FIELD OF THE INVENTION

The present invention relates to kits and method of using the kits in the treatment of malaria in humans and, more specifically, to systems, methods and kits for rapid effective treatment in the field or healthcare facilities.

BACKGROUND OF THE INVENTION

Malaria is a known mosquito-borne and transmitted infection affecting humans through parasitic Plasmodium. There are at least five known species of Plasmodium known to be transmitted to humans, with P. falciparum and P. vivax being of greater concern because the majority of deaths arise from these two species. P. ovale and P. malariae typically result in milder infections and symptoms. Cerebral malaria, resulting from infections of P. falciparum, is the most severe neurological complication. Patients, who survive cerebral malaria, can have increased risk of deficits in neurological and cognitive abilities, and difficulties with behavior and likelihood of epilepsy in young victims.

As it relates to human infection, the life cycle of the malaria-causing Plasmodium begins with an infected female mosquito, i.e. , an Anopheles mosquito (definitive-primary host), which transfers a motile infective sporozoite to a human (secondary host) when the mosquito takes a blood meal from the human. The sporozoite is transferred from the infected mosquito into the human skin through the female mosquito's saliva. The sporozoite then travels through the circulatory system of the human, ultimately reaching the liver cells, where it undergoes asexual reproduction, spawning thousands of merozoites. In turn, these infect new red blood cells and begin multiplication cycles, which produce 8 to 24 new infective merozoites, resulting in the rupturing of cells and restarting of the infective cycle. Once a human is infected, or other vertebrates targeted by these mosquitoes, a non-infected mosquito can acquire the infection through feeding on infected humans, and thereby having the ability to transmit the infection through a subsequent blood meal taken from the skin of the human.

Malaria is prevalent in tropical/subtropical regions around the world, including regions of Sub-Saharan Africa, Asia and the Americas along the equatorial line. Malaria infections in these regions can result in hundreds of thousands to over a million deaths per year. Approximately 3.4 billion people - about half of the population - are at risk of malaria. In 2014, the WHO estimates that 207 million people contracted malaria in 2013. Many of the concerned areas comprise rural areas, with many areas having limited health care facilities and/or limited access to health care and health care facilities. More concerning is the fact that millions of travelers from around the world travel to these regions every year, with tens of thousands to over a million contracting malaria. Given the known life cycle of the infection, many of these travelers can become infected and return to their home countries before they are diagnosed with malaria. For those persons indigenous to these regions, obtaining proper or correct treatment can be challenging given the limited facilities and/or resources (e.g. , medications, testing equipment, patient care over time of required treatment). Untreated humans become symptomatic within one to three weeks, once infected.

Many exhibit symptoms similar to an influenza infection. Such other symptoms can include, for example, joint pain, nausea and vomiting, hemolytic anemia, hemoglobin excretion, convulsion, fever, and headaches. The presentation of symptoms may be similar to that of conditions of intestinal infections, for example. Therefore, diagnosis can be late in the life cycle of the infection at which point the infected patient may not have time for transfer to proper facilities when and where possible. These situations presently occur due to the lack of timely availability of treatments.

Time is of the essence when the patient is presented later in the infection. For example, infection with P. falciparum can lead to cerebral malaria, which can result in long term detrimental effects and death. The World Health Organization (WHO) classifies malaria as either severe or uncomplicated, from which P. falciparum- aisida. is classified as severe. Because of the third-world conditions in many of these locations, there is a need for a rapid treatment kit that prepares the health care providers, caregivers, leaders and individuals the ability to treat and diagnose malarial infections in a timely and effective manner. SUMMARY OF THE INVENTION

Embodiments of the present invention solve many of the problems and/or overcome many of the drawbacks and disadvantages of the prior art by providing kits and methods for treating malaria.

Embodiments of the present invention may include a malaria treatment kit for use in general settings and advanced, rural and/or isolated areas around the world where malaria infections tend to be and are problematic to travelers and indigenous persons, especially in remote areas that are distant from health care facilities or aid centers. Malaria treatment kits of the present invention may comprise one or more WHO approved malaria treatment drugs and recovery components manufactured and packaged by WHO approved and certified facilities. In certain embodiments, the malaria treatment kits can comprise, for example, effective doses of malaria treatment drugs including, artemether, artemisinin-based combination therapies (ACT), primaquine, combinations and various forms thereof and various other WHO approved treatment components. The effective doses can be in one or more delivery forms, including, but not limited to, injectable forms, oral forms, sublingual forms, rapid dissolvable forms or combinations and variations thereof. Other forms include tablets, capsules, pills, chewables, liquids, gels, powders, combinations thereof and the like.

