Composition and method for treating leishmaniasis

Abstract

The presently disclosed subject matter provides a method and pharmaceutical composition for use in treating disease conditions caused by Leishmania species parasites such as Leishmaniasis. The pharmaceutical composition includes a dose of Itraconazole and a dose of Amiodarone in an amount effective to treat Leishmaniasis, along with a pharmaceutically acceptable carrier, and may be in a solid form such as a tablet, capsule, caplet, powder, or a suspension. The form of itraconazole used in the pharmaceutical composition may be one prepared for administration by virtue of a hot melt extrusion process so as to improve bioavailability and other properties. The method for treating Leishmania disease is carried out by using an effective amount of Itraconazole and Amiodarone to treat a subject in need thereof, and the present compositions, methods, and uses are safer and more effective than previous compositions for treating leishmaniasis, and with fewer undesirable side effects.

Description

COMPOSITION AND METHOD FOR TREATING LEISHMANIASIS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Application 63 / 452,565, filed March 16, 2023, said application being incorporated herein by reference in its entirety. FIELD The presently disclosed subject matter relates to a pharmaceutical composition and method for treating the parasitic diseases known as Leishmaniasis. More particularly, the presently disclosed subject matter relates to a pharmaceutical composition comprising a dose of Itraconazole and a dose of Amiodarone, a method of preparing the pharmaceutical composition, and a method of administering this pharmaceutical composition in order to treat human and animal Leishmaniasis patients. BACKGROUND Leishmaniasis is a parasitic disease that has severe effects on humans and animals throughout the world. This disease primarily affects canines, felines, and humans is found in parts of the tropics, subtropics, and southern Europe, and it is classified as a neglected tropical disease (or NTD). Leishmaniasis is caused by infection with Leishmania parasites, which are spread by the bite of insects such as phlebotomine sand flies. In one mode of transmission, sand flies become infected by sucking blood from an infected animal or person. Some types of Leishmania parasites also may be spread via contaminated needles (needle sharing), blood transfusions, or 1 VI133W:223897:574168:1:ALEXANDRIAeven congenital transmission from a pregnant woman to her baby. There are thus multiple modes of transmission that can cause the spread of this condition to many parts of the World. The number of new cases may vary or change over time and are difficult to estimate, but it is estimated that there are over a million new cases of Leishmaniasis per year. In the Eastern Hemisphere, Leishmaniasis is found in some parts of Asia, the Middle East, Africa (particularly in the tropical region and North Africa, with some cases elsewhere), and southern Europe. It is not found in Australia or the Pacific Islands. In the Western Hemisphere. leishmaniasis is found in some parts of Mexico, Central America, South America, and North America. In the US, incidents of leishmaniasis have been reported in Oklahoma and Texas, and many cases have arisen in U.S. civilian travelers that were acquired in common tourist destinations in Latin America, such as in Costa Rica. U.S. military personnel have become infected in various countries, such as Iraq and Afghanistan. There are several different forms of leishmaniasis in people. The most common forms are cutaneous leishmaniasis, which causes skin sores, and visceral leishmaniasis, which affects several internal organs (usually spleen, liver, and bone marrow). Still other forms of diseases caused by Leishmania include subcutaneous Leishmaniasis and mucocutaneous Leishmaniasis. Despite the growing interest in the development of new drugs for treatment, current therapies for Leishmania disease remain unsatisfactory. Previously, a combination of amiodarone and itraconazole was used in the treatment of Chagas disease as set forth in US Patent No.10,736,891 (Madigan et al.), but a reported 2 VI133W:223897:574168:1:ALEXANDRIAattempt to use this technology in Leishmania amazonensis did not result in a successful treatment regimen (see Anversa et al., Int’l Journal of Antimicrobial Agents, 50:159-165, 2017). However, it appears this treatment failed because the authors of the article used a compounded form of itraconazole prepared using a dilution and ultrasonic bath which limited its effects. In addition, therapeutic levels of both itraconazole and amiodarone in the subject’s plasma were not monitored, and the itraconazole was not treated so as to make it more bioavailable. It thus appears that the treated animals only absorbed a sub-therapeutic and non-bioavailable amount which led to the erroneous conclusion that such a combination could not be made to work against Leishmania amazonensis. As set forth below, the present inventors have thus determined that the proper use and administration of a combination of Amiodarone and Itraconazole in a more therapeutic and bioavailable form can be utilized in a successful treatment of Leishmaniasis without adverse side effects and thus fill an important need in the industry to develop a safe and effective treatment of parasites of species of the genus Leishmania. As shown below, Applicant’s invention provides an efficient way of making use of the relative mechanisms of action of itraconazole and amiodarone, and the combined effects of amiodarone and itraconazole when used in the proper bioavailable form and resulting sufficient amount in plasma of the subject is useful in providing an effective treatment of Leishmaniasis in a way that was not previously possible. In addition, Anversa also noted that the combination failed to stop the development of cutaneous lesions. As indicated above, Leishmaniasis disease exists in many forms, namely the cutaneous form that results in cutaneous lesions, and in other forms including the visceral and mucocutaneous forms of Leishmaniasis in humans and 3 VI133W:223897:574168:1:ALEXANDRIAanimals. All of these forms, namely visceral, mucocutaneous, and cutaneous, along with their carious symptoms, including one or more cutaneous lesions, sores, or ulcers on the skin, swollen glands, fever, weight loss, enlargement (swelling) of the spleen and liver, and abnormal blood counts, can be treated by the present method and pharmaceutical composition for use in treating leishmaniasis as set forth in detail herein. SUMMARY In accordance with the present invention, the presently disclosed subject matter provides a pharmaceutical composition and method for use in treating diseases caused by parasites of the genus Leishmania, otherwise known as Leishmania disease or Leishmaniasis. The pharmaceutical composition for use in treating Leishmaniasis in accordance with the invention comprises as active ingredients a dose of Itraconazole and a dose of Amiodarone, and in certain embodiments, the active ingredients can be in the form of a pharmaceutical composition that includes the active ingredient in a pharmaceutically acceptable carrier. In further embodiments, the pharmaceutical composition for use in treating Leishmaniasis may also include a second pharmaceutically acceptable carrier. In some embodiments, the presently disclosed subject matter provides that the dose of Itraconazole is first mixed with the second pharmaceutically acceptable carrier. In certain exemplary embodiments, the dosage of Itraconazole in the pharmaceutical composition for use in treating Leishmaniasis may be in the range of about 3 mg / kg to about 12 mg / kg based on the approximate weight of the subject receiving said treatment, and the dosage of Amiodarone in the pharmaceutical 4 VI133W:223897:574168:1:ALEXANDRIAcomposition for use in treating Leishmaniasis may be in the range of about 2 mg / kg to about 10 mg / kg based on the approximate weight of the subject receiving said treatment. In one exemplary embodiment, the dosages are administered once per day, and in other embodiments, the dosage can be provided in multiple amounts so that the total amount administered is in the range of about 3-12 mg / kg of Itraconazole and 2-10 mg / kg of Amiodarone per day. The active ingredients can also be administered simultaneously or separately to the patient. In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml of the active ingredients, or in another embodiment from about 0.3 to 2.0 μg / ml. In other embodiments, the dosage range of Itraconazole can be from about 5 to about 10 mg / kg or from about 7 to about 8 mg / ml, and the dosage range of Amiodarone can be from about 2.5 to about 8.0 mg / kg, from about 3 to about 7.5 mg / kg, or from about 6 or 7 to about 8 mg / ml. The dosage of Amiodarone can also be about 7.5 mg / ml / In one embodiment, the Itraconazole and Amiodarone are administered along with a pharmaceutically acceptable carrier. In exemplary embodiments of the invention, the Itraconazole and Amiodarone are administered at the same time for use in the treatment of Leishmaniasis, either in a combined dose or separately. The Itraconazole and Amiodarone may also be administered in a combined form or separately. The Itraconazole and Amiodarone may be administered once daily, or may be administered in multiple dosages per day to achieve the total amounts as set forth herein. In general, one exemplary method of use for treatment of Leishmaniasis may be carried out over a long period of time, such as from one month to two years. In addition, as described further herein, the Itraconazole 5 VI133W:223897:574168:1:ALEXANDRIAand Amiodarone can be administered for use in a subject in need of treatment for Leishmaniasis in two phases comprising an initial phase wherein a loading dose is administered to the subject and a second phase wherein a maintenance dose is administered to the phase, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone. In certain embodiments, the loading dose may be administered for a period of from about 1 to 3 months, and the maintenance dose may be administered for a period of about 3 months to 2 years following the completion of the loading dose period. In certain embodiments of the invention, the dose of Itraconazole used to treat a subject or patient in need of treatment for Leishmaniasis may be in the range of about 5 mg / kg to about 10 mg / kg, or may be in the range of about 7 mg / kg to about 8 mg / kg. In certain embodiments, the dose of Amiodarone is in the range of about 2.5 mg / kg to about 8.5 mg / kg, or may be in the range of about 3 mg / kg to about 7.5 mg / kg. The dose of Amiodarone may also be in the range of about 6 or 7 mg / kg to about 8 mg / kg. In general, the dose of one or both of the active ingredients can be sufficient to result in a plasma concentration in the patient of from about 0.1 to 3.0 μg / ml, or from about 0.3 to 2.0 μg / ml, of the active ingredients. In additional embodiments, the active ingredients may be combined with an immunomodulator, and in one exemplary embodiment, the Itraconazole may be prepared using a hot melt extrusion process. In certain embodiments, the dosage regimen of the active ingredients for use in treating Leishmaniasis may be administered to the patients in a method wherein there is 6 VI133W:223897:574168:1:ALEXANDRIAan initial dosage or “loading dosage” of the active ingredients for an initial period of time that is followed with a second period of treatment known where the active ingredients are at a different dosage, or maintenance dosage, that follows the initial period wherein the loading dosage is administered. In certain embodiments, the amount of one or both of the active ingredients during the maintenance dosage phase may be less than the amounts administered during the loading dosage period. In certain embodiments, the intimal or loading dose period may be in the range of from 1 to 3 months or longer, and the maintenance period may be in the range of 3 months to two years or longer following the ending of the loading dose period. In certain embodiments, the dosage range of Itraconazole may be the same during both the loading dose period and the maintenance dose period, and the dosage of Amiodarone will be in the range of about 6 or 7 to about 8 during the loading dose period, and then from about 3 to about 7.5 mg / kg during the maintenance dosage period. The dosage of Amiodarone may also be about 7.5 during the loading dose period, and then from about 3 to about 7.5 mg / kg during the maintenance dosage period. The active ingredients may also be given with food and ,ay ne administered directly, or with a pharmaceutically acceptable carrier.. In certain embodiments of the presently disclosed subject matter, the active ingredients in the compositions used for treating Leishmaniasis can be administered in solid form, including such forms as tablets, capsules, caplets, films, implants, and powders. In other embodiments, the active ingredients are administered in the form of a suspension, or a heterogeneous mixture of fluid and solid particles wherein the particles do not dissolve in the fluid / Still further, the active ingredients may be administered in liquid form, such as a liquid oral suspension of a pharmaceutical composition. In one 7 VI133W:223897:574168:1:ALEXANDRIAsuch embodiment, the pharmaceutical composition includes a mixture of a dose of Itraconazole and a dose of Amiodarone in a