WO2003037908A1 - Antiviral combination therapy and compositions - Google Patents

Antiviral combination therapy and compositions Download PDF

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Publication number
WO2003037908A1
WO2003037908A1 PCT/US2002/035155 US0235155W WO03037908A1 WO 2003037908 A1 WO2003037908 A1 WO 2003037908A1 US 0235155 W US0235155 W US 0235155W WO 03037908 A1 WO03037908 A1 WO 03037908A1
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Prior art keywords
nucleoside analog
nucleoside
viramidine
ribavirin
cytokine
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PCT/US2002/035155
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French (fr)
Inventor
Johnson Lau
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Ribapharm Inc.
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Publication date
Priority to US60/335,095 priority Critical
Priority to US33509701P priority
Priority to US33509601P priority
Priority to US33509501P priority
Priority to US33509901P priority
Priority to US60/335,097 priority
Priority to US60/335,099 priority
Priority to US60/335,096 priority
Application filed by Ribapharm Inc. filed Critical Ribapharm Inc.
Publication of WO2003037908A1 publication Critical patent/WO2003037908A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056Triazole or tetrazole radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/21Interferons [IFN]

Abstract

Contemplated antiviral composition and method of treatment of a patient include administration of a pharmaceutical composition that comprises a first nucleoside analog in an amount effective to change expression of at least one of a Th1 cytokine and a Th2 cytokine, a second nucleoside that exhibits organ-specific antiviral activity, and optionally a cytokine. Still further contemplated compositions may comprise a biological structure to which an antiviral drug is coupled, wherein the half-life time of the biological structure is greater than the half-life time of the antiviral drug, and wherein the antiviral drug is present in the composition in an amount of at least 1000 mg.

Description

ANTIVIRAL COMBINATION THERAPY AND COMPOSITIONS

This application claims priority to U.S. provisional application number 60/335,099, filed 10/31/01, U.S. provisional application number 60/335096, filed 10/31/01, U.S. provisional application number 60/335097, filed 10/31/01, and U.S. provisional application number 60/335095, filed 10/31/01, all of which are incorporated herein by reference.

Field of The Invention

The field of the invention is treatment of viral infections and compositions therefor.

Background of The Invention

Various antiviral compositions are well known in the art, and depending on the particular virus, the mechanism of action will vary. For example, while some antiviral drugs act as protease inhibitors (e.g., Indinavir, Ritonavir, Saquinavir, etc.), other antiviral drugs act as viral polymerase inhibitors (e.g., 3-TC, AZT, Lamivudine, etc.). While most of the known antiviral drugs exhibit at least some satisfactory biological effect over some time, various problems remain.

Among other things, resistance towards a single drug tends to develop relatively quickly, and especially where a treatment regimen is not strictly adhered to. Furthermore, even if a patient strictly follows his or her administration protocol, relatively high dosages and prolonged exposure to such drugs tend to produce adverse side effects. Thus, combinations of direct antiviral drugs (i.e., drugs targeting viral replication) have been developed to reduce at least some of the problems associated with administration of single drugs. For example, Lamivudine and Zidovudine (e.g., in Combivir™) have been combined to reduce the frequency of development of resistant HIV strains. While such combinations generally have at least some advantage over individual drugs, new problems arise. Unfortunately, side effects seem to increase rather than decrease. Moreover, administration of such combinations tends to increase the cost of treatment.

Alternatively, some antiviral drugs are administered in combination with an interferon. For example, hepatitis C is often treated with a combination of Ribavirin and interferon alpha. While such combinations are relatively well tolerated, significant problems associated with toxicity (e.g., hemotoxicity of Ribavirin) and immunogenicity (e.g., from recombinant interferon) frequently arise.

Moreover, treatment of chronic or persistent viral diseases often requires repeated administration of drugs over a relatively long period following a particular regimen. Consequently, to achieve a treatment goal, patients with such treatment regimens are typically forced to strictly adhere to such regimens, which may be problematic with at least some patients (e.g., infants or elderly). Furthermore, unexpected disruption of the supply of the drug (and especially where a steady-state concentration of the drug in the patient is required) may compromise the treatment goal.

