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WO2009032244A1 - Procédé pour le traitement d'une infection par le virus du vih/le sida par utilisation d'acyclovir chez des sujets identifiés - Google Patents

Procédé pour le traitement d'une infection par le virus du vih/le sida par utilisation d'acyclovir chez des sujets identifiés Download PDF

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Publication number
WO2009032244A1
WO2009032244A1 PCT/US2008/010316 US2008010316W WO2009032244A1 WO 2009032244 A1 WO2009032244 A1 WO 2009032244A1 US 2008010316 W US2008010316 W US 2008010316W WO 2009032244 A1 WO2009032244 A1 WO 2009032244A1
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Prior art keywords
acyclovir
hiv
hhv
treating
subject
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English (en)
Inventor
Leonid Margolis
Andrea Lisco
Christophe Vanpouille
Jean-Charles Grivel
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US Department of Health and Human Services
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US Department of Health and Human Services
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the human body coexists with a menagerie of microbes that interact through a complex network of positive and negative signals.
  • HIV HIV
  • BOS2691665.1 becomes part of these interactions. It had been hypothesized [1] that non-HIV microbes can be used to suppress HIV either by using their negative signals [2-4], or by eliminating microbes that upregulate HIV [5].
  • Acyclovir is a guanosine analogue particularly active against ⁇ - herpesviruses HHV-I, HHV-2, and HHV-3 (respectively known as herpes simplex viruses 1 and 2 and varicella zoster virus). It can also inhibit, although with lower efficiency, replication of ⁇ -herpesviruses HHV-5 (known as cytomegalovirus or CMV), HHV-6, and HHV-7, and ⁇ -herpesviruses HHV-4 and HHV-8 (respectively known as Epstein-Barr virus and Kaposi's sarcoma herpesvirus).
  • ACV is phosphorylated in herpesvirus-infected cells by a viral kinase.
  • the resulting monophosphate is then converted into ACV triphosphate (ACV-TP) by cellular enzymes and is subsequently incorporated in the nascent viral DNA chain, causing its obligate termination.
  • ACV-TP causes the viral DNA polymerase to become irreversibly bound to the terminated chain[7].
  • the sensitivity of different HHVs to ACV is determined by the rate of its phosphorylation by HHV kinase and by the rate of incorporation of ACV-TP into the viral DNA chain [8-9].
  • ACV is considered to be inactive against other viruses.
  • ACV has regained attention in HIV therapy research as in several clinical trials aimed at establishing the role of HSV-2 in HIV disease progression it was found that administration of ACV prodrug valacyclovir (500 mg twice daily) to individuals coinfected with HSV-2 and HIV-I resulted not only in HSV-2 suppression but also in a decrease in the HIV-I load in genital, rectal, and peripheral blood compartments (by approximately 50%, 30% and by 50-70% respectively) [22-23] .
  • the present invention is based, in part, on the discovery that acyclovir triphosphate, the active form of acyclovir generated in infected cells infected with one or more herpesviruses, is a potent inhibitor of HIV-I reverse transcriptase.
  • acyclovir triphosphate the active form of acyclovir generated in infected cells infected with one or more herpesviruses
  • HIV-I reverse transcriptase HIV-I reverse transcriptase.
  • acyclovir a relatively common pharmaceutical with low toxicity and low cost
  • the use of an endogenous microbe to convert an inactive drug into an inhibitor of another microbe is an effective biotechnological tool - a"binary weapon" - against human pathogens.
  • the present invention provides, a method of treating an HIV infection in a subject comprising identifying a subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate; and administering to said subject an effective amount of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof such that said acyclovir is metabolized into an effective amount of acyclovir triphosphate.
  • the invention provides, a method of treating an HIV infection in a subject comprising identifying a subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate; and administering to said subject an amount of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof that preserves replication of the herpesvirus infection at a rate
  • B0S2691665.1 sufficient to convert said acyclovir into an amount of acyclovir triphosphate effective to treat said HIV infection.
  • the herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is an HHV-6a or HHV-6b infection. In another embodiment of the invention, the herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is an HHV-I or HHV-2 infection.
  • the herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is an HHV-3, HHV-4, HHV-5, HHV-7 or HHV-8 infection.
  • the subject is identified as possessing a herpesvirus infection by quantifying the viral load for a herpesvirus present in a subject.
