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Title:
METHOD OF TREATING INFECTIOUS MONONUCLEOSIS WITH ACYLIC NUCLEOSIDE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2011/022712
Kind Code:
A1
Abstract:
This invention relates to the use of antivirals and in particular to derivatives of acyclic nucleosides for the treatment of infectious mononucleosis. The invention also provides the use of antivirals and in particular to derivatives of acyclic nucleosides for reducing the amount of Epstein-Barr viral load in subjects suffering from infectious mononucleosis and for reducing the transmissibility of Epstein-Barr virus from subjects suffering from infectious mononucleosis.

Inventors:
MURPHY, Brian (41 Chandon, Newport Coast, California, 94111, US)
Application Number:
US2010/046250
Publication Date:
February 24, 2011
Filing Date:
August 20, 2010
Export Citation:
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Assignee:
EPIPHANY BIOSCIENCES, INC. (One California Street, Suite 2000San Francisco, California, 94111, US)
MURPHY, Brian (41 Chandon, Newport Coast, California, 94111, US)
International Classes:
C07H19/00
Foreign References:
US6255312B1
US20060122203A1
US20050113393A1
Attorney, Agent or Firm:
BEDI, Harmohinder (EcoTech Law Group, P.C.201 Spear St. Ste. 110, San Francisco California, 94105, US)
Download PDF:
Claims:
CLAIMS

What is claimed is:

1. A method of treating infectious mononucleosis in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):

^OR2

or pharmaceutically acceptable salts, solvates or hydrates thereof:

wherein Ri is hydrogen, -C(O)CH(CH(CH3)2)NH2 or -C(O)CH(CH(CH3)CH2CH3)NH2 and R2 is hydrogen, -C(O)C3-C2I saturated or monounsaturated, optionally substituted alkyl; or

Ri is hydrogen, -C(O)C3-C2I saturated or monounsaturated, optionally substituted alkyl and R2 is hydrogen, -C(O)CH(CH(CH3)2)NH2 or -C(O)CH(CH(CH3)CH2CH3)NH2; and

R3 is OH or H.

2. The method of Claim 1 wherein R3 is OH.

3. The method of Claim 1, wherein R1 is -C(O)CH(CH(CH3)2)NH2 or

-C(O)CH(CH(CH3)CH2CH3)NH2 and R2 is -C(O)C3-C2I saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro.

4. The method of Claim 1, wherein Ri or R2 are -C(O)(Cg-Cn) saturated or

monounsaturated alkyl.

5. The method of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

(R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(myristoyloxymethyl)-4- (L-valyloxy)butyl] guanine, (R)-9- [2-(oleoyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9- [2-

(butyrloyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-

[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-(palmitoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L-isoluecyloxy)butyl]guanine, (R)-9- [2-(4-acetylbutryloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(valyloyloxymethyl)-4- (L- stearoyloxy)butyl] guanine, (R)-9-[4-(isoleucyloxymethyl)-2-(L- stearoyloxyethyl)butyl] guanine and (R)-9-[4-(isoleucyloxymethyl)-2-(L- Myristoyloxymethyl)butyl] guanine.

6. The method of Claim 1, wherein the compound of Formula (I) is (R)-9-[2- (stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

7. The method of Claim 1, wherein the compound of Formula (I) is administered at a daily culmative dose of between about 500 mg and 3000 mg, in split dosing either BID or TID.

8. The method of Claim 1, wherein the compound of Formula (I) is administered at a dose of between about 1.0 g QD and about 3.0 g BID.

9. The method of Claim 1, wherein the compound of Formula (I) is administered at a dose of between about 1.5 g and about 2.5 g BID.

10. The method of Claim 1, wherein the compound of Formula (I) is administered at a dose of between about 2.0 g BID.

11. The method of Claim 1, wherein the compound of Formula (I) is administered for between about 3 weeks to about 12 weeks.

12. The method of Claim 1, wherein the compound of Formula (I) is administered for about about 8 weeks.

13. The method of Claim 1, wherein the compound of Formula (I) is administered for about about 4 weeks.

14. The method of Claim 1, wherein the compound of Formula (I) is administered for about 3 weeks.

15. A method of reducing Epstein-Barr virus load in a subject suffering from infectious mononucleosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

^OR2 or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1, R2 and R3 are as defined above.