In some cases, controlled-release formulations may be orally or otherwise administered to reduce the frequency of administration of a drug. While controlled-release formulations are relatively successful in at least some cases, various problems may persist. For example, where the drug concentration in the patient needs to be maintained at a relatively high level, the capacity of controlled-release formulations may be exhausted relatively fast.

Alternatively, relatively high dosages of a particular drug may be administered to achieve prolonged presence of the drug in the patient. However, administration of high dosages is generally prohibitive where the toxicity or other undesirable side effects will increase with the dosage of the drug. Moreover, depending on the particular pharmacokinetic behavior of the drug, high dosage administration may not achieve prolonged presence of the drug in the patient. Therefore, there is still a need to provide improved administration of drugs to a patient.

Summary of the Invention

The present invention is directed to compositions and methods of treatment of a patient having a viral infection. Particularly preferred compositions will generally include a first nucleoside analog in an amount effective to change expression of at least one of a Thl cytokine and a Th2 cytokine, and further comprise a second nucleoside that exhibits organ- specific antiviral activity.

In one aspect of the inventive subject matter, the first nucleoside analog has a D-configuration (most preferably D-Ribavirin), while the second nucleoside analog is D-Viramidine or L-Viramidine. Alternatively, the first nucleoside analog has an L-configuration (most preferably L-Ribavirin), while the second nucleoside analog is D-Viramidine or L-Viramidine. Still further preferred compositions may optionally include a cytokine (e.g., an interferon, and most preferably an alpha or gamma interferon, or fragment thereof).

Consequently, a method of treating a patient having a viral infection may comprise a step in which an antiviral composition is administered to the patient, wherein the composition comprises a first nucleoside analog in an amount effective to change expression of at least one of a Thl cytokine and a Th2 cytokine. In another step a second nucleoside is administered to the patient wherein the second nucleoside analog exhibits organ-specific antiviral activity. Optionally, a cytokine may further be administered to the patient. With respect to the first and second nucleosides, and the cytokine, the same considerations as described above apply.

In still further contemplated aspects of the inventive subject matter, a pharmaceutical composition may comprise a biological structure that is isolated from a donor, wherein an antiviral drug selected from the group consisting of D-Ribavirin, L-Ribavirin, D-Viramidine, and L-Viramidine is coupled to the biological structure, wherein the biological structure has a half-life time that is greater than a half-life time of the drug, and wherein the antiviral drug is present in the composition in an amount of at least 1000 mg.

Preferred biological structures include a cell (e.g., erythrocyte) or a serum protein

(e.g., albumin), and particularly preferred donors include human donors (and most preferably a homologous donor). Particularly preferred compositions comprise at least 3000 mg of the drug and have a half-life time of at least three days, and even more preferably at least 5000 mg of the drug and have a half-life time of at least five days.

Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention.

Detailed Description

Conventional antiviral drugs typically target a single molecular entity. Consequently, and especially where the antiviral drug is administered over a prolonged period or at relatively high concentrations, resistant viral strains tend to develop. For this and further reasons (see below), the inventors contemplate a combination therapy in which antiviral treatment has at least two different targets.

More particularly, the inventors contemplate that a combination therapy that includes a systemic treatment portion and a local treatment portion may advantageously be employed to reduce the incidence of resistance development, increase the overall rate of success of treatment, and/or reduce undesirable side effects associated with conventional antiviral treatments. Therefore, the inventors contemplate an antiviral composition comprising a first nucleoside analog in an amount effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and further comprising a second nucleoside that exhibits organ-specific antiviral activity.

In particularly preferred aspects of the inventive subject matter, the first nucleoside analog comprises Ribavirin (l-beta-D-ribofuranosyl-l,2,4-triazole-3-carboxamide) or a prodrug thereof in a concentration effective to systemically modulate the Thl/Th2 profile in a mammal. The term "Thl/Th2 profile" as used herein refers to the balance of at least one (and more typically more than one) Thl cytokine to at least one (and more typically more than one) Th2 cytokine. Furthermore, the term "modulate the Thl/Th2 profile" refers to changing the expression of at least one Thl cytokine and/or at least one Th2 cytokine. Therefore, the terms "modulate the Thl/Th2 profile" and "change expression of at least one of a Thl cytokine and a Th2 cytokine" are used interchangeably herein. Furthermore, the term

"systemic expression" as used herein refers to expression of the respective cytokines in a location other than an organ. Consequently, systemic expression can easily be determined by venipuncture and biochemical analysis of the so obtained blood or blood component.