pharmaceutically acceptable carrier. The active ingredients may also be administered to the patient separately or simultaneously in a single solid or liquid pharmaceutical form. In some embodiments, the composition may further include a second pharmaceutically acceptable carrier, and in some embodiments, the invention provides a composition wherein the dose of Itraconazole is mixed with the second pharmaceutically acceptable carrier. In certain embodiments, the Itraconazole is micronized or nanomilled to a small particle size of about 1 to 400 nm. In further embodiments, the Itraconazole may be made more bioavailable and more suitable for treatment of Leishmaniasis by virtue of its preparation using a hot melt extrusion (HME) process. The hot melt extrusion process would be well known to those skilled in the art, including the art of manufacturing pharmaceuticals, such as described in Patil et al., AAPS PharmSciTech, Vol 17, No.1, February 2016. The HME process is a continuous pharmaceutical process that involves pumping polymeric materials with a rotating screw at temperatures above their glass transition temperature and sometimes above their melting temperature in order to achieve molecular level mixing of the active compound along with thermoplastic binders, polymers or both. This molecular mixing may convert the components into an amorphous product with a uniform shape and density, thereby increasing the dissolution profile of a poorly water-soluble drug. The process offers environmental advantages as well because it eliminates some of the harmful solvents such as those used in a spray-drying process. In an exemplary embodiment of the present invention, the Itraconazole is prepared in a form suitable for the pharmaceutical composition of the present invention by virtue of a hot melt extrusion 8 VI133W:223897:574168:1:ALEXANDRIAprocess which results in improved properties such as increased bioavailability, stability, and shelf life, and such a process allows for greater amounts of Itraconazole to be produced for use in the present methods of treatment faster and less expensively than other processes. In some embodiments, the presently disclosed subject matter provides a method of treating diseases caused by parasites of the species Leishmania in a subject in need thereof. The method comprises administering to the subject a pharmaceutical composition comprising a dose of Itraconazole and a dose of Amiodarone as described above. In certain embodiments, the dosage of Itraconazole administered in the method of treatment according to the invention may be in the range of about 3 mg / kg to about 12 mg / kg based on the approximate weight of the subject receiving said treatment, and the dosage of Amiodarone may be in the range of about 2 mg / kg to about 10 mg / kg based on the approximate weight of the subject receiving said treatment. In one exemplary embodiment, the dosages are administered once per day, and in other embodiments, the dosage can be provided in multiple amounts so that the total amount administered is in the range of about 3-12 mg / kg of Itraconazole and about 2-10 mg / kg of Amiodarone per day. The active ingredients can also be administered simultaneously or separately to the patient. In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml of the active ingredients, or in another embodiment from about 0.3 to 2.0 μg / ml. In other embodiments, the dosage range of Itraconazole can be from about 5 to about 10 mg / kg or from about 7 to about 8 mg / ml, and the 9 VI133W:223897:574168:1:ALEXANDRIAdosage range of Amiodarone can be from about 2.5 to about 8.5 mg / kg, from about 3.5 to about 7.5 mg / kg, or from about 6 or 7 to about 8 mg / kg The period of treatment may vary depending on the patient and the severity of the Leishmaniasis condition, as well as the type of Leishmaniasis that the patient has. In certain embodiments, the course of treatment may extend over a period of a few months through a few years. In certain embodiments, the active ingredients are administered in an initial dosage, also known as a loading dose, and in some embodiments, this initial period may be up to about 1 to 3 months or longer depending on the condition of the patient. Once the objects of the loading dose period have been achieved, a second lower dosage may be used, and this is known as a maintenance dosage. This maintenance dosage will normally be administered for a longer period than the initial or loading dosage and may be administered for a period of up to 1 to 2 years or longer depending on the condition of the patient. In certain embodiments, the maintenance dosage is lower with regard to only one of the two active ingredients, and in certain embodiments, the maintenance dose of amiodarone will be less than the initial or loading dose of the amiodarone ingredient in the pharmaceutical compositions of the present invention. For example, the initial dosage of amiodarone in the composition for use in treating Leishmaniasis may be in the range of about 6 or 7 to about 8.0 mg / kg, wherein the maintenance dosage of the amiodarone may be in the range of about 3 to 7.5 mg / kg. In certain embodiments, the loading dosage and maintenance dosage of itraconazole are the same. Still further provided in accordance with the presently disclosed subject matter is a method of producing the pharmaceutical composition of the present invention for use 10 VI133W:223897:574168:1:ALEXANDRIAin treating Leishmaniasis wherein a solid form of the active ingredient is provided. For example, in certain embodiments in the preparation of the pharmaceutical composition, the active ingredient itraconazole is prepared for the composition using a hot melt extrusion (HME) such as described above process which improves the stability and bioavailability of itraconazole in a manner not previously possible. In certain embodiments, the process results in a solid pharmaceutical composition comprising a dose of amiodarone, a dose of itraconazole, and a pharmaceutically acceptable carrier. In other embodiments, methods and pharmaceutical compositions for use are provided wherein Leishmaniasis may be treated in a human or animal patient by administering to said human or animal patient active ingredients comprising a dose of Itraconazole of from about 40 mg to about 60 mg; and a dose of Amiodarone of from about 30 mg to about 175 mg. The Itraconazole and Amiodarone may also are administered in two phases comprising an initial phase wherein a loading dose is administered to the subject and a second phase wherein a maintenance dose is administered to the phase, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone. In one exemplary embodiment, the loading dose of Itraconazole can be in the range of about 45 to 55 mg Itraconazole and about 70 to 80 mg of Amiodarone, and the maintenance dose may be in the range of about 45 to 55 mg Itraconazole and about 30 to 45 mg of Amiodarone. The loading dose of Itraconazole may also be about 45 to 55 mg and about 125 to175 mg of Amiodarone, and the maintenance dose may also be in the range of about 45 to 55 mg Itraconazole and about 30 to 45 mg of Amiodarone. In certain embodiments, the loading dose and 11 VI133W:223897:574168:1:ALEXANDRIAthe maintenance dose of Itraconazole remains the same, and the loading dose and the maintenance dose of Amiodarone can be different. In certain embodiments, the loading dose of Amiodarone can be higher than the maintenance dose of Amiodarone. In some embodiments, the maintenance does of Amiodarone may be about half of the loading dose of Amiodarone. When administered, the Itraconazole and Amiodarone in the pharmaceutical composition for use in treating Leishmaniasis may be in a solid form, such as in a form selected from the group consisting of a tablet, a capsule, a film, a caplet, a powder, and other solid forms. In one embodiment, a pharmaceutical composition for use in treating Leishmaniasis can comprise Itraconazole and Amiodarone at the levels set forth herein and can include a pharmaceutically acceptable vehicle, carrier, or excipient. In addition, the pharmaceutical composition of the invention may further comprise a second pharmaceutically acceptable carrier, wherein the dose of Itraconazole is mixed with the second pharmaceutically acceptable carrier. In other embodiments, the pharmaceutical composition of the invention may be in a liquid form or in the form of a suspension. In other embodiments, the Itraconazole has a particle size of from about 1 to 400 nm. In accordance with the invention, a solid form for use in treating Leishmaniasis is provided that comprises a mixture of a dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg of a subject and a dose of Amiodarone in the range of about 2 mg / kg to about 10 mg / kg of a subject . In other embodiments, a suspension for treating Leishmaniasis is provided that comprises a mixture of a dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg of a subject and a dose of Amiodarone in the range of about 2 mg / kg to about 10 mg / kg of a subject. 12 VI133W:223897:574168:1:ALEXANDRIAAs described further below, Applicant herein describes several embodiments of the presently-disclosed subject matter, and, in many cases, lists variations and permutations of these embodiments. This disclosure is thus merely exemplary of the numerous and varied embodiments falling with the present invention. The recitation of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, and those features can be applied to other embodiments of the presently- disclosed subject matter, whether listed or not. To avoid excessive repetition, this section does not list or suggest all possible combinations of such features. In certain embodiments, the subject or patient treated by the Itraconazole and Amiodarone may be a human or animal patient. In other embodiments, the subject or patient may be a mammal, and may also be selected from the group consisting of a human, a dog, a cat, and a monkey. Advantages of the presently-disclosed subject matter will become evident to those of ordinary skill in the art after a study of the description, and non-limiting Examples as set forth herein. DESCRIPTION OF EXEMPLARY EMBODIMENTS The details of one or more exemplary non-limiting embodiments of the presently- disclosed subject matter are set forth herein. Modifications to embodiments described herein and other embodiments will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the exemplary embodiments as 13 VI133W:223897:574168:1:ALEXANDRIAdescribed, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. While the terms used herein are believed to be well-understood by one of ordinary skill in the art, definitions are set forth to facilitate explanation of the presently-disclosed subject matter. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently-disclosed subject matter belongs. Although a number of methods, devices, and materials similar or equivalent to those described herein may be used in the practice or testing of the presently-disclosed subject matter, representative methods, devices, and materials are now described. Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a subject” includes a plurality of such subjects, and so forth. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter. As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in 14 VI133W:223897:574168:1:ALEXANDRIAsome embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method. The presently disclosed subject matter relates to a pharmaceutical composition for use in treating Leishmania disease, methods of treatment thereof, and methods of producing the active ingredients and pharmaceutical compositions containing said active ingredients. More particularly, the presently disclosed subject matter relates to a composition for use in treating Leishmaniasis in humans and animals comprising a dose of Itraconazole and a dose of Amiodarone, and a method of treatment comprising administering this composition for treatment of Leishmaniasis. In some embodiments, the presently disclosed subject matter provides a pharmaceutical composition for use in treating Leishmaniasis. In an exemplary embodiment, the pharmaceutical composition includes a dose of Itraconazole and a dose of Amiodarone as active ingredients. These active ingredients may be in the form of a pharmaceutical composition used in treating Leishmaniaisis which contains a pharmaceutically acceptable vehicle, carrier or excipient including those forms which are well known to individuals skilled in the art of preparing pharmaceutical compositions for use in treating parasitic disease. As set forth herein, the present inventors have found that the proper use and administration of a combination of Amiodarone and Itraconazole in a more therapeutic and bioavailable form than previously available can be utilized in a successful treatment of Leishmaniasis without adverse side effects and thus fill an important need in the industry to develop a safe and effective treatment of parasites of species of the genus Leishmania. In particular, it is the inventors’ understanding that the normal mechanism 15 VI133W:223897:574168:1:ALEXANDRIAof action for the amiodarone is to disrupts mitochondrial Ca2+ homeostasis in the Leishmania parasite, and for the itraconazole, this compound acts as an antifungal agent and impairs ergosterol biosynthesis so as to affect certain enzymes and inhibit cell growth of parasites of the Leishmania species. The inventors have thus discovered that these mechanisms can work together with