16. The method of Claim 15, wherein the viral load is reduced in the oral compartment of the subject.

17. The method of Claim 15, wherein the viral load is reduced in the cells and the supernatant of the oral compartment.

18. The method of Claim 15, wherein the viral load in the supernatant of the oral

compartment is reduced to about 0.

19. The method of Claim 15, wherein the viral load in the cells of the oral compartment is reduced by between about 50% and about 12%.

20. The method of Claim 15, wherein the viral load in the cells of the oral compartment is reduced by about 25%.

21. A method of reducing transmissibility of Epstein-Barr virus from a first subject suffering from infectious mononucleosis to other subjects comprising administering to the first subject in need thereof a therapeutically effective amount of a compound of Formula (I):

^OR2

or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1, R2 and R3 are as defined above.

Description:
METHOD OF TREATING INFECTIOUS MONONUCLEOSIS WITH ACYCLIC

NUCLEOSIDE DERIVATIVES

TECHNICAL FIELD

This invention relates to the use of antivirals and in particular to the use of derivatives of acyclic nucleosides for the treatment of infectious mononucleosis. The invention also provides the use of anti-virals and in particular to the use of derivatives of acyclic nucleosides for reducing the amount of Epstein-Barr viral load in subjects suffering from infectious

mononucleosis and for reducing the transmissibility of Epstein-Barr virus from subjects suffering from infectious mononucleosis.

BACKGROUND

The practical utility of many acyclic nucleosides is limited by their relatively modest pharmacokinetics. A number of prodrug approaches have been explored in an effort to improve the bioavailability of acyclic nucleosides in general. One of these approaches involves the preparation of ester derivatives, particularly aliphatic esters, of one or more of the hydroxy groups on the acyclic side chain of the nucleoside.

Englehardt et ah, U.S. Patent No. 5,689,493 described diester derivatives of

9- [4-hydroxy-(2-hydroxymethyl)butyl] guanine (European patent EP165 289), otherwise known as H2G which were able to provide significantly improved oral bioavailability relative to the parent compounds such as H2G.

Acute infectious mononucleosis ("AIM") most often occurs among young adults in developed countries and younger children in the rest of the world. The infection is spread by saliva and has an incubation period of four to seven weeks.

The symptoms of AIM were first described by Emil Pfeiffer in 1889 and consists of sore throat, fever, fatigue, pharyngeal inflammation and petechiae. Clinical signs include

lymphadenopathy, especially in the cervical chain, splenomegaly, hemolysis sometimes and occasionally thrombocytopenia (Longmore et ah, Oxford Handbook of Clinical Medicine, 7 th Edition; 2007: 389).

Currently, treatment of AIM currently consists of supportive/symptomatic care, including non-steroidal anti-inflammatory drugs and acetaminophen. Antibiotics are not useful in treating AIM and in fact, the penicillin-based therapies of amoxicillin and ampicillin can precipitate a non-allergic rash in more than 90% of patients who receive these antibiotics. Steroids are not recommended unless there is a threat of airway obstruction, severe splenomegaly, or hemolytic anemia/thrombocytopenia (Candy et ah, Cochrane Database Sys Rev; 2006). Accordingly, there is a need for new methods for treating infectious mononucleosis.

SUMMARY

The current invention satisfies these and other needs by providing diester derivatives of H2G which can be used to treat infectious mononucleosis, reduce the amount of Epstein-Barr viral load in subjects suffering from infectious mononucleosis and reduce the transmissibility of Epstein-Barr virus from subjects suffering from infectious mononucleosis.

In a first aspect, a method of treating infectious mononucleosis in a subject is provided. The method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I):

OR 2

or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:

Ri is hydrogen, -C(O)CH(CH(CH 3 ) 2 )NH 2 or -C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 and R 2 is hydrogen, -C(O)C 3 -C 2I saturated or monounsaturated, optionally substituted alkyl; or

Ri is hydrogen, -C(O)C 3 -C 2I saturated or monounsaturated, optionally substituted alkyl and R 2 is hydrogen, -C(O)CH(CH(CH 3 ) 2 )NH 2 or -C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 ; and R 3 is OH or H.

In a second aspect, a method of reducing Epstein-Barr virus load in a subject suffering from infectious mononucleosis is provided. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

OR 2

or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R 1 , R 2 and R 3 are as defined above.