With respect to Thl cytokines it is generally contemplated that Thl cells stimulate relatively strong cellular immunity, but only weak and transient antibody responses. Typically, Thl responses are stimulated by intracellular pathogens (viruses, some mycobacteria, some yeasts , and some parasitic protozoans), and Thl cells produce a number of cytokines (known as Thl cytokines or Type-1 cytokines), including IL-2 , IFN-gamma , IL-12 and TNF-beta. In contrast, Th2 cells are thought to evoke especially strong antibody responses but relatively weak cellular activity. Th2 responses are usually elicited by free- living bacteria and other parasites. Th2 cells produce cytokines that are known as Th2 cytokines or Type-2 cytokines, including IL-4 , IL-5 , IL-6 , IL-10 , and IL-13.

Particularly preferred first nucleoside analogs include those having non-natural heterocyclic bases covalently coupled to the sugar moiety and may have either D- or L- configuration. Consequently, especially preferred first nucleoside analogs include D- and L- Ribavirin or various D- and L-Ribavirin analogs, which may or may not be administered in the form of a pharmaceutically acceptable salt and/or a prodrug. In further especially preferred aspects, the first nucleoside analogs are administered in an amount effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine. Modulation of the Thl/Th2 balance by Ribavirin is well known in the art, and exemplary modes of administration and uses are described in U.S. Pat. No. 5,767,097, U.S. Pat. No. 6,063,772, and U.S. Pat. No. 6,150,337, all to Tarn, and all of which are incorporated by reference herein. Synthesis of Ribavirin is well known in the art, and all of the known methods are contemplated suitable for use herein (see e.g., Wittkowski et al. in J Med Chem. 1973 Aug; 16(8):935-7, or US 4,138,547incorporated by reference herein).

Where the viral infection is an HCV infection, it should be particularly appreciated that administration of the first nucleoside will advantageously modulate the Thl/Th2 balance to increase the systemic Thl expression (i.e., at least one Thl cytokine is expressed at a higher level as compared to the expression of the same cytokine before administration of the first cytokine) and to decrease the systemic Th2 expression (i.e., at least one Th2 cytokine is expressed at a lower level as compared to the expression of the same cytokine before administration of the first cytokine). Such modulation is thought to be particularly beneficial where the liver of a patient exhibits moderate to significant inflammatory response.

Especially preferred second nucleoside analogs include D-Viramidine (1-beta-D- ribofuranosyl-l,2,4-triazole-3-carboxamidine), which may also be in L-configuration (1-beta- D-ribofuranosyl-l,2,4-triazole-3-carboxamidine). Synthesis of Viramidine is well known in the art, and all of the known methods are contemplated suitable for use herein (see e.g., WO01/60379, which is incorporated by reference herein). Viramidine is known to exhibit significant organ specificity (especially towards hepatocytes) as described in copending U.S. application with the serial number 10/227235 (filed 10/22/02 as national phase of PCT application with serial number PCT/US01/40148, incorporated by reference herein) and PCT application with the serial number PCT/USO 1/26057 (published as WO 02/15904, incorporated by reference herein).

In further contemplated aspects of the inventive subject matter, various nucleoside analogs other than D- and L-Viramidine may also be administered to the patient so long as such nucleoside analogs have at least some specificity towards an organ, and particularly to the liver. Consequently, all known antiviral drugs suitable for treatment of hepatitis (most preferably HCV) are considered suitable for use, and particularly include 9-(2- phosphonylmethoxy) ethyladenine di(pivaloyloxymethyl)ester (BisPOM-PMEA), and other nucleoside/nucleotide analogs (AZT, ddl, etc.) with a prodrug form that is specific to the liver.