In certain embodiments, the malaria treatment kits are provided with effective doses for full course treatments as prescribed for the various malaria infections. The length of course of treatments will depend on the type of malaria infection and is governed by the instructions provided with the malaria treatment kits. In another embodiment, the malaria treatment kit comprises a malaria rapid detection test (RDT) kit for determining the type of malaria infection in the individual.

In other embodiments, the malaria treatment kits comprise a comprehensive set or sets of instructions for use of each of the WHO approved drugs and components, including, but not limited to, procedures for treating an individual exhibiting symptoms of malaria infection and procedures for diagnosing the presence of a malaria infection and type of malaria infection. Other embodiments encompassed by the present invention include, rapid rehydration powders for mixing with various liquids or premixed liquid packets, wherein the rehydration components are WHO approved for such uses. These embodiments also encompass instructions for proper use of the rehydration packets. In various other embodiments, the malaria treatment kits comprise anti-counterfeiting check verification characteristics. These embodiments allow the malaria treatment kit users to verify that the kits are the WHO-approved malaria treatment kits manufactured by WHO approved facilities. Other embodiments provide for customer service characteristics for aiding kit users with any questions and comments pertaining to use of the kits in treating individuals or addressing various governmental, regional, and local rules and regulations pertaining to the kits. In this capacity, the some embodiments include customizable kits for distribution in different areas requiring certain rules and regulations be met prior to distribution of malaria treatment kits of the present invention.

Also provided are certain embodiments for using the malaria treatment kits. These embodiments include instructions and method steps for effectively and timely diagnosing and treating individuals exhibiting symptoms of a malaria infection, wherein the instruction manual or manuals, address preferred drug treatment regimens and treatment of secondary symptoms common to the various types of malaria infections. Certain embodiments include packaging requirements that insure adequate preservation of the various components within the malaria treatment kits as well as the kit overall. Additional features, advantages, and embodiments of the invention are set forth or apparent from consideration of the following detailed description, drawings and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Kits and methods are described for rapid and effective treatment of malaria. The kits and methods described herein may be used in different areas and settings, including, for example, in areas where malaria infections are prevalent, rural areas, health care facilities, pseudo- and temporary health care facilities, by health care providers, caregivers and individuals, and others.

Although not required, the kits and methods are described in the general context of kits comprising components necessary for diagnosis, treatment and follow-up processing of individuals infected with malaria at all levels of the infection. The kits typically include one or more components for treating any one of main types of malaria infections as well as components for diagnosing the type of malaria infection in a rapid and effective manner. Key aspects include, but are not limited to, WHO-approved malaria treatment components from WHO-approved facilities, comprehensive instructions for insuring best treatment approach and use of the kits, anti-counterfeiting and verification characteristics, customer support characteristics, and kit customization for meeting and abiding by different governmental, regional and local rules and requirements without deviating from the WHO requirements for the kit components. The kits comprise everything for treatment of the various types of malaria and conditions of the patient from diagnosis to hydration to appropriate medicine - all within minutes. It effectively handles the emergency conditions of patients suffering from cerebral or severe falciparum. In a timely manner, one can be treated or self-treated for emergency condition, thereby saving lives and decreasing mortality numbers. Therefore, global distribution of the kits of present invention to areas around the world with high malarial concerns can save lives. While the kits and methods are described in the foregoing context, further requirements described hereinafter may also be implemented in the kits and/or methods.

In certain embodiments, the malaria treatment (or malaria survival) kits comprise an effective amount of artemether. This drug is WHO-approved and is highly effective against both malarial parasites P. falciparum and P. vivax. WHO guidelines recommend artemisinin- based combination therapy (ACT), where uncomplicated/afc/param malaria is involved. In various embodiments, the artemether-form is used in the ACT and provided as such in the kit. The ACT, therefore, would include artemether and lumefantrine in a fixed-dose combination. Lumefantrine is an antimalarial agent used to treat acute uncomplicated malaria. It is administered in combination with artemether for improved efficacy. This combination therapy exerts its effects against the erythrocytic stages of Plasmodium spp. and may be used to treat infections caused by P. falciparum and infections acquired in chloroquine-resistant areas. The ACT is also on the WHO's Essential Medicines list. The ACT, artemether and/or lumefantrine can be in many delivery forms for purposes of the present invention, including, but not limited to, tablets, capsules, dispersibles, pills and the like.