the combination of itraconazole with amiodarone in a complete fashion so as to treat the disease. Accordingly, the present invention allows one to obtain efficient use of the mechanisms and combined effects of itraconazole and amiodarone when using these compounds in a bioavailable form and ensuring that these bioavailable forms are at the proper levels in the plasma of a subject undergoing this treatment. As thus shown herein, Applicant’s invention provides an efficient way of making use of the relative mechanisms of action, and the combined effects of amiodarone and itraconazole when used in the proper bioavailable form and in a resulting sufficient amount in plasma is useful in providing an effective treatment of Leishmaniasis in a way that was not previously possible. In exemplary embodiments, the dosage of Itraconazole administered in the method of treatment according to the invention may be in the range of about 3 mg / kg to about 12 mg / kg based on the approximate weight of the subject receiving said treatment, and the dosage of Amiodarone may be in the range of about 2 mg / kg to about 10 mg / kg based on the approximate weight of the subject receiving said treatment. In one exemplary embodiment, the dosages are administered once per day, and in other embodiments, the dosage can be provided in multiple amounts so that the total amount administered is in the range of about 3-12 mg / kg of Itraconazole and 2-10 16 VI133W:223897:574168:1:ALEXANDRIAmg / kg of Amiodarone per day. The active ingredients can also be administered simultaneously or separately to the patient. In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml of the active ingredients, or in another embodiment from about 0.3 to 2.0 μg / ml. In other embodiments, the dosage range of Itraconazole can be from about 5 to about 10 mg / kg or from about 7 to about 8 mg / ml, and the dosage range of Amiodarone can be from about 2.5 to about 8.5 mg / kg, from about 3 to about 7.5 mg / kg, or from about 6 or 7 to about 8.0 mg / kg In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml, or in another embodiment, from about 0.3 to 2.0 μg / ml. Of the active ingredients in accordance with the invention, Amiodarone is well known as an antiarrhythmic agent used for various types of cardiac dysrhythmias, both ventricular and atrial. As a versatile anti-arrhythmic agent, Amiodarone is frequently prescribed to patients due to the presence of complex arrhythmias having various causes, and in the present invention, this ingredient is now used in a method of treating the proliferative stages of parasitic infections caused by species of the genus Leishmania. As used herein, the present subject matter provides a pharmaceutical composition containing a dosage of the active ingredients Itraconazole and Amiodarone in amounts effective for the treatment of leishmaniasis in human or animal patients. In some embodiments, the amounts used in the present compositions and methods have a range, such as the ranges for both Itraconazole and Amiodarone, whether taken simultaneously in a single pharmaceutical form or administered separately. In these ranges, it is contemplated that the range covers any range that falls within the extent of the range. For example, the 17 VI133W:223897:574168:1:ALEXANDRIAdosages may include every 0.5 mg / kg interval within said range, for example, a range of 2.0 to 10.0 would include specific dosages such as about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, and so forth up to and including about 10.0 mg / kg. Further, the disclosed ranges include every range included within a larger range, such that an exemplary range of 2.0 to 10.0 would include ranges of about 2.0 and 9.5, between about 2.5 and 10, between about 2.5 and 9.5, and so forth through the entire amount of said range including the upper amount in said range. In addition, the specific amount used may include any specific amount in the range, such as in 0.1 mg.kg increments, so that amounts of 2.0, 2.1, 2.2, 2.3 and so forth up and including through 10.0 could be administered in accordance with the present invention. Itraconazole is a synthetic imidazole-triazole derivative prescribed to patients with fungal infections. Itraconazole may be given orally or intravenously and has been used in treatments of various fungal infections, such as described in Mawby et al., J. Vet. Intern. Med., 28(1):72-77 (Jan-Feb 2014), incorporated herein by reference. In the present invention, it is now used successfully for the first time in a pharmaceutical composition for treating parasitic disease caused by species of the genus Leishmania. As used herein, in some embodiments, the presently disclosed subject matter provides a pharmaceutical composition for use in treating Leishmaniasis that contains a daily dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg based on the approximate weight of the subject receiving said treatment, and the dosage of Amiodarone may be in the range of about 2 mg / kg to about 10 mg / kg based on the approximate weight of the subject receiving said treatment. In one exemplary embodiment, the dosages are administered to a subject or patient in need thereof once 18 VI133W:223897:574168:1:ALEXANDRIAper day, and in other embodiments, the dosage can be provided in multiple amounts so that the total amount administered is in the range of about 3-12 mg / kg of Itraconazole and 2-10 mg / kg of Amiodarone per day. The active ingredients can also be used to treat Leishmaniasis by administering these ingredients simultaneously or separately to the patient. In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml of the active ingredients, or in another embodiment from about 0.3 to 2.0 μg / ml. In other embodiments, the dosage range of Itraconazole can be from about 5 to about 10 mg / kg or from about 7 to about 8 mg / ml, and the dosage range of Amiodarone can be from about 2.5 to about 8.5 mg / kg, from about 3 to about 7.5 mg / kg, or from about 6 or 7 to about 8.0 mg / kg In particular, any dosage within this range is contemplated for use in the treatment of Leishmaniasis, as well as any smaller range within the larger range. For example dosages of either Itraconazole or Amiodarone may be at every 0.5 mg / kg interval within the total range, namely the lower limit may be about 0.5 mg / kg, about 1.0 mg / kg, about 1.5 mg / kg, and so forth all the way throughout the range to the upper limit. In an exemplary embodiment of the present invention, a pharmaceutical composition for use in treating Leishmaniasis is provided which comprises as active ingredients a dose of Itraconazole and a dose of Amiodarone, and in certain embodiments, the active ingredients can be in the form of a pharmaceutical composition that includes the active ingredient in a pharmaceutically acceptable carrier. In further embodiments, the pharmaceutical composition for use in treating Leishmaniasis may also include a second pharmaceutically acceptable carrier. In some embodiments, the 19 VI133W:223897:574168:1:ALEXANDRIApresently disclosed subject matter provides that the dose of Itraconazole is first mixed with the second pharmaceutically acceptable carrier. The method of treatment and use of the composition of the invention may also be carried out in two phases. For example, the Itraconazole and Amiodarone may be administered in two phases comprising an initial phase wherein a loading dose for Leishmaniasis treatment is administered to the subject and a second phase wherein a maintenance dose Leishmaniasis treatment is administered to the subject, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone. For example, in one embodiment, the loading dose of Amiodarone may be in the range of about 7.0 to about 8.0 mg / kg, wherein the maintenance dose of the Amiodarone is in the range of about 3 to 7.5 mg / kg. The loading dose of Amiodarone may also be about 7.5 mg / kg, and the maintenance dose of Amiodarone can be in the range of about 3 to about 7.5 mg / kg. In some embodiments of the invention, the loading dose of the Itraconazole may be the same as the maintenance dose of Itraconazole, and in some cases, this dose may be the same or similar. In some embodiments, the loading dose is administered for a period of from about 1 to 3 months, and the maintenance dose is administered for a period of about 3 months to 2 years following the completion of the loading dose period. In the present disclosure, the terms “treatment” or “treating” refer to the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, 20 VI133W:223897:574168:1:ALEXANDRIAtreatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In some embodiments, the associated disease is Leishmaniasis. In some embodiments, the pharmaceutical composition for use in treating Leishmaniasis further includes a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suspended in the pharmaceutically acceptable carrier. A non-limiting example of a pharmaceutically acceptable carrier is one that is a solid form, liquid form, or a suspension. In another non-limiting example, an oily solvent medium may also be used. As would be recognized by one of ordinary skill in the art, the oily solvent medium can be any pharmaceutically acceptable oil suitable to act as a solvent for the active ingredients. The oily solvent medium can be a vegetable oil or a nut oil, with one non-limiting example of the oily solvent medium being almond oil. As used herein, the term “pharmaceutical carrier” or “pharmaceutically acceptable carrier” may refer to any of a wide variety of materials known for general 21 VI133W:223897:574168:1:ALEXANDRIAusage in delivering a pharmaceutical agent or agents to a patient. Non-limiting examples of such carriers include solid forms such as tablets, caplets, films, caplets, powders, and other solid forms. In addition, the pharmaceutical carriers may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made- by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be 22 VI133W:223897:574168:1:ALEXANDRIAdissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. For oral administration, the compositions for use in treating Leishmaniasis can take the form of, for example, tablets or capsules prepared by a conventional technique with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets can be coated by a number of conventional methods well known in the art. The form of the present composition may be a suspension as disclosed herein, but may take on other suitable forms including a capsule, tablet, film, caplet, powder, or any other convention form for administering pharmaceutical compounds and compositions. Administration can be in a number of suitable ways including oral administration, intravenously, parenteral, or by topical administration. Further provided, in some embodiments of the presently disclosed subject matter, is a second pharmaceutically acceptable carrier. In some embodiments, the dose of Itraconazole is mixed with the second pharmaceutically acceptable carrier. One non-limiting example of the second pharmaceutically acceptable carrier is lactose. [hot melt extrusion, cited article. Further still, in some embodiments, the presently disclosed subject matter provides that the pharmaceutical composition for use in treating Leishmaniasis further contains a flavor enhancer which may be a fruit-flavored enhancer. Non-limiting 23 VI133W:223897:574168:1:ALEXANDRIAexamples of the flavor enhancer is stevia and banana. In some embodiments of the presently disclosed subject matter, the pharmaceutical composition is adapted for a once-daily oral dosing. Suitable formulations of the present composition for use in treating Leishmaniasis may include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. The pharmaceutical compositions for use in accordance with the present invention may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients Itraconazole and Amiodarone can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a frozen or freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carrier immediately prior to use. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional techniques with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated 24 VI133W:223897:574168:1:ALEXANDRIAedible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate. Preparations for oral administration can be suitably formulated to give controlled release of the active compound. For buccal administration the compositions can take the form of tablets or lozenges formulated in conventional manner. The compositions can also be formulated as a preparation for implantation, injection, or a variety of other administration modes that would be well known to one of ordinary skill in the art. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). The compositions can also be formulated in rectal compositions (e.g., suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides), creams or lotions, or transdermal patches. In some embodiments of the presently disclosed subject matter, an oral suspension for treating Leishmaniasis is provided. The oral suspension contains a mixture of a dose of Itraconazole and a dose of Amiodarone suspended in a pharmaceutically acceptable carrier. A non-limiting example of the pharmaceutically acceptable carrier is an oily solvent medium such as almond oil. In some embodiments, the oral suspension of the disclosure may further contain a second pharmaceutically acceptable carrier, and the Itraconazole is mixed with the 25 VI133W:223897:574168:1:ALEXANDRIAsecond pharmaceutically acceptable carrier. A non-limiting example of the second pharmaceutically acceptable carrier is lactose. In further embodiments, the Itraconazole used in the composition for use in treating Leishmaniasis may be prepared using a hot melt extrusion (HME) process. The hot melt extrusion process would be well known to those skilled in the art, including the art of manufacturing pharmaceuticals, such as described in Patil et al., AAPS PharmSciTech, Vol 17, No.1, February 2016, incorporated herein by reference. The HME process is a continuous pharmaceutical process that involves pumping polymeric materials with a rotating screw at temperatures above their glass transition temperature and sometimes above their melting temperature in order to achieve molecular level mixing of the active compound along with thermoplastic binders, polymers or both. This molecular mixing may convert the components into an amorphous product with a uniform shape and density, thereby increasing the dissolution profile of a poorly water- soluble drug. The process offers environmental advantages as well because it eliminates some of the harmful solvents such as those used in a spray-drying process. In an exemplary embodiment of the present invention, the Itraconazole is prepared in a form suitable for the pharmaceutical composition of the present invention by virtue of a hot melt extrusion process which results in improved properties such as increased bioavailability, stability, and shelf life, and such a process allows for greater amounts of Itraconazole to be produced for use in the present methods of treatment faster and less expensively than other processes. Further provided, in some embodiments of the presently disclosed invention, is a pharmaceutical composition and method for use in treating Leishmaniasis that contains 26 VI133W:223897:574168:1:ALEXANDRIAan amount of Itraconazole suitable to attain a blood concentration of Itraconazole in the range of from about 0.1 μg / mL to about 3.0 μg / mL, or in another embodiment, from about 0.3 μg / ml to about 2.0 μg / ml. In additional embodiment, the Itraconazole therapeutic efficacy may be maximized when serum concentrations exceed 0.5 mcg / mL for localized infections, or 1.0 mcg / mL for systemic infections. In one embodiment of the presently disclosed invention, the itraconazole may be prepared as a formulation for use in treating Leishmaniasis through a process of micronization or nanomilling. Such a process is useful in order to greatly increase bioavailability of itraconazole by 2000% or greater, for example by reducing the particle size of itraconazole to between 1 and 400 nm, e.g., around 240-280 nm, or 260 nm. In such a process, the itraconazole can be spray dried onto a suitable carrier such as a sugar molecule (e.g., lactose or mannitol) and given orally. Such a micronization process allows for minimizing the amount of the drug used in patients with the same therapeutic effect. For example, compared to the non-micronized version, the micronized version allows for the compositions of the present invention to use roughly 1 / 20 of the drug in the pharmaceutical composition, and this will substantially reduce manufacturing costs and be able to substantially reduce the cost of treatment to the patient. essentially save our target population a significant amount of expense. Similarly, preparing itraconazole by means of a hot melt extrusion process will allow for a larger amount of the itraconazole to be produced in less time with greater yields. Once again, this is advantageous because it will lower the costs involved in drug manufacture and allow for a less expensive product. Both of these processes allow for significant cost savings that can be passed on to prospective patients, and this is 27 VI133W:223897:574168:1:ALEXANDRIAparticularly important considering that there are large numbers of patients with Leishmaniasis in Central and South America where a large percentage of patients are impoverished. In one embodiment of preparing the Itraconazole in accordance with the present invention, the Itraconazole can be nanometrically milled using conventional wet milling equipment well known in the art. In one suitable process, itraconazole (1%, w / v) can be suspended in a desired concentration of an aqueous stabilizer solution, and the prepared suspension can be stirred for 30 minutes or more for complete wetting of the drug by the stabilizer solution. The suspension (e.g., 150 mL) may then be wet milled or wet grinded using a conventional wet milling or grinding device such as a media mill, for example, such as those manufactured by Netzsch of Exton, Pennsylvania. Using this equipment, the mill may be operated at a suitable speed, e.g., 2500 rpm in a continuous mode for a time suitable to reduce particle size to a range of 1 and 400 nm, e.g., 75 minutes. The temperature of the sample can be maintained at below 25ºC during the process, and as needed, two cooling bath recirculators may be used, including one attached to the milling device and the other attached to suspension recirculation chambers. After the milling process, the nano- and microcrystalline suspensions of itraconazole may be spray dried onto a suitable substrate, such as a sugar molecule (e.g., lactose or mannitol) using a conventional spray drying apparatus such as a B-290 spray drier manufactured by Buchi Labortechnik AG of Flawil, Switzerland. In the spray drying process, the drier is set at a suitable temperature, e.g.75ºC for the outlet and 110 ºC for the inlet. As indicated above, the spray drying using a suitable excipient, 28 VI133W:223897:574168:1:ALEXANDRIAe.g., lactose or mannitol, which is useful in preventing against nanocrystal aggregation. The spray-dried powders resulting from this process contain itraconazole at a reduced particle size, e.g., 1-400 nm, and these powders can be used in accordance with the present invention. The pharmaceutical composition for use in the treatment of Leishmaniasis in accordance with the invention may further include or may be administered with an immunomodulator. Immunomodulators are a group of drugs that primarily work on the immune system directly by turning down some proteins and turning up others. Examples of suitable imunomodulators include Thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst) which are known as immunomodulating drugs (or IMiDs). In some embodiments, the presently disclosed subject matter provides a pharmaceutical composition for use in treating parasitic diseases caused by species of the genus Leishmania that contains a daily dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg based on the approximate weight of the subject receiving said treatment, and the dosage of Amiodarone may be in the range of about 2 mg / kg to about 10 mg / kg based on the approximate weight of the subject receiving said treatment. In one exemplary embodiment, the dosages are administered once per day, and in other embodiments, the dosage can be provided in multiple amounts so that the total amount administered is in the range of about 3-12 mg / kg of Itraconazole and 2-10 mg / kg of Amiodarone per day. The active ingredients can also be administered simultaneously or separately to the patient. In general, the dosage should be sufficient to result in a plasma concentration in the patient of about 0.1 to 3.0 μg / ml of the active 29 VI133W:223897:574168:1:ALEXANDRIAingredients, or in another embodiment from about 0.3 to 2.0 μg / ml. In other embodiments, the dosage range of Itraconazole can be from about 5 to about 10 mg / kg or from about 7 to about 8 mg / ml, and the dosage range of Amiodarone can be from about 2.5 to about 8.5 mg / kg, from about 3 to about 7.5 mg / kg, or from about 6 or 7 to about 8.0 mg / kg. The presently disclosed subject matter further provides a method of treating Leishmaniasis in a subject in need thereof. In some embodiments, the Itraconazole and Amiodarone are administered in the form of a pharmaceutical composition, and in other embodiments, the Itraconazole and Amiodarone are administered separately. In additional embodiment, the subject is a mammal, such as a human, dog, cat, or monkey. In some embodiments, the Itraconazole and Amiodarone are administered once daily, and in other embodiment, they may be taken in conjunction with a meal or food. In some embodiments, the presently disclosed subject matter provides a use of the above pharmaceutical composition in a method of treating Leishmaniasis in a subject in need thereof. The method includes administering to the subject a solid, liquid, or suspension of Itraconazole and Amiodarone, or may comprise a liquid oral suspension. The liquid oral suspension may contain a mixture of a dose of Itraconazole and a dose of Amiodarone suspended in a pharmaceutically acceptable carrier. In some embodiments, the subject is a human, but may also be a cat, a dog or a monkey. In some embodiments, the suspension is administered once daily. In some embodiments, the suspension is taken in conjunction with a meal. 30 VI133W:223897:574168:1:ALEXANDRIAFurther provided, in some embodiments of the presently disclosed subject matter, is a method of producing an oral suspension containing the pharmaceutical composition for use in treating Leishmaniasis as described above. The method may include the steps of (a) applying a dose of Itraconazole to a pharmaceutically acceptable beads, (b) admixing the beads of step (a) with a dose of Amiodarone, wherein the Amiodarone is in a powdered form, and (c) suspending the mixture of step (b) in a pharmaceutically acceptable carrier. In some embodiments, the method further includes the step of adding a flavor enhancer, and in other embodiments, the pharmaceutically acceptable beads are sugar beads. In other embodiments, the method includes micronizing or nano-milling the Itraconazole to a particle size of about 1 to 400 nm. The pharmaceutically acceptable carrier may also be an oily solvent medium. In some embodiments, the method provides that the dose of Itraconazole in the suspension is in the range of about 3 to about 12 mg / kg, and is given once daily. In some embodiments, the total daily dosage is about 5 to about 10 mg / kg per day. In some embodiments, the method provides that the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg, and is given once daily. In some embodiment, the total daily dosage is about 7.5 mg / kg per day of Amiodarone. In some embodiments, the dosages of Itraconazole and Amiodarone are given at the same time, whether sequentially or together in a single composition, e.g., suspension or capsule, and in other embodiments, they can be administered separate times of the day (e.g., 12 hours apart), but overall can be administered together every 24 hours. The dosages are also preferably administered with food, and may be administered orally. 31 VI133W:223897:574168:1:ALEXANDRIAThe term “administering” refers to any method of providing a compound and / or pharmaceutical composition thereof to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition (e.g., Leishmaniasis). In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition caused by a parasite of the species Leishmania. A listing of the Leishmania species that are treated by the present composition and method is included in Table 1 In some embodiments, the pharmaceutical composition for use in treating Leishmaniasis will be administered to a subject in need thereof in an effective amount of the pharmaceutical composition. In this respect, the term “effective amount” refers to an amount that is sufficient to achieve the desired treatment result or to have an effect on the undesired condition being treated. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but that will reduce or eliminate adverse side effects. The specific therapeutically effective dose level for use in the treatment of any particular patient will depend upon a variety of factors including the disorder being treated and the 32 VI133W:223897:574168:1:ALEXANDRIAseverity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect against Leishmaniasis and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. Accordingly, the presently disclosed subject matter provides a method and composition for use in treating Leishmaniasis comprising administering to a subject in need thereof an effective amount of a dose of Itraconazole and a dose of Amiodarone. The effective amount will generally be that amount that is useful in treating Leishmaniasis. The Itraconazole and Amiodarone may be administered separately or simultaneously such as in the form of a pharmaceutical composition. The pharmaceutical composition for use in treating Leishmaniasis may be in the form of a 33 VI133W:223897:574168:1:ALEXANDRIAsuspension and may include a suitable pharmaceutical carrier such as an oily solvent medium. Additionally, the terms “subject” or “subject in need thereof” or “patient” or “patient in need thereof” refer to a target of administration, which optionally displays symptoms related to a particular disease, pathological condition, disorder, or the like. The subject of the herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, dog, horse, pig, rabbit, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “subject” includes human and veterinary subjects. In accordance with the present invention, a combination is provided comprising a combination of itraconazole and amiodarone for use in treating leishmaniasis in a human or animal subject in need thereof. The itraconazole and the amiodarone of the combination may be administered simultaneously or separately. In certain embodiments, the dosage in the combination is a dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of the subject, and a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject. The present invention also embodies the use of itraconazole and amiodarone for the manufacture of a medicament for the treatment of Leishmaniasis in a human or animal subject in need thereof. In this use, the dose of itraconazole may be in the range of about 3 mg / kg to about 12 mg / kg of a subject, and the dose of amiodarone 34 VI133W:223897:574168:1:ALEXANDRIAmay be in the range of about 2 mg / kg to about 10 mg / kg of the subject. The invention thus also relates to the use of a combination of itraconazole and amiodarone for the manufacture of a medicament for the treatment of Leishmaniasis in a human or animal subject in need thereof wherein the combination may also include a pharmaceutically acceptable carrier. The manufacture of the medicament can be carried out in a variety of ways including the methods of manufacture as described herein. In accordance with the present invention, a combination is provided comprising a combination of itraconazole and amiodarone for use in treating leishmaniasis in a human or animal subject in need thereof. The itraconazole and the amiodarone of the combination may be administered simultaneously or separately. In certain embodiments, the dosage in the combination is a dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of the subject, and a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject. The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. Some of the following examples are prophetic, notwithstanding the numerical values, results and / or data referred to and contained in the examples. EXAMPLES The examples below refer to methods of preparation and treatment of Leishmaniaisis using a combination of Itraconazole and Amiodarone in accordance with the present invention. 35 VI133W:223897:574168:1:ALEXANDRIAEXAMPLE 1 In one embodiment of preparing the Itraconazole for use in accordance with the present invention, the Itraconazole can be nanometrically milled using conventional wet milling equipment well known in the art. In one suitable process, itraconazole (1%, w / v) can be suspended in a desired concentration of an aqueous stabilizer solution, and the prepared suspension can be stirred for 30 minutes or more for complete wetting of the drug by the stabilizer solution. The suspension (e.g., 150 mL) may then be wet milled or wet grinded using a conventional wet milling or grinding device such as a media mill, for example, such as those manufactured by Netzsch of Exton, Pennsylvania. Using this equipment, the mill may be operated at a suitable speed, e.g., 2500 rpm in a continuous mode for a time suitable to reduce particle size to a range of 1 and 400 nm, e.g., 75 minutes. The temperature of the sample can be maintained at below 25ºC during the process, and as needed, two cooling bath recirculators may be used, including one attached to the milling device and the other attached to suspension recirculation chambers. After the milling process, the nano- and microcrystalline suspensions of itraconazole may be spray dried onto a suitable substrate, such as a sugar molecule (e.g., lactose or mannitol) using a conventional spray drying apparatus such as a B-290 spray drier manufactured by Buchi Labortechnik AG of Flawil, Switzerland. In the spray drying process, the drier is set at a suitable temperature, e.g.75ºC for the outlet and 110 ºC for the inlet. As indicated above, the spray drying using a suitable excipient, e.g., lactose or mannitol, which is useful in preventing against nanocrystal aggregation. The spray-dried powders resulting from this process contain itraconazole at a reduced 36 VI133W:223897:574168:1:ALEXANDRIAparticle size, e.g., 1-400 nm, and these powders can be used in accordance with the present invention to treat Leishmaniasis. In an example of a use for treatment of Leishmaniasis in accordance with the invention, a daily dose of the oral suspension may be provided wherein the Itraconazole is in an amount of about 5 to about 10mg / kg and the Amiodarone is provided as a dosage of about 7.5mg / kg at first in a loading dose, and this dosage may be lowered to about 3 to about 7.5 mg / kg of the patient in a maintenance dose following the loading dose period. In an example of making this oral suspension composition for use in a subject or patient in need thereof, the Itraconazole may first be infused to lactose “sugar” beads, and mixed with a pure powdered form of Amiodarone. Then the mixture of Itraconazole and Amiodarone can be suspended in an almond oil base and flavored with a flavoring ingredient such as stevia and / or banana. The pharmaceutical composition when taken by human or animal patients with a meal can thus be used to greatly assist in relieving suffering from Leishmania’ disease. The oral suspension may be administered once daily for a period of a few months to one to two years with strict monitoring of hepatic, renal and cardiovascular function, and one such mode of treatment is having the patient receive the loading dose for an initial period of time, followed by the patient receiving the maintenance dose of the pharmaceutical composition of the invention as described herein.. EXAMPLE 2 In another exemplary embodiment, the pharmaceutical composition for use in treating Leishmaniasis in accordance with the present invention may be prepared in 37 VI133W:223897:574168:1:ALEXANDRIAsolid form. In this example, Itraconazole and Amiodarone were prepared in solid tablet for treatment for Leishmaniasis as described below. In particular, while Amiodarone was prepared for the pharmaceutical composition used in the invention by conventional means, the Itraconazole was prepared using a hot melt extrusion (HME process. Such a process is described, for example, in Patil et al., AAPS PharmSciTech, Vol 17, No.1, February 2016. The HME process is a continuous pharmaceutical process that involves pumping polymeric materials with a rotating screw at temperatures above their glass transition temperature and sometimes above their melting temperature in order to achieve molecular level mixing of the active compound along with thermoplastic binders, polymers or both. This molecular mixing may convert the components into an amorphous product with a uniform shape and density, thereby increasing the dissolution profile of a poorly water-soluble drug. The process offers environmental advantages as well because it eliminates some of the harmful solvents such as those used in a spray-drying process. Accordingly, in this example, the Itraconazole is prepared in a form suitable for the pharmaceutical composition of the present invention by virtue of a hot melt extrusion process which results in improved properties such as increased bioavailability, stability, and shelf life, and such a process allows for greater amounts of Itraconazole to be produced for use in the present methods of treatment faster and less expensively than other processes. In prior forms, and using conventional preparation, it has been found that solubility of Itraconazole is generally poor, and bioavailability is minimal. As a result, it is advantageous in accordance with the invention that the Itraconazole is prepared for the pharmaceutical composition using a hot melt extrusion process. 38 VI133W:223897:574168:1:ALEXANDRIAOnce the Amiodarone and Itraconazole are prepared using the methods as described above, they can be administered for use in treatment of the patient separately, or can be prepared into a pharmaceutical tablet or capsule using procedures well known by those skilled in the art. For example, for oral administration, the compositions can take the form of tablets or capsules prepared by a conventional technique with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets can be coated by a number of conventional methods well known in the art. In addition to the active ingredients an immunomodulator may also be added. In accordance with the invention, a pharmaceutical composition for use in treating Leishmaniasis may be prepared which includes Itraconazole and Amiodarone in amounts effective to treat Leishmaniasis. In one example, the pharmaceutical compositions are prepared in two different concentrations so that they can be used in a treatment process that includes an initial phase of treatment also known as the “loading dose”, and the second concentration may be used during a second phase of treatment known as the “maintenance dose.” In one such example, pharmaceutical compositions for use in the invention can be provided wherein a first tablet is prepared as a loading dose which contains 50 mg of Itraconazole and 75 mg of Amiodarone. In a second tablet, 50 mg of Itraconazole is again used, but the dose of Amiodarone is reduced to 37.5mg, and this second tablet can be used for the maintenance dose. 39 VI133W:223897:574168:1:ALEXANDRIAIn a second example, a first tablet is prepared which contains 50mg of Itraconazole and 150mg Amiodarone to be used as the loading dose for the subject to be treated. A second formulation is prepared which contains 50 mg of Itraconazole and 37.5 mg of Amiodarone, and again this second tablet is used for the maintenance dose following the completion of the loading does period. This treatment will be useful against leishmaniasis caused by any of the variety of Leishmania species parasites, such as those included in Table I. The diseases caused by Leishmania species can thus be treated in a variety of human and animal patients, including canines and felines, and these compositions of the invention can specifically be used to treat visceral, mucocutaneous and cutaneous Leishmaniasis disease in cats, dogs and people. In general, the compositions for use in treating Leishmaniasis are designed so that the patient will be treated with an amount of itraconazole in the range of about 5 to 10 mg / kg per day, both in the loading dose and in the maintenance dose. The amount of amiodarone will generally be administered so that the patient will receive around 7.5 mg / kg / day during the loading dose phase, which drops to about 3.0 to about 7.5 mg / kg / day in the maintenance dose. In the normal case, the pharmaceutical compositions will be taken once per day with food. With regard to the determination of how long the loading dose will be administered, this will be based on the condition of the patient and the course of treatment, but in the average case, the loading dose will be administered for about 1 to 3 months following start of the treatment. The maintenance dose can be administered for a period of for about 3 months to 2 years or longer following the loading dose period, and this will also depend on the condition of the patient and the course of treatment as determined by a doctor, veterinarian, or other clinician. As indicated 40 VI133W:223897:574168:1:ALEXANDRIAabove, the pharmaceutical drug of the invention may be administered for use in treating Leishmaniasis in a solid form such as tablet, or as an oral suspension. Such treatments are highly effective against Leishmania parasites based on the specific combination of the amounts of Itraconazole and Amiodarone and the synergistic effects obtained thereby. The combination tablet or other formulation as set forth above provides superior plasma levels, improved tissue penetration, and enhanced bioavailability of the active ingredients in order to maximize the ability to treat Leishmaniasis in a manner that has not previously been possible. Accordingly, the methods and compositions for use in treating Leishmaniasis in accordance with the present invention is more effective and safer than previous attempts at treatment of Leishmaniasis. Further, the once daily treatment regimen simplifies dosing for patients and increases compliance of taking the necessary doses by providing patients a simple to follow formula. Moreover, either the tablets of the flavored oral suspensions as described herein improves patient compliance in taking the medication, and this is advantageous due to the long potential treatment regimen as described herein. 41 VI133W:223897:574168:1:ALEXANDRIATable 1: List of Leishmania species by subgenus Subgenus Leishmania Ross, 1903 sensu Saf'janova, 1982 ^ Leishmania aethiopica Bray, Ashford & Bray, 1973 ^ Leishmania amazonensis Lainson & Shaw, 1972 (includes garnhami Scorza et al., 1979) ^ Leishmania arabica Peters, Elbihari & Evans, 1986 ^ Leishmania aristidesi Lainson & Shaw, 1979 ^ Leishmania donovani (Laveran & Mesnil, 1903) ^ Leishmania forattinii Yoshida, Cuba, Pacheco, Cupolillo, Tavares, Machado, Homen & Grimaldi, 1993 ^ Leishmania gerbilli Wang, Qu & Guan, 1964 ^ Leishmania infantum Nicolle, 1908 (subspecies chagasi Cunha & Chagas, 1937) ^ Leishmania killicki Rioux, Lamotte & Pratlong, 1986 ^ Leishmania major Yakimoff & Schokhor, 1914 ^ Leishmania mexicana Biagi, 1953 ^ Leishmania pifanoi Medina & Romero, 1959 ^ Leishmania tropica (Wright, 1903) ^ Leishmania turanica Strelkova, Shurkhal, Kellina, Eliseev, Evans, Peters, Chapman, Le Blancq & van Eys, 1990 ^ Leishmania venezeulensis Bonfante-Garrido, 1980 ^ Leishmania waltoni Shaw, Pratlong & Dedet 2015 Subgenus Mundinia Shaw,Camargo and Teixeira 2016 ^ Leishmania enriettiiMuniz & Medina, 1948 ^ Leishmania macropodum Barratt, Kaufer, Peters, Craig, Lawrence, Roberts, Lee, McAuliffe, Stark, Ellis, 2017 ^ Leishmania martiniquensis Desbois, Pratlong, Quist and Dedet,2014