In a first preferred aspect of the inventive subject matter, it should be recognized that administration of D-Ribavirin as a systemic immunomodulator with D-Viramidine as a liver specific antiviral drug will provide numerous advantages. Among other things, administration of D-Ribavirin will increase systemic Thl expression relative to systemic Th2 expression (with Th2 expression preferably reduced as compared to pre-treatment condition). While depending on the dosage of D-Viramidine, D-Viramidine may act as a liver specific immunosuppressor at relatively high concentrations or as a second immunomodulator with increased specificity towards the liver, thereby reducing the overall circulating amount of D-Ribavirin, which is known to induce hemolytic anemia over prolonged periods of administration.

Thus, it should be appreciated that the second nucleoside analog may be employed in one of two functions, wherein the function will generally be determined by the administered dosage. A person of ordinary skill in the art will readily be able to determine which function will be prevalent (e.g., by obtaining liver biopsy material and analyzing same for cytokine expression). With respect to the ratio of D-Ribavirin to -Viramidine, it is contemplated that various ratios are suitable, and the particular treatment goal will determine a particular ratio. For example, where D-Ribavirin is administered as an immunomodulator, a dosage of 100- 600 mg per day may be suitable, while D-Viramidine may be administered in a dosage of 1 - 200 mg per day as a second immunomodulator with increased specificity towards the liver or in a dosage of 200-800 mg per day as an organ specific immunosuppressor. Alternatively, in a second preferred aspect of the inventive subject matter, L- Ribavirin may be administered as a systemic immunomodulator together with D-Viramidine as a liver specific antiviral drug. Such combination will particularly provide reduced hemotoxicity, especially where the combination has a relatively high first-nucleoside-analog- to-second nucleoside analog ratio (L-Ribavirin is typically not taken up by erythrocytes). Thus, similarly to the combination D-Ribavirin plus D-Viramidine, administration of L- Ribavirin will increase systemic Thl expression relative to systemic Th2 expression (with Th2 expression preferably reduced as compared to pre-treatment condition) with reduced hemotoxicity (as compared to D-Ribavirin). While depending on the dosage of D- Viramidine, D-Viramidine may act as a liver specific immunosuppressor at relatively high concentrations or as a second immunomodulator with increased specificity towards the liver.

In a third preferred aspect of the inventive subject matter, D- or L-Ribavirin may be administered as a systemic immunomodulator together with L-Viramidine as a liver specific antiviral drug. Such combination will particularly provide reduced hemotoxicity, especially where the combination has a relatively low first-nucleoside-analog-to-second nucleoside analog ratio. Thus, similarly with the combination D-Ribavirin plus D-Viramidine, administration of D- or L-Ribavirin will increase systemic Thl expression relative to systemic Th2 expression (with Th2 expression preferably reduced as compared to pre- treatment condition). While depending on the dosage of L-Viramidine, L-Viramidine may act as a liver specific immunosuppressor at relatively high concentrations or as a second immunomodulator with increased specificity towards the liver. Metabolic conversion of L-Viramidine into L-Ribavirin will advantageously not increase circulating amounts of potentially hemotoxic D-Ribavirin while maintaining antiviral and/or immunosuppressive effect.

Therefore, contemplated total daily dosages (of both first and second nucleoside analogs) are typically in the range between about 50 mg and 2000 mg, and more preferably between about 200 mg and 1500 mg, and most preferably between about 400 mg and 1000 mg. Moreover, administration is preferably oral coadministration, however, numerous other routes, dosages and schedules are also suitable so long as such protocols will reduce viral load in the patient. For example, administration may be sequentially administered (orally or via injection), or in further examples one nucleoside may be orally administered while the other nucleoside may be injected. It should further be appreciated that at least one of the first and second nucleosides may be in prodrug form. The term "prodrug-form" as used herein refers to all modifications of the nucleoside that will render the modified nucleoside less active in at least one compartment and/or non-target cell, and that will (at least partially) react back to the nucleoside in the target cell. Especially contemplated prodrugs include C5'-modifications (e.g., phosphorylation with modified or unmodified phosphates, amino acid esters, etc.) and cyclic phosphate esters.