In other embodiments, the kits can include artesunate, as another antimalarial agent. For example, the artesunate can be in tablet form (e.g. , 50 mg), or powder form for injection (e.g. , 60 mg) of anhydrous artesunate in 1-ml ampoules + 5% sodium bicarbonate in 0.6-ml ampoule. Artesunate is a water-soluble hemisuccinate derivative of artemisinin. It is unstable in neutral solution and the injectable formulation must be prepared immediately before use in 5% (w/v) sodium bicarbonate solution to produce the salt sodium artesunate. After parenteral administration, it is rapidly hydrolyzed to the active metabolite

dihydroartemisinin. The oral formulation is probably hydrolyzed completely before entering the systemic circulation. Artesunate has been reported to clear fever in patients with severe falciparum malaria 16-25 hours after parenteral administration. Oral is recommended for treatment of uncomplicated falciparum malaria in areas where there is evidence of chloroquine, pyrimethamine/sulfadoxine, mefloquine and quinine resistance. For example, adults and children over six months it is recommended that treatment begin with 5 mg/kg orally on the first day followed by 2.5 mg/kg on the second and third days in combination with mefloquine (e.g. , 15 mg/kg) in a single dose on the second day. In a few areas, a higher dose (25 mg/kg) of mefloquine may be required for a cure to be obtained. Oral artesunate should not be used during the first trimester of pregnancy.

Parenteral treatment is recommended for treatment of severe falciparum in areas where there is evidence of quinine resistance. Radical cure is then effected with a full course of an effective oral antimalarial treatment regimen. The powder for injection should be reconstituted with 5% sodium bicarbonate and diluted in an equal volume of physiological saline or 5% (w/v) glucose. It should be administered immediately by either intravenous or intramuscular injection. A loading dose of 2 mg/kg should followed by 1 mg/kg after 4 hours and 24 hours. Thereafter, a dose of 1 mg/kg should be given daily until the patient is able to tolerate oral artesunate or for a maximum of 7 days. Parenteral artesunate should be used for the treatment of severe falciparum malaria only where there is evidence that the antimalarial efficacy of quinine is declining. The powder for injection is difficult to dissolve and care should be taken to insure that it is completely dissolved before parenteral administration. It should always be used immediately following reconstitution. If the solution is cloudy or a precipitate is present, the parenteral preparation should be discarded. While there is limited information related to use of the parenteral preparations in pregnancy, the parenteral preparations should not be withheld if it is considered life-saving to the mother.

Storage of the oral and parenteral forms (tablets, pills, capsules, powders, etc.) should be in tightly closed containers and protected from light to protect the shelf life of the products.

In various embodiments, kits can comprise primaquine. This drug is to be used in the treatment of P. vivax or P. ovale malaria. Use of the drug in its various forms, works to clear dormant liver forms of the parasites once the parasite has been eliminated from the bloodstream. This requires a 14 day course of the drug, which is a radical cure. Treatment of patients with P. vivax or P. ovale infections with the primaquine works to reduce and/or eliminate potential relapses of infection weeks later. Single doses of the drug is used for rapid response against later stage infections oi falciparum. This results in a rapid reduction in transmission, and is useful in combinations with antimalarial drugs focused on earlier stages of infection. Kits of the present invention may include prevent doses and/or treatment doses of primaquine. For example, primaquine present in packets of single doses (0.25 mg/kg) is safe to give for purposes of preventing transmission of falciparum malaria. For pregnant patients, it should be noted that primaquine is contraindicated due to the unknown glucose-6- phosphate dehydrogenase status of the fetus. For dosing purposes, primaquine doses are always expressed as a base but not as a salt.

As discussed herein, artemether can be delivered as an injectable, oral, rapid dissolvable, or combinations thereof. Therefore, the kits of the present invention can comprise one or more deliverable forms of artemether. The ACT can be in the form of a tablet, pill or capsule. The kits provide ACT and instructions for its use wherein the ACT is a four day treatment course delivering the necessary amounts of the drugs to effectively treat the malaria. The primaquine can be in a delivery form of a tablet capsule or pill. Primaquine delivery forms can be formulated to deliver an effective amount of the drug for a two week (14 days) treatment course. In all cases, the delivery forms of the drugs are formulated to deliver an effective amount of the drug for the purposes of treating the patient infected with or suspected of malarial infection. The effective doses can be in one or more delivery forms, including, but not limited to, injectable forms, oral forms, sublingual forms, rapid dissolvable forms or combinations and variations thereof. Other forms include tablets, capsules, pills, chewables, liquids, gels, powders, combinations thereof and the like. In all instances, the kits provide instructions for use of the drugs for effective life saving measures.