In a third aspect, a method of reducing transmissibility of Epstein-Barr virus from a subject suffering from infectious mononucleosis to other subjects is provided. The method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I):

^

OR.

or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R 1 , R 2 and R 3 are as defined above.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates a plot of the log 10 Pe/Sx score versus time during the dosing period.

BRIEF DESCRIPTION

Definitions

"Compounds" refers to compounds encompassed by structural formulae disclosed herein and includes any specific compounds within these formulae whose structure is disclosed herein. Compounds may be identified either by their chemical structure and/or chemical name. The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or

diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. The compounds may be isolated in crystal form, preferably homogenous crystals, and thus the compounds of Formula I may be provided in substantially pure crystalline form, comprising >70%, preferably >90% homogeneous crystalline material for example >95% homogeneous crystalline material. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

The term 'lower alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec -butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2- methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "pharmaceutically acceptable salts" as used herein refers to salts of the compounds of formula I such as, for example, salts of organic acids, especially carboxylic acids, including but not limited to, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2- napthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids.

The term "pharmaceutically acceptable vehicle" as used herein refers to a diluent, adjuvant, excipient or carrier with which an antiviral agent is administered.

The terms "subject," "individual" or "patient" as used herein are used interchangeably herein and refer to a vertebrate such as a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.

The terms "preventing" or "prevention" as used herein refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

The terms "treating" or "treatment" of any disease or disorder refers, in some

embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

The term "therapeutically effective amount" as used herein means the amount of an antiviral agent that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the antiviral agent the disease and its severity and the age, weight, etc., of the subject to be treated.

Compounds

The compounds used herein to treat infectious disease, include, inter alia, the compounds of Formula (I):

^OR 2

or pharmaceutically acceptable salts, solvates or hydrates thereof wherein:

R 1 is hydrogen, -C(O)CH(CH(CH 3 ) 2 )NH 2 or -C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 and R 2 is hydrogen, -C(O)C 3 -C 21 saturated or monounsaturated, optionally substituted alkyl; or

R 1 is hydrogen, -C(O)C 3 -C 21 saturated or monounsaturated, optionally substituted alkyl and R 2 is hydrogen, -C(O)CH(CH(CH 3 ) 2 )NH 2 or -C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 ; and R 3 is OH or H.

In some embodiments, the compounds of formula I are at least between about 70% and about 90% R form. In other embodiments, the compounds of formula I are greater than about 95% the R form. In still other embodiments, the compounds of formula I are greater than about 99% the R form. In still other embodiments, the compounds of formula I are greater than about 99.9 % the R form.

In some embodiments, R 1 is hydrogen, -C(O)CH(CH(CH 3 ) 2 )NH 2 or

-C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 and R 2 is -C(O)C 3 -C 21 saturated or monounsaturated, optionally substituted alkyl; or R 1 is hydrogen, -C(O)C 3 -C 21 saturated or monounsaturated, optionally substituted alkyl and R 2 is -C(O)CH(CH(CH 3 ) 2 )NH 2 or

-C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 ; and R 3 is OH or H.

In some embodiments, the amino acid of group R 1 or R 2 is derived from an L-amino acid. In some embodiments, the fatty acid of group R 1 or R 2 have in total an even number of carbon atoms, in particular, decanoyl (C 1 O), lauryl (C 12 ), myristoyl (C 14 ), palmitoyl (C 16 ), stearoyl (C 18 ) or eicosanoyl (C 2 o). In other embodiments, the fatty acid of group R 1 or R 2 include butyryl, hexanoyl, octanoyl or behenoyl (C 22 ). In still other embodiments, the fatty acid of group R 1 or R 2 include those derived from myristoleic, myristelaidic, palmitoleic,

palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic or brassidic acids.

Monounsaturated fatty acid esters typically have the double bond in the trans configuration, preferably in the Cϋ-6, Cϋ-9 or ω-11 position, depending upon their length. In some embodiments, the the fatty acid of group R 1 or R 2 are derived from a fatty acid which comprises a C 9 to C 17 saturated, or n:9 monounsaturated alkyl.

In some embodiments, the saturated or unsaturated fatty acid of group R 1 or R 2 may optionally be substituted with up to five similar or different substituents including those such as hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro, and the like.