While not wishing to be bound by a particular theory or mechanism, the inventors contemplate that Ribavirin will act systemically as an immunomodulator. Thus, it is contemplated that Ribavirin may at least partially replace an interferon in a combination therapy by administering Ribavirin in a relatively low dosage or L-configuration (and thereby reduce hemotoxic side effects). Interferons that are contemplated to be replaced in this manner include interferon alpha and beta, either or both of which can be pegylated or otherwise modified. The inventors further contemplate that Viramidine (in D- or L- configuration) will, due to its liver-specific activation in hepatocytes to Ribavirin, act as a direct and/or indirect antiviral agent in the liver, which is thought to be particularly advantageous in viral hepatitis (e.g., HBV and/or HCV). Thus, it is contemplated that while administering Ribavirin at a relatively low concentration and Viramidine at a relatively high concentration, a therapeutic effect may be achieved with significantly reduced side effects when compared to previously known combination therapy of Ribavirin as an antiviral agent and interferon as an immunomodulatory compound.

Nevertheless, the inventors contemplate that suitable antiviral compositions may include a cytokine, and particularly an interferon (alpha or gamma, and/or a fragment thereof). With respect to the dosage of contemplated interferons, it is contemplated that all dosages are suitable, so long as such dosages directly or indirectly reduce the virus load in a patient. Particularly contemplated interferons are administered in at least 3,000,000 units, between three times per week and once per day. Pegylated and other modified interferons are also contemplated. PEGINTRON™ is contemplated to be administered at a dosage that provides between about 0.5 and 2.0 micrograms/kg once per week. PEGASYS™ is contemplated to be administered at a dosage that provides between about 50 and 250 micrograms once per week. With respect to route, dosage, and/or frequency, administration of contemplated cytokines will preferably follow well known coadministration protocols, and a particularly contemplated protocol is the protocol for administration of REBETOL™ (e.g., US 6,299,872, incorporated by reference herein). However, in alternative aspects, it is contemplated that the dosage or frequency of cytokine administration may be less than that already known for administration of REBETOL™.

Therefore, the inventors contemplate a method of treating a patient having a viral infection in which in one step an antiviral composition is administered to the patient, wherein the antiviral composition comprises a first nucleoside analog in an amount effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine. In another step, a second nucleoside is administered to the patient that exhibits organ-specific antiviral activity.

With respect to the first and second nucleoside analogs, and the cytokines, the same considerations as discussed for contemplated antiviral compositions above apply. Therefore, especially preferred first nucleoside analogs include L- and D-Ribavirin, especially preferred second nucleoside analogs include L- and D-Viramidine, and a cytokine (most preferably an interferon) may optionally be coadministered with the first and second nucleoside analogs. Furthermore, in preferred aspects of the inventive subject matter, it is contemplated that the first and second nucleoside analogs are administered at the same time (e.g., in an orally administered mixture of first and second nucleoside analogs).

Consequently, the inventors contemplate a kit for treatment of a viral infection (and particularly HCV) that comprises an instruction and at least one of a first nucleoside analog and a second nucleoside analog, wherein the instruction identifies a dosage for the first and second nucleoside analogs, and wherein the dosage for the first nucleoside analog is effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and wherein the second nucleoside exhibits organ-specific antiviral activity. Suitable instructions may include sales brochures, drug labeling, or prescription information for the patient and or prescribing physician. The term "dosage" as used herein is meant to include both a particular dosage as well as a dosage range between a first and a second dosage.

Therefore, a method of selling a pharmaceutical product may include one step in which at least one of a first nucleoside analog and a second nucleoside analog is provided to a customer. In another step, information is received that administration of the first nucleoside analog to a patient at a dosage is effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and that the second nucleoside exhibits organ-specific antiviral activity, in yet another step, an instruction and at least one of the first and second nucleoside analogs is offered to the customer, wherein the instruction advises a patient to consume (e.g., orally, parenterally, or via other routes) the first nucleoside analog at the dosage.