Table 1 illustrates WHO-approved malarial treatment drugs and combinations, including formulation and strengths, as well as packaging descriptions. These may be used in any necessary combination depending on any number of factors including, but not limited to, local, regional and governmental regulations and approvals, requirements for treatments of particularly prevalent forms of malaria infections and/or various types of resistance to known treatments:

TABLE 1: sodium chloride injection (5ml:45mg)]

Artesunate Powder for injection 30mg Vial; 1 vial of artesunate powder is co-packed with 1 ampoule of sodium bicarbonate injection (0.5mL:25mg) and 1 ampoule of sodium chloride injection (2.5mL:22.5mg)

Artesunate Powder for injection Vial; 1 vial of artesunate powder is co-packed

120mg with 1 ampoule of sodium bicarbonate injection (2mL: 100mg) and 1 ampoule of sodium chloride injection (10mL:90mg)

Artesunate + [Sulfadoxine + Tablets + Tablets 50mg + PVC/Alu blister 3 + 1 ; 6 + 2

Pyrimethamine] [500mg + 25mg]

Artesunate + Amodiaquine (as Tablets 25mg + 67.5mg Alu/Alu blister 1 x 3

hydrochloride)

Artesunate + Amodiaquine (as Tablets 50mg + 135mg Alu/Alu blister 1 x 3

hydrochloride)

Artesunate + Amodiaquine (as Tablets lOOmg + 270mg Alu/Alu blister 1 x 3, 1 x 6

hydrochloride)

Artesunate + Mefloquine (as Tablets 25mg + 50mg Alu/Alu strip 1 x 3, 2 x 3

hydrochloride)

Artesunate + Mefloquine (as Tablets lOOmg + 200mg Alu/Alu strip 1 x 3, 2 x 3

hydrochloride)

In various other embodiments of the invention, the kits can comprise additional components necessary in the treatment and/or diagnosis of the malaria infection. In one embodiment, the kit comprises a malaria rapid test kit. Instructions are provided for using the malaria test kits. The kits of the present invention can provide a malaria rapid test kit capable of diagnosis within 15-20 minutes of opening the malaria treatment kit. The patient can be effectively diagnosed through a care giver, for example, or self-diagnosed, and started on a treatment course by a self or a care giver, e.g. , clinician or care giver. The ability to rapidly test and begin immediate treatment with the malaria specific drug from the malaria treatment kit greatly enhances survival chances and minimizes unnecessary organ damage from lack of proper and timely treatment. This is appropriate for severe (emergency) malaria conditions to moderate and even relapse malaria conditions caused by vivax. A standard malaria test kit, the tester will be instructed to collect whole blood specimens following regular clinical laboratory procedures and store specimens in a refrigerator if not used the same day. A 0.1% of sodium azide can be added to specimens as a preservative without affecting results of the assay. Store as packaged in a sealed pouch at 2-30 degrees C and not in direct sunlight. The test is stable through the expiration date printed on the sealed pouch. The test must remain in the sealed pouch until use and should not be frozen. Collection should be at room

temperature with the supplied materials being at room temperature as well. Collection can be done by the patient or care provider or other personnel by taking blood sample from the finger using the supplied lancet, test cassette, sealed pouch and sample diluents. Applying sufficient amounts of sample diluents is essential for a valid test result. Adjustments to amounts of diluents may be necessary to insure a proper and timely test result. The instructions will provide for such steps, e.g. , if migration (the wetting of membrane of the cassette) is not observed in the test window after one minute, add one more drop of the kit- supplied diluent to the sample. A positive result could appear as soon as one minute for a sample with high levels of malaria, but results should not be interpreted after 30 minutes. The membranes of the cassettes will be marked accordingly for an interpretation of the results. The cassettes may be marked for one or more types of malaria infections.

As described herein, once the testing begins, one can also simultaneously self-hydrate and not rely on the intravenous hydration that may or may not be available in the patients location. For example, one does not have to rely on the medicine inventory in a hospital or local pharmacy to resolve their condition if the individual has ready access to a malaria treatment kit of the present invention.

In situations where waiting for the results is potentially life threatening for the infected person, treatment should begin immediately to insure that further internal organ damage does not occur. For example, an ACT treatment could begin immediately while waiting for the test results. In other embodiments of the invention, the kits may comprise a rapid rehydration powder that can be mixed with a liquid of choosing or a premixed liquid for oral

consumption. These powders or mixes are meant to provide rehydration to the patient in need or to prepare the infected patient for duration of the infection while under treatment. These liquids may be adapted for intravenous use where patients are unable take oral consumption of the rapid rehydration mixes, i.e. , where the patient is weak, catatonic or comatose.

