically acceptable derivative thereof. A method for treating an individual suffering from a disease mediated by a Flaviviridae virus according to claim 10, wherein the virus causes dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley brain Murray Valley encephalitis, St. Louis encephalitis, Tick-borne encephalitis, West Nile encephalitis, yellow fever and hepatitis C virus infection. A method of treating an individual suffering from a disease mediated by a Flaviviridae virus, according to claim 11, wherein the first composition is artemether. A method of treating an individual suffering from a disease mediated by a Flaviviridae virus according to claim 12, wherein the artemether is administered sublingually. A method of treating an individual suffering from a disease mediated by a Flaviviridae virus according to claim 10, wherein the second composition is artesunate. A method of treating an individual suffering from dengue fever comprising the steps of: administering to a subject a first composition comprising a therapeutically effective amount of artemether or a pharmaceutically acceptable salt thereof; administering to the individual Providing a second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable salt thereof; administering to the individual a third composition comprising a therapeutically effective amount Scopolamine or a pharmaceutically acceptable salt thereof. A method of treating an individual suffering from dengue as claimed in claim 15 wherein the first composition is administered sublingually or by injection. A method of treating an individual suffering from dengue as claimed in claim 16 wherein the sublingual delivery is via a spray. A method of treating an individual suffering from dengue as claimed in claim 15 wherein the spray comprises a mucosal absorption enhancer. A method of treating an individual suffering from dengue as claimed in claim 16 wherein the second and third compositions are delivered via the oral route. A method of treating an individual suffering from dengue as claimed in claim 16 wherein the second and third compositions are in the form of pills or capsules. A method of treating an individual suffering from dengue as claimed in claim 16 wherein the step of administering the artemether comprises delivering a single dose. A method of treating an individual suffering from dengue as claimed in claim 16 further comprising the step of administering an additional dose of the second and third compositions for a predetermined period of time. A kit for treating a microbial disorder, comprising: a first composition comprising a therapeutically effective amount of an artemisinin derivative; a second composition comprising a therapeutically effective amount of a second artemisinin derivative, the second artemisinin The derivative is different from the first composition; the third composition comprises an effective amount of berberine or a pharmaceutically acceptable derivative thereof. The kit for treating a microbial disease according to claim 23, wherein the first composition is artemether, the second composition is artesunate, and the third composition is berberine. A kit for treating a microbial disorder according to claim 24, wherein the artemether is a spray. A kit for treating a microbial disorder according to claim 24, wherein the artemether is in an injectable form. A kit for treating a microbial disorder as claimed in claim 26, wherein the artemether is preloaded into a syringe. A kit for treating a microbial disorder according to claim 24, wherein the second and third compositions are prefilled. A kit for treating a microbial disorder according to claim 24, wherein the artemether spray comprises a mucosal absorption enhancer.