In some embodiments, R 1 is -C(O)CH(CH(CH 3 ) 2 )NH 2 or

-C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 and R 2 is -C(O)C 9 -C 17 saturated alkyl. In other embodiments, Ri is -C(O)CH(CH(CH 3 ) 2 )NH 2 or -C(O)CH(CH(CH 3 )CH 2 CH 3 )NH 2 and R 2 is -C(O)C 3 -C 2I saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro. In still other embodiments, Ri is hydrogen. In still other embodiments, Ri and R 2 are hydrogen. In still other embodiments, R 3 is OH. In still other embodiments, Ri or R 2 are -C(O)(Cg-Cn) saturated or monounsaturated alkyl.

In some embodiments, the compounds of formula I include, (R)-9-[2-

(butyryloxymethyl)-4-(L-isoleucyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutyryloxymethyl)-4-(L- isoleucyloxy)butyl] guanine, (R)-9-[2-(hexanoyloxymethyl)-4-(L-isoleucyloxy)butyl]guanine , (R)-9-[4-(L-isoleucyloxy)-2-(octanoyloxymethyl)butyl] guanine, (R)-9-[4-(L-isoleucyloxy)-2- (decanoyloxymethyl)butyl] guanine, (R)-9-[4-(L-isoleucyloxy)-2- (dodecanoyloxymethyl)butyl] guanine, (R)-9-[4-(L-isoleucyloxy)-2- (tetradecanoyloxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (hexadecanoyloxymethyl)butyl] guanine, (R)-9-[4-(L-isoleucyloxy)-2- (octadecanoyloxymethyl)butyl]guanine, (R)-9-[2-(eicosanoyloxymethyl)-4-(L- isoleucyloxy)butyl] guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-isoleucyloxy)butyl]guani ne, (R)-9-[4-(L-isoleucyloxy)-2-((9-tetradecenoyl)oxymethyl)buty l] guanine, (R)-9-[2-((9- hexadecenoyl)oxymethyl)-4-(L-isoleucyloxy)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2-((6- octadecenoyl)oxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2-((9- octadecenoyl)oxymethyl)-butyl]guanine, (R)-9-[2-((l l-eicosanoyl)-oxymethyl)-4-(L- isoleucyloxy)butyl] guanine, (R)-9-[2-((13-docosenoyl)-oxymethyl)-4-(L- isoleucyloxy)butyl] guanine, (R)-2-amino-9-[2-(butyryloxymethyl)-4-(L- isoleucyloxy)butyl]purine, R)-2-amino-9-[2-(4-acetylbutyryloxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[2-(hexanoyloxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (octanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (decanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (dodecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (tetradecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (hexadecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (octadecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (eicosanoyloxymethyl)butyl]purine, (R)-2-amino-9-[2-(eicosanoyloxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[2-(docosanoyloxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((9- tetradecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9-[2-((9-hexadecenoyl)oxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((6- octadecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((9- octadecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9-[2-((l l-eicosanoyl)oxymethyl)-4-(L- isoleucyloxy)butyl]purine and (R)-2-amino-9-[2-((13-docosenoyl)oxymethyl)-4-(L- isoleucyloxy)butyl]purine. In other embodiments, the compounds of Formula I include (R)-9-[2- (butyryloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutyryloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(hexanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (octanoyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9- [2-(tetradecanoyloxymethyl-4-(L-valyloxy)butyl]guanine, (R)-9-[2-hexadecanoyloxymethyl)-4- (L-valyloxy)butyl] guanine, (R)-9- [2- (octadecanoyloxymethyl)-4- (L-valyloxy)butyl] guanine, (R)-9-[2-(eicosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(eicosanoyloxymethyl)- 4- (L-valyloxy)butyl] guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-((9-tetradecenoyl)oxymethyl)-4-(L-valyloxy)butyl]gu anine, (R)-9-[2-((9- hexadecenoyl)oxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-((6-octadecenoyl)oxymethyl)- 4-(L-valyloxy)butyl] guanine, (R)-9-[2-((9-octadecenoyl)oxymethyl)-4-(L-valyloxy)- butyl] guanine, (R)-9-[2-((l l-eicosanoyl)oxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-((13- docosenoyl)oxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-2-amino-9-[2-(butyryloxymethyl)-4- (L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(4-acetylbutyryloxymethyl)-4-(L- valyloxy)butyl]purine, (R)-2-amino-9-[2-(hexanoyloxymethyl)-4-(L-valyloxy)butyl]pur ine, (R)- 