[0026] ^ Leishmania orientalis Jariyapan, Daroontum, Jaiwong,Sor-Suwan, Siriyasatien, Somboon, Bates, Bates, 2018 Subgenus Sauroleishmania Ranque, 1973 sensu Saf'janova, 1982 ^ Leishmania adleri Heisch, 1958 ^ Leishmania agamae David, 1929 ^ Leishmania ceramodactyli Adler & Theodor, 1929 ^ Leishmania gulikae Ovezmukhammedov & Saf'janova, 1987 ^ Leishmania gymnodactyli † Khodukin & Sofiev, 1940 42 VI133W:223897:574168:1:ALEXANDRIA^ Leishmania helioscopi † Chodukin & Sofiev, 1940 ^ Leishmania hemidactyli Mackie, Gupta & Swaminath, 1923 ^ Leishmania hoogstraali McMillan, 1965 ^ Leishmania nicollei Chodukin & Sofieff, 1940 ^ Leishmania platycephala Telford, 2009 ^ Leishmania phrynocephali Chodukin & Sofieff, 1940 ^ Leishmania senegalensis Ranque, 1973 ^ Leishmania sofieffi ↑ Markov, Lukina & Markova, 1964 ^ Leishmania tarentolae Wenyon, 1921 ^ Leishmania zmeevi ↑ Andruchko & Markov 1955 ^ Leishmania zuckermani Paperna, Boulard, Hering-Hagenbeck & Landau, 2001 ↑ Species described as Sauroleishmania. Their development is not like other members of the subgenus and so their taxonomic position is doubtful. Subgenus Viannia Lainson & Shaw 1987 ^ Leishmania braziliensis Vianna, 1911 ^ Leishmania guyanensis Floch, 1954 ^ Leishmania lainsoni Silveira, Shaw, Braga & Ishikawa, 1987 ^ Leishmania lindenbergi Silveira, Ishikawa, De Souza & Lainson, 2002 ^ Leishmania naiffi Lainson & Shaw, 1989 ^ Leishmania panamensis Lainson & Shaw, 1972 ^ Leishmania peruviana Velez, 1913 ^ Leishmania shawi Lainson, Braga & de Souza, 1989 ^ Leishmania utingensis Braga, Lainson, Ishikawa & Shaw 2003 . 43 VI133W:223897:574168:1:ALEXANDRIA