In still further contemplated aspects of the inventive subject matter, and especially where relatively high dosages of an antiviral drug are administered to a patient over an extended treatment period, the inventors contemplate a pharmaceutical composition that includes a biological structure that is isolated from a donor, wherein an antiviral drug selected from the group consisting of D-Ribavirin, L-Ribavirin, D-Viramidine, and L-Viramidine is coupled to the biological structure, wherein the biological structure has a half-life time that is greater than a half-life time of the drug, and wherein the antiviral drug is present in the composition in an amount of at least 1000 mg.

In a particularly preferred aspect of the inventive subject matter, contemplated antiviral drugs in such pharmaceutical compositions include Ribavirin and Viramidine, wherein each of Ribavirin and Viramidine may be in D-configuration or L-configuration. However, alternative antiviral drugs also include reverse transcriptase inhibitors, protease inhibitors, and other compounds with antiviral effect (e.g., reduction of viral load in blood, reduction of symptoms caused by the virus, reduction of infectivity, etc.) that do not fit into the previous categories. Viewed from another perspective, especially suitable drugs particularly include nucleosides and nucleoside analogs, wherein nucleosides may include naturally occurring nucleosides, and wherein nucleoside analogs will include all compounds that have a sugar moiety (modified or unmodified) coupled to a heterocyclic base (e.g. , purine-type, pyrimidine-type, or triazole-type). Of course it should be recognized that contemplated antiviral drugs also include phosphorylated forms and prodrug forms (i.e., forms that are converted in a target cell or organ to a more active form) thereof.

It is generally contemplated that a suitable antiviral drug will be coupled to a biological structure of a donor (typically human or non-human mammal) having a half-life time that is higher than the half-life time of the particular drug. Such coupling may be covalent or non-covalent, and may include an additional coupling moiety. However, it should be recognized that a particular coupling will predominantly depend on a particular drug and/or structure.

For example, where the drug includes a polyanionic portion, the coupling may be non-covalent via a polycationic moiety on the structure or coupling moiety. In another example, antiviral nucleoside analog drugs may be esterified via a sugar hydroxyl group and a (hetero/homo)bifunctional linker to an amino group of the biological structure.

Alternatively, non-covalent coupling may include hydrogen bonding, hydrophobic or hydrophilic interactions, electrostatic interactions, etc. On the other hand, where covalent coupling is especially desirable, covalent coupling may be done in numerous forms, including coupling via enzymes, coupling ex -vivo with activators and/or catalysts, etc. Still further, it should be recognized that contemplated drugs may be "loaded" into a structure by physical means. For example, suitable drugs may be loaded into erythrocytes or other cells using electroporation. Alternatively, and especially lipophilic compounds may be mixed with lipids previously extracted from the patient.

One class of particularly preferred structures includes serum proteins with relatively high abundance to which contemplated drugs may be coupled. For example, albumin is present in serum at a relatively high concentration with an approximate half-life time of about 12-15 days. Albumin can be extracted from serum in a relatively simple manner. Moreover, albumin provides a relatively small ratio in molecular weight to the molecular weight of contemplated drugs, thereby potentially decreasing immunogenicity. However, and especially where immunogenicity is a concern, it is contemplated that serum proteins conjugated with contemplated drugs may be coated with a compound that decreases immunogenicity (e.g., using polyethylene glycol), which may further increase the serum half-life time of the serum protein conjugated with contemplated drugs. However, numerous alternative serum proteins are also contemplated, and preferred alternative serum proteins include globulins and especially gamma-globulins.

Another class of particularly preferred structures include blood cells with relatively high abundance in whole blood to which contemplated drugs may be coupled. For example, erythrocytes are present in whole blood at a relatively high concentration with an approximate half-life time of about 120 days. Erythrocytes can be extracted from whole blood in a relatively simple manner. Moreover, erythrocytes include glycophorin A as a major surface protein to which target molecules may be coupled. Alternatively, contemplated drugs may also be imported into the erythrocytes via intrinsic transporters. For example, it is well known that erythrocytes import and accumulate D-Ribavirin to a significant degree. Where such importers are not present, it is contemplated that physical methods may be applied to increase the intracellular concentration of contemplated drugs (e.g., electroporation, fusion with loaded liposomes, etc.). Alternative cells include platelets, B- and T-lymphocytes in various stages of differentiation, etc. It is further contemplated that the structures to which contemplated drugs are coupled are preferably autologous structures (i.e., donor is also recipient of the structure), however, non-autologous structures (and synthetic structures) are also included.