2-amino-9-[2-(octanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2- (decanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(dodecanoyloxymethyl)-4- (L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(tetradecanoyloxymethyl)-4-(L- valyloxy)butyl]purine, (R)-2-amino-9-[2-(hexadecanoyloxymethyl)-4-(L-valyloxy)butyl ]purine, (R)-2-amino-9-[2-(octadecanoyloxymethyl)-4-(L-valyloxy)-buty l]purine, (R)-2-amino-9-[2- (eicosanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(docosanoyloxymethyl)-4- (L-valyloxy)butyl]purine, (R)-2-amino-9-[2-((9-tetradecenoyl)oxymethyl)-4-(L- valyloxy)butyl]purine, (R)-2-amino-9-[2-((9-hexadecenoyl)oxymethyl)-4-(L- valyloxy)butyl]purine, (R)-2-amino-9-[2-((6-octadecenoyl)oxymethyl)-4-(L- valyloxy)butyl]purine, (R)-2-amino-9-[2-((9-octadecenoyl)oxymethyl)-4-(L-valyloxy)- butyl]purine, (R)-2-amino-9-[2-((l l-eicosenoyl)-oxymethyl)-4-(L-valyloxy)butyl]purine and (R)-2-amino-9-[2-((13-docosenoyl)-oxymethyl)-4-(L-valyloxy)b utyl]purine. In still other embodiments, the compounds of formula I include (R)-9-[4-(butyryloxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-(4-acetylbutyryloxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-(hexanoyloxy)-2-(L-valyloxymethyl)butyl] guanine, (R)- 9-[4-(octanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(decanoyloxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-(dodecanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(tetradecanoyloxy)-2-(L-valyloxymethyl)butyl]guanin e, (R)-9-[4-hexadecanoyloxy)-2- (L- valyloxymethyl)butyl] guanine, (R)-9-[4-(octadecanoyloxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-(eicosanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(docosanoyloxy)-2-(L-valyloxymethyl)butyl] guanine, (R)-9-[4-((9-tetradecenoyl)oxy)- 2-(L-valyloxymethyl)butyl] guanine, (R)-9-[4-((9-hexadecenoyl)oxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-((6-octadecenoyl)oxy)-2-(L- valyloxymethyl)butyl] guanine, (R)-9-[4-((9-octadecenoyl)oxy)-2-(L-valyloxymethyl)- butyl] guanine, (R)-9-[4-((l l-eicosenoyl)oxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-((13- docosenoyl)-oxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-2-amino-9-[4-(butyryloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(4-acetylbutyryloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(hexanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(octanoyloxy)-2-(L- valyloxymethyl)butyl]purine,(R)-2-amino-9-[4-(decanoyloxy)-2 -(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(dodecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(tetradecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(hexadecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(octadecanoyloxy)-2-(L-valyloxymethyl)- butyl]purine, (R)-2-amino-9-[4-(eicosanoyloxy)-2-(L-valyloxymethyl)butyl]p urine, (R)-2- amino-9-[4-(docosanoyloxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((9- tetradecenoyl)oxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((9-hexadecenoyl)oxy)- 2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((6-octadecenoyl)oxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((9-octadecenoyl)oxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((l l-eicosenoyl)oxy)-2-(L- valyloxy)butyl]purine, and (R)-2-amino-9-[2-((13-docosenoyl)oxymethyl)-2-(L- valyloxy)butyl] purine. In still other embodiments, the compounds of Formula (I) include (R)-9- [2-(Stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(Myristoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(Oleoyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2- (butyrloyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9- [2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl] guanine, (R)-9-[2-(palmitoyloxymethyl)-4-(L- valyloxy)butyl] guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L-isoluecyloxy)butyl]guanine , (R)-9- [2-(4-acetylbutryloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(valyloyloxymethyl)-4- (L- stearoyloxy)butyl] guanine, (R)-9-[4-(isoleucyloxymethyl)-2-(L- stearoyloxyethyl)butyl] guanine and (R)-9-[4-(isoleucyloxymethyl)-2-(L- Myristoyloxymethyl)butyl]guanine. In still other embodiments, the compound of Formula (I) is (R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine. In still other embodiments, the compound of Formula (I) is (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine.

The compounds of Formula (I) may be made by the methods described in Englehardt et al., U.S. Patent No. 5,689,493 or by other methods known to the skilled artisan.