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition for treating Leishmaniasis comprising: (a) a dose of Itraconazole wherein the dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of the subject, and (b) a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject.

2. The pharmaceutical composition of claim 1 wherein the Itraconazole and Amiodarone are administered in a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claims 1 or 2 wherein the Itraconazole and Amiodarone are administered together..

4. The pharmaceutical composition of claims 1 or 2 wherein the Itraconazole and Amiodarone are administered separately.

5. The pharmaceutical composition of any of claims 1-4, wherein the Itraconazole and Amiodarone are administered once daily.

6. The pharmaceutical composition of any of claims 1-5, wherein the Itraconazole and Amiodarone are administered for a period of from one month to two years. 44 VI133W:223897:574168:1:ALEXANDRIA7. The pharmaceutical composition of any of the preceding claims, wherein the dose of Itraconazole is in the range of about 5 mg / kg to about 10 mg / kg.

8. The pharmaceutical composition of any of the preceding claims, wherein the dose of Itraconazole is in the range of about 7 mg / kg to about 8 mg / kg.

9. The pharmaceutical composition of any of the preceding claims, wherein the dose of Amiodarone is in the range of about 2.5 mg / kg to about 8.5 mg / kg.

10. The pharmaceutical composition of any of the preceding claims, wherein the dose of Amiodarone is in the range of about 3 mg / kg to about 7.5 mg / kg. 11 The pharmaceutical composition of any of claims 1-9, wherein the dose of Amiodarone is in the range of about 6 or 7 mg / kg to about 8 mg / kg.

12. The pharmaceutical composition of any of the preceding claims, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.1 to 3.0 μg / ml of the active ingredients.

13. The pharmaceutical composition of any of the preceding claims, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.3 to 2.0 μg / ml of the active ingredients. 45 VI133W:223897:574168:1:ALEXANDRIA14. The pharmaceutical composition of any of the preceding claims, further comprising an immunomodulator.

15. The pharmaceutical composition of any of the preceding claims, wherein the Itraconazole is prepared using a hot melt extrusion process.

16. The pharmaceutical composition of any of the preceding claims, wherein the Itraconazole and Amiodarone are used for treatment of Leishmaniasis by being administered in two phases, said two phases comprising an initial phase wherein a loading dose is administered to the subject and a second phase wherein a maintenance dose is administered to the phase, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone.

17. The pharmaceutical composition of claim 16 wherein the loading dose of Amiodarone is in the range of about 7.0 to about 8.0 mg / kg, wherein the maintenance dose of the amiodarone is in the range of about 3 to 7.5 mg / kg.

18. The pharmaceutical composition of claims 16 or 17 wherein the loading dose of Amiodarone is about 7.5 mg / kg, wherein the maintenance dose of the amiodarone is in the range of about 3 to 7.5 mg / kg. 46 VI133W:223897:574168:1:ALEXANDRIA19. The pharmaceutical composition of claim 16 wherein the loading dose and the maintenance dose of Itraconazole remains the same.

20. The pharmaceutical composition of any of claims 16-19 wherein the loading dose is administered for a period of from about 1 to 3 months, and wherein the maintenance dose is administered for a period of about 3 months to 2 years following the completion of the loading dose period.

21. A method for use in treating Leishmaniasis in a human or animal subject in need thereof, comprising administering to the subject (a) a dose of Itraconazole wherein the dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of the subject, and (b) a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject.

22. The method of claim 21 wherein the Itraconazole and Amiodarone are administered in a pharmaceutically acceptable carrier.