Other components for use in the kits include, but not limited to, thermometers, space blankets, treatment logs, patient tags and treatment schedules. The malaria treatment kits of the present invention are designed for use by healthcare providers, aid givers and the like, but are also designed for self-diagnosis and treatment through use of the instructions provided with each kit. This permits the malaria treatment kits to be distributed to remote areas around the world where a patient may be considerable distance from a healthcare facility or aid center. Again, the present invention is equipped to maximize survival of the infected patient.

It will be understood that these kits are provided with clear instructions on administration of drugs, testing and diagnosis. Therefore, an individual can self-treat if necessary. This can occur in situations where individuals are in remote areas where access to proper facilities are distant and treatment is necessary immediately.

In certain embodiments, a kit and/or one or more components of a kit may include one or more systems and/or methods for product tracking and/or anti-counterfeiting.

Embodiments may possess the ability to store and/or access transactional activity. In certain embodiments, systems and methods may consolidate a portion or all transactional activity around one or more individual products and/or packages within a kit and/or one or more packages for the kit as a whole. In certain embodiments, the transactional activity may be stored and/or accessed as a single, cohesive analytical view with a system for product tracking and/or anti-counterfeiting.

Certain embodiments may include a location system. Certain embodiments may include a data storage system. In certain embodiments, systems may include a geo-location system and temporal data storage system for tracking and/or locating one or more products. The systems may allow tracking and/or locating in real-time, near real-time, on demand, at predetermined intervals, etc. depending on specific requirements of users and/or products. Certain embodiments may also include world-wide web (internet) interfaces and applications programming interfaces (APIs) for easy access to analytics and connections with enterprise CRM (Customer Relationship Management), MES (Manufacturing Execution System), ERP (Enterprise Resource Planning) systems. Systems may operate in conjunction with a wide range of product identifiers, including ID barcodes, QR codes, serial or tracking numbers, active/passive RFID, and NFC tags, or any other information coming directly from the product by sensor feeds that are traceable by the systems.

The kits, methods and systems may include enhanced semantic product information and may support anti-counterfeiting tracking and/or analysis. Certain embodiments may include alert triggers. Anti-counterfeiting applications and techniques may cover the malaria treatment kit from the point of departure of the malaria treatment kit, to loading for shipment on pallets, boxes, inner cartons and individual component pouches or containers within the malaria treatment kit. Various anti-counterfeiting systems and methods may be used for individual components of a kit or a kit as a whole. In certain embodiments, anti- counterfeiting systems and methods may include microtags. Microtags may be made of various materials, such as silica (silicon dioxide - Si0 ₂ ) or other biologically inert materials. In certain embodiments, the microtag material may be generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA). Microtags may also be safe for the environment. Microtags may have a high melting point and/or a shelf life that meets or exceeds the product lifetime. Microtags may be encoded with a unique spectral pattern to operate as a microscopic bar code. The unique spectral pattern may be predetermined based on required information to be stored in the microtag. The microtags may be applied directly to products and/or incorporated into substrates and coatings. A field reader may be used to very product information directly from the product, such as a dosage unit or other item, without relying on external packaging. In certain embodiments, the microtags may be included on, in or otherwise associated with the packaging. When a field reader locates a product code and a matched is found in one or more databases, relevant product information may be provided to a user. Information from the microtags may include, but is not limited to, product, lot number, item number, authorized country of sale, dosage, manufacturing site, manufacturing date, expiration date, etc. The product information may include whether the product is authentic and/or matches context-specific requirements, such as districution channels, territories, and/or packaging data. Systems may allow conversion of the unique spectral codes into an identification number that can be added to a database or other data storage system. This identification number may then be linked to other fields of information as needed. Mictrotags may be read directly by the field reader or may be forensically recovered and/or reconstructed at a laboratory or other facility. By way of example, one such technology is that provided under the trademark TRUTAG™ (TRUTAG™ Technologies, 2045 Lauwiliwili Street, Unit 301, Kapolei, HI 96707).

Packaging of the kits is required in all facets to insure maximum shelf life. The individual components of the kits are preserved in own packaging within the kits. This is necessary where only certain components of the kits are required for a particular malaria event. The kits are also capable of being customized to account for specific regions around the world where certain types of malaria are of more concern, or where local, regional or governmental requirements only permit use of certain kit components. The adaptability of kit components is necessary to insure maximum survival in regions of malarial prevalence. Although the foregoing description is directed to the preferred embodiments of the invention, it is noted that other variations and modifications will be apparent to those skilled in the art, and may be made without departing from the spirit or scope of the invention. Moreover, features described in connection with one embodiment of the invention may be used in conjunction with other embodiments, even if not explicitly stated above.