Pharmaceutical Compositions and Methods of Administration

The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with infectious mononucleosis and/or for reducing the amount of Epstein-Barr viral load in a subject and for reducing the transmissibility of Epstein-Barr virus from subjects and a pharmaceutically acceptable vehicle. Pharmaceutical vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

The compositions contain one or more compounds provided herein. The compounds are, in some embodiments, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral

administration, as well as transdermal patch preparation and dry powder inhalers. In some embodiments, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to

Pharmaceutical Dosage Forms, Seventh Edition (1999).

In the compositions, effective concentrations of one or more compounds or

pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical vehicle. The compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with associated withassociated with infectious mononucleosis and/or for reducing the amount of Epstein-Barr viral load in a subject, and for reducing the transmissibility of Epstein-Barr virus from subjects. In some embodiments, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of a compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.

The active compound is included in the pharmaceutically acceptable vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems well known to those of skill in the art and then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with viral infections or inappropriate cell proliferation, as described herein.

In some embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50- 100 μg/ml. The pharmaceutical compositions, in other embodiments, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined

empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

The pharmaceutical compositions may be provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are, in some embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a

predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. Examples of unit- dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit- dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions thereof.

Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%.

In certain embodiments, the compositions are lactose-free compositions containing excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions contains active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Particular lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.

Further provided are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time (Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are generally packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated.

Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms such as for example, capsules or tablets. The tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating. Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic- coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

The compound, or pharmaceutically acceptable derivative thereof, could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, formulations may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in- water or water- in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable vehicles used in elixirs include, but are not limited to, solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include, but are not limited to, diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include, but are not limited to, organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

Solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol and syrup.

Examples of preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Examples of emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.

Sweetening agents include, but are not limited to, sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include, but are not limited to, citric and tartaric acid. Sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. Coloring agents include, but are not limited to, any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include, but are not limited to, natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for example, propylene carbonate, vegetable oils or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos.

4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid vehicle, e.g., water, to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those set forth in U.S. Patent Nos. RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any

pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

Parenteral administration, in some embodiments, is characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include, but are not limited to, sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous. If administered intravenously, suitable carriers include, but are not limited to, physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable vehicles used in parenteral preparations include, but are not limited to, aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include, but are not limited to, Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include, but are not limited to, fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include, but are not limited to, phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include, but are not limited to, sodium chloride and dextrose. Buffers include, but are not limited to, phosphate and citrate. Antioxidants include, but are not limited to, sodium bisulfate. Local anesthetics include, but are not limited to, procaine hydrochloride. Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcelluose, hydroxypropyl methylcellulose and

polyvinylpyrrolidone. Emulsifying agents include, but are not limited to, Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include, but are not limited to, EDTA. Pharmaceutical carriers also include, but are not limited to, ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The concentration of pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In one embodiment, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, in certain embodiments more than 1% w/w of the active compound to the treated tissue(s).

The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of

administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.

Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Patent No. 3,710,795) is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene,

polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers,

polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross- linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809;

3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;

5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945;

5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;

6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include, but are not limited to, extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially release an amount of drug

(active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al, N. Engl. J. Med. 321:574 (1989). In other embodiments, polymeric materials can be used. In other embodiments, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984). In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). The active ingredient can be dispersed in a solid inner matrix, e.g.,

polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene- vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.

Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels. The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, an antioxidant, a buffer and a bulking agent. In some embodiments, the excipient is selected from dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose and other suitable agent. The solvent may contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, at about neutral pH.

Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In one embodiment, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 0 C to room temperature.

Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in some embodiments, have diameters of less than 50 microns, in other embodiments less than 10 microns.

The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

For nasal administration, the preparation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application. The carrier may contain solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives.

These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic solutions, pH about 5-7, with appropriate salts. Other routes of

administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein. Transdermal patches, including iotophoretic and electrophoretic devices, are well known to those of skill in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

Pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.

Examples of bases include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include, but are not limited to, spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use with the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. In some embodiments, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers.

These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

The compounds or pharmaceutically acceptable derivatives may be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with viral infections or inappropriate cell proliferation, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable derivative thereof, is used for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with viral infections or inappropriate cell proliferation.

The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of

pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder associated with infectious mononucleosis.

Dosages

In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The pharmaceutical compositions, in another embodiment, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared, e.g., to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form. In other embodiments, the compounds may be administered at a daily dose generally in the range 0.1 mg/kg/day to 200 mg/kg/day, 0.5 mg/kg/day to 100 mg/kg/day, 10 mg/kg/day to 50 mg/kg/day or 10 mg/kg/day to 25 mg/kg/day.