23. The method of claim 21 or 22 wherein the Itraconazole and Amiodarone are administered together..

24. The method of claim 21 or 22 wherein the Itraconazole and Amiodarone are administered separately. 47 VI133W:223897:574168:1:ALEXANDRIA25. The method of any of claims 21-24, wherein the Itraconazole and Amiodarone are administered once daily.

26. The method of any of claims 21-25, wherein the Itraconazole and Amiodarone re administered for a period of from one month to two years.

27. The method of any of claims 21-26, wherein the dose of Itraconazole is in the range of about 5 mg / kg to about 10 mg / kg.

28. The method of any of claims 21-27, wherein the dose of Itraconazole is in the range of about 7 mg / kg to about 8 mg / kg.

29. The method of any of claims 21-28, wherein the dose of Amiodarone is in the range of about 2.5 mg / kg to about 8.5 mg / kg.

30. The method of any of claims 21-29, wherein the dose of Amiodarone is in the range of about 3 mg / kg to about 7.5 mg / kg. 31 The method of any of claims 21-28, wherein the dose of Amiodarone is in the range of about 6 or 7 mg / kg to about 8 mg / kg. 48 VI133W:223897:574168:1:ALEXANDRIA32. The method of any of claims 21-31, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.1 to 3.0 μg / ml of the active ingredients.

33. The method of any of claims 21-32, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.3 to 2.0 μg / ml of the active ingredients.

34. The method of any of claims 21-33, further comprising the administration of an immunomodulator.

35. The method of any of claims 21-34, wherein the Itraconazole is prepared using a hot melt extrusion process.

36. The method of any of claims 21-35, wherein the Itraconazole and Amiodarone are administered in two phases comprising an initial phase wherein a loading dose is administered to the subject and a second phase wherein a maintenance dose is administered to the phase, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone. 49 VI133W:223897:574168:1:ALEXANDRIA37. The method of claim 36 wherein the loading dose of Amiodarone is in the range of about 7.0 to about 8.0 mg / kg, wherein the maintenance dose of the amiodarone is in the range of about 3 to 7.5 mg / kg.

38. The method of claims 36 or 37 wherein the loading dose of Amiodarone is about 7.5 mg / kg, and wherein the maintenance dose of the amiodarone is in the range of about 3 to 7.5 mg / kg.

39. The method of claim 36 wherein the loading dose and the maintenance dose of Itraconazole remains the same.

40. The method of any of claims 36-39 wherein the loading dose is administered for a period of from about 1 to 3 months, and wherein the maintenance dose is administered for a period of about 3 months to 2 years following the completion of the loading dose period.

41. The method of any of claims 21-40 wherein the Itraconazole and Amiodarone are administered with food.

42. A method of treating Leishmania disease in a human or animal subject in need thereof, comprising administering to the subject: (a) a dose of Itraconazole of from about 40 mg to about 60 mg; and (b) a dose of Amiodarone of from about 30 mg to about 175 mg. 50 VI133W:223897:574168:1:ALEXANDRIA43 The method of claim 42 wherein the Itraconazole and Amiodarone are administered in two phases comprising an initial phase wherein a loading dose is administered to the subject and a second phase wherein a maintenance dose is administered to the phase, wherein in the second phase, the level of the maintenance dose is less than the level of the loading dose for either Itraconazole or Amiodarone, or for both Itraconazole and Amiodarone.

44. The method of claims 42 or 43 wherein the loading dose of Itraconazole is in the range of about 45 to 55 mg Itraconazole and about 70 to 80 mg of Amiodarone, and the maintenance dose is in the range of about 45 to 55 mg Itraconazole and about 30 to 45 mg of Amiodarone.

45. The method of claims 42 or 43 wherein the loading dose of Itraconazole is in the range of about 45 to 55 mg Itraconazole and about 125 to175 mg of Amiodarone, and the maintenance dose is in the range of about 45 to 55 mg Itraconazole and about 30 to 45 mg of Amiodarone.

46. A method of treating Leishmaniasis in a human or animal subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising: (a) a dose of Itraconazole wherein the dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of the subject; 51 VI133W:223897:574168:1:ALEXANDRIA(b) a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject; and (c) a pharmaceutically acceptable carrier.

47. The method of claim 46 wherein the Itraconazole and Amiodarone are administered together.

48. The method of claim 46 wherein the Itraconazole and Amiodarone are administered separately.

49. The method of any of claims 46-48, wherein the Itraconazole and Amiodarone are administered once daily.

50. The method of any of claims 46-49, wherein the Itraconazole and Amiodarone claim 26 wherein the Itraconazole and Amiodarone are administered with food.

51. The method of any of claims 46-50, wherein the Itraconazole and Amiodarone are administered for a period of from one month to two years.

52. The method of claim 46, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.1 to 3.0 μg / ml of the active ingredients. 52 VI133W:223897:574168:1:ALEXANDRIA53. The method of claim 46, wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.3 to 2.0 μg / ml of the active ingredients.

54. The method of any of claims 46-53, wherein the Itraconazole is prepared using a hot melt extrusion process.

55. A pharmaceutical composition having an effective amont of active ingredients for treating Leishmaniasis, comprising as active ingredients: (a) a dose of Itraconazole wherein the dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of a subject, and (b) a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of a subject; and a pharmaceutically acceptable carrier.

56. The pharmaceutical composition of claim 55 wherein the dose of Itraconazole is in the range of about 5 mg / kg to about 10 mg / kg.

57. The pharmaceutical composition of claim 55 or 56 wherein the dose of Amiodarone is in the range of about 2.5 mg / kg to about 8 mg / kg.

58. The pharmaceutical composition of any of claims 55-57 wherein the dose is sufficient to result in a plasma concentration in the patient of from about 0.1 to 3.0 μg / ml of the active ingredients. 53 VI133W:223897:574168:1:ALEXANDRIA59. The pharmaceutical composition of any of claims 55-58 for use in treating Leishmaniasis comprising as active ingredients a dose of Itraconazole and a dose of Amiodarone.

60. The pharmaceutical composition of claim 59 further compirsing a pharmaceutically acceptable carrier 61. A pharmaceutical composition for use in treating Leishmaniasis comprising: (a) a dose of Itraconazole wherein the dose of Itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of a subject, and (b) a dose of Amiodarone wherein the dose of Amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of a subject.

62. A solid form for treating Leishmaniasis comprising a mixture of a dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg of a subject and a dose of Amiodarone in the range of about 2 mg / kg to about 10 mg / kg of a subject 63. The solid form of claim 62, wherein the Itraconazole is in an amount sufficient to attain a blood concentration of from about 0.1 μg / mL to about 3.0 μg / m in a subject. 54 VI133W:223897:574168:1:ALEXANDRIA64. A suspension for treating Leishmaniasis comprising a mixture of a dose of Itraconazole in the range of about 3 mg / kg to about 12 mg / kg of a subject and a dose of Amiodarone in the range of about 2 mg / kg to about 10 mg / kg of a subject.

65. The suspension of claim 64, wherein the Itraconazole is in an amount sufficient to attain a blood concentration of from about 0.1 μg / mL to about 3.0 μg / m in a subject.

66. The suspension of claims 64 or 65, wherein the of Itraconazole has a particle size of from about 1 to 400 nm.

67. A method of treating Leishmaniasis in a human or animal subject in need thereof, comprising: administering to the subject an effective amount of the pharmaceutical composition of any of claims 55-60.

68. The method of claim 67, wherein the subject is a mammal.

69. The method of claims 67 or 68, wherein the subject is selected from the group consisting of a human, a dog, a cat, and a monkey.

70. A method of treating Leishmaniasis in a human or animal subject in need thereof, comprising administering to the subject an effective amount of the solid form of claim 62. 55 VI133W:223897:574168:1:ALEXANDRIA71. A method of treating Leishmaniasis in a human or animal subject in need thereof, comprising administering to the subject an effective amount of the suspension of claim 63.

72. Use of itraconazole and amiodarone for the manufacture of a medicament for the treatment of Leishmaniasis in a human or animal subject in need thereof.

73. The use of claim 72 wherein the dose of itraconazole is in the range of about 3 mg / kg to about 12 mg / kg of a subject, and the dose of amiodarone is in the range of about 2 mg / kg to about 10 mg / kg of the subject.

74. Use of a combination of itraconazole and amiodarone for the manufacture of a medicament for the treatment of Leishmaniasis in a human or animal subject in need thereof.

75. Combination comprising itraconazole and amiodarone for use in treating leishmaniasis.

76. The combination of claim 75 wherein the itraconazole and amiodarone may be administered simultaneously or separately.

77. The combination of claims 75 or 76 wherein the itraconazole and amiodarone are administered simultaneously. 56 VI133W:223897:574168:1:ALEXANDRIA78. The combination of claims 75 or 76 wherein the itraconazole and amiodarone are administered separately. 57 VI133W:223897:574168:1:ALEXANDRIA

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