Thus, specific embodiments and applications of antiviral combination therapies and compositions have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Claims

CLAIMSWhat is claimed is:
1. A kit comprising: an instruction and at least one of a first nucleoside analog and a second nucleoside analog;
wherein the instruction identifies a dosage for the first and second nucleoside analogs; and
wherein the dosage for the first nucleoside analog is effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and wherein the second nucleoside exhibits organ-specific antiviral activity.
2. The kit of claim 1 wherein the first nucleoside analog has a D-configuration.
3. The kit of claim 2 wherein the first nucleoside analog is D-Ribavirin.
4. The kit of claim 3 wherein the second nucleoside analog is D-Viramidine.
5. The kit of claim 3 wherein the second nucleoside analog is L-Viramidine.
6. The kit of claim 1 wherein the first nucleoside analog has a L-configuration.
7. The kit of claim 6 wherein the first nucleoside analog is L-Ribavirin.
8. The kit of claim 7 wherein the second nucleoside analog is D-Viramidine.
9. The kit of claim 8 wherein the second nucleoside analog is L-Viramidine.
10. The kit of claim 1 further comprising a cytokine.
11. The kit of claim 10 wherein the cytokine comprises an interferon.
12. A method of treating a patient having a viral infection comprising administering to the patient an antiviral composition comprising a first nucleoside analog in an amount effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and further administering a second nucleoside that exhibits organ-specific antiviral activity.
13. The method of claim 12 wherein the first nucleoside is D-Ribavirin.
14. The method of claim 13 wherein the second nucleoside analog is D-Viramidine or L- Viramidine.
15. The method of claim 12 wherein the first nucleoside is L-Ribavirin.
16. The method of claim 15 wherein the second nucleoside analog is D-Viramidine or L- Viramidine.
17. The method of claim 12 further comprising a step of administering a cytokine.
18. A method of selling a pharmaceutical product comprising: providing at least one of a first nucleoside analog and a second nucleoside analog to a customer;
receiving information that administration of the first nucleoside analog to a patient at a dosage is effective to change systemic expression of at least one of a Thl cytokine and a Th2 cytokine, and that the second nucleoside exhibits organ- specific antiviral activity; and
offering an instruction and the at least one of the first and second nucleoside analogs, wherein the instruction advises a patient to consume the first nucleoside analog at the dosage.
19. The method of claim 18 wherein the first nucleoside analog is D-Ribavirin or L- Ribavirin.
20. The method of claim 19 wherein the second nucleoside analog is D-Viramidine.
21. The method of claim 19 wherein the second nucleoside analog is L-Viramidine.
22. The method of claim 19 further comprising providing an interferon to the customer.
23. A pharmaceutical composition comprising a biological structure that is isolated from a donor, wherein an antiviral drug selected from the group consisting of D-Ribavirin, L-Ribavirin, D-Viramidine, and L-Viramidine is coupled to the biological structure, wherein the biological structure has a half-life time that is greater than a half-life time of the drug, and wherein the antiviral drug is present in the composition in an amount of at least 1000 mg.
24. The composition of claim 23 wherein the biological structure is a cell or a serum protein.
25. The composition of claim 24 wherein the cell is an erythrocyte.
26. The composition of claim 24 wherein the serum protein is an albumin.
27. The composition of claim 23 wherein the donor is a human.
28. The composition of claim 23 wherein the antiviral drug is L-Ribavirin or L-Viramidine.
PCT/US2002/035155 2001-10-31 2002-10-31 Antiviral combination therapy and compositions WO2003037908A1 (en)

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WO2011080562A1 (en) 2009-12-29 2011-07-07 Hetero Research Foundation Novel aza-peptides containing 2,2-disubstituted cyclobutyl and/or substituted alkoxy benzyl derivatives as antivirals
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US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
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WO2016178092A2 (en) 2015-02-09 2016-11-10 Hetero Research Foundation C-3 novel triterpenone with c-28 reverse amide derivatives as hiv inhibitors

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