In some embodiments, the compounds are administered at a daily cumulaative dose of between about 500 mg and 3000 mg, in split dosing either BID or TID. In other embodiments, the compounds are administered at a dose of between about 1.0 g QD and about 3.0 g BID. In still other embodiments, the compounds are administered at a dose of between about 1.5 g and about 2.5 g BID. In still other embodiments, the compounds are administered at a dose of between about 2.0 g BID.

The amount of active ingredient in the formulations provided herein, which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.

Exemplary doses of a formulation include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., from about 1 micrograms per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram).

It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

In certain embodiments, administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

In some embodiments, the compounds are administered for between about 3 weeks to about 12 weeks. In other embodiments, the compounds are administered for about 8 weeks. In still other embodiments, the compounds are administered for about 4 weeks. In still other embodiments, the compounds are administered for about 3 weeks.

Methods of Use of the Compounds and Compositions

Methods of treating, preventing, or ameliorating one or more symptoms of infectious mononucleosis using the compounds and compositions are provided. In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered. In certain embodiments, the methods provided herein are for the preventing, or ameliorating one or more symptoms of infectious mononucleosis. In further embodiments, methods for using the compounds and compositions described herein to reduce the amount of Epstein-Barr viral load in subjects suffering from infectious mononucleosis are provides. In still other embodiments, methods for using the compounds and compositions described herein to reducing the transmissibility of Epstein-Barr virus from subjects suffering from infectious mononucleosis are provided.

Combination Therapy

The compounds and compositions provided herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination, or sequentially, with another therapeutic agent. Such other therapeutic agents include, but are not limited to, those known for treatment, prevention, or amelioration of one or more symptoms associated with viral infections or inappropriate cell proliferation. Such therapeutic agents include, but are not limited to, acyclovir, valcyclovir, penciclovir, famciclovir, ganciclovir and its prodrugs, cidofovir, foscarnet, AZT, ddl, ddC, d4T, 3TC, foscarnet, ritonavir, indinavir, saquinavir, delaviridine, Vertex VX 478, Agouron AG1343 and the like.

Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by reference in their entirety. The following example is provided for illustrative purposes only and is not intended to limit the scope of the invention.

EXAMPLE

A clinical study evaluated the anti-viral activity of valomaciclovir against EBV in patients with acute infectious mononucleosis (AIM). Patients who met the eligibility criteria which included, but was not limited to, age equal to or older than 16 years, positive heterophile test and positive anti-EBV VCA IgM but negative for anti-EBV EBNA IgG antibody were treated with valomaciclovir.

Patients were randomly treated with valomaciclovir two-grams BID for 21 days or with placebo in this double-blind study. All subjects were instructed to take medicine with food. EBV was assessed in the oral cell pellet (OCP), the oral supernatant (OS; saliva) and in peripheral blood mononuclear cells (PBMCs). Viral status was assessed at day 1, day 5, day 10, day 14, day 18, day 22, day 28, day 42, day 84, and day 168. The median decrease in EBV viral loads in the oral cells and oral supernatant was statistically significantly greater in the valomaciclovir arm versus the placebo arm (Table 1). Additionally, the valomaciclovir arm had a faster time to achieve <1000 copies of EBV in both the oral cells and oral supernatant.

Table 1

Effect of a 21 day course of valomaciclovir 2 gms BID on decrease in Epstein-Barr Virus (EBV) viral load in the oral compartment

*Mann-Whitney test, 2sided. Physical examination/ Symptom (Pe/Sx) scores were determined during the history and physical exanimation at each study visit. Ten parameters were evaluated including: pharyngitis, anterior cervical lymphadenopathy, posterior cervical lymphadenopathy, sore throat, headache, feels febrile, tiredness, loss of appetite, abdominal pains, and nausea. These parameters were graded on a scale of: 0 = Absent; 1 = Mild; or 2 = Moderate to Severe. The total Pe/Sx scores indicated that, upon entry to the study, the valomaciclovir subjects were sicker than their placebo counterparts. Nevertheless, those treated with valomaciclovir improved more rapidly than the placebo group. The slopes of the improvement in Pe/Sx scores were found to be significantly different as shown in Figure 1.




 
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