  • the viral load for a herpesvirus in a subject is at least 1 DNA copy to about 1000 DNA copies per 10 4 cells; at least 10 DNA copies per 10 4 cells; at least 50 DNA copies per 10 4 cells, or at least 100 DNA copies per 10 4 cells.
  • the invention provides the methods described herein further comprising administering a therapeutically effective amount of at least one other antiviral agent.
  • the other antiviral agent is an agent used for highly active antiretro viral therapy.
  • the other agent or agents are nucleoside HTV reverse transcriptase inhibitors, non-nucleoside HTV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, HIV entry inhibitors, CCR5 inhibitors, CXCR.4 inhibitors, HIV budding or maturation inhibitors, or HIV integrase inhibitors or combinations thereof.
  • the acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, topically or orally.
  • the subject is a mammal, preferably a human.
  • the human subject is a male or a female.
  • the human subject is an elderly individual (e.g. an individual at least 55, 60 or 65 years of age), an adult individual (e.g. an individual at least 18, 21 or 25
  • BOS2 691665.1 years of age or an adolescent individual (e.g. an individual at least 10, 12, 14 or 16 years of age).
  • Acyclovir suppresses viral infection in human tonsillar tissue coinfected with HIV-I AND HSV-2.
  • Blocks of human tonsillar tissue were inoculated ex vivo with HSV-2 strain G, HIV- 1 LAI . 4 or with both viruses together and treated or not with acyclovir (30 ⁇ M). HIV-I replication was monitored by measuring p24 antigen accumulation in culture media. Presented are means ⁇ SEM of the results with tissues from 4 to 17 donors. For each donor each data point represents pooled viral release from 27 tissue blocks.
  • Figure 2. Acyclovir suppresses HIV infection in various human tissues a.
  • Blocks of human lymphoid tonsillar, lymph node, colorectal and cervicovaginal tissues were inoculated ex vivo with HIV-I LA1 4 and treated with acyclovir (30 ⁇ M). HIV-I replication was monitored by measuring p24 antigen accumulation in culture media. For each tissue from each donor HIV-I replication in 9 to 27 treated blocks was compared with that in 9 to 27 matched untreated blocks. Presented are means ⁇ SEM of the results with tonsils from 36 donors, lymph nodes from 7 donors, colorectal tissue from 3 donors and cervicovaginal tissues from 3 donors. Note that acyclovir efficiently suppresses HIV-I replication in all the tissues tested. b. Dose-dependence of acyclovir-mediated suppression of HIV-I replication. HTV-I replication was measured in tonsillar blocks infected with HIV-I LA1 4 as described in a.
  • Acyclovir was added at the concentration of 03, 3, 30, and lOO ⁇ M and its anti- HIV activity was evaluated by suppression of viral replication compared to matched
  • Acyclovir triphosphate inhibits HIV-I reverse transcriptase a. Exogenous template reverse transcriptase assays were performed in presence of different concentrations of acyclovir or acyclovir triphosphate as described in Methods. All deoxynucleotide triphosphates were used at a final concentration of 3,38 ⁇ M except for dGTP which was used at 1 ⁇ M. Presented are means ⁇ SEM of the results of 2 experiments performed in duplicates. Note that acyclovir triphosphate inhibits HIV-I reverse transcriptase in a dose dependent manner. b.
  • Blocks of human tonsillar tissue were inoculated ex vivo with HIV-1 LAI . O 4 and treated with acyclovir or acyclovir triphosphate (30 ⁇ M). HIV-I replication was monitored by measuring p24 antigen accumulation in culture media. Presented are
  • BOS2 691665.1 means ⁇ SEM of the results with tonsils from 4 donors. For each donor each data point represents pooled viral release from 27 tissue blocks. Note that acyclovir triphosphate suppresses HIV-I replication similarly to acyclovir.
  • acyclovir refers to acycloguanosine, which is a guanine analogue antiviral drug, marketed under trade names such as ZOVIRAX® and ZOVTR®.
  • Acyclovir can be readily synthesized using known techniques or purchased commercially.
  • Acyclovir has the chemical formula:
  • acyclovir triphosphate or "ACV-TP” or “Acylco-GTP” refers to acyclo-guanosine triphosphate, which is the active triphosphate form of acyclovir.
  • ACV-TP is produced by phosphorylation of acyclovir by a viral kinase to the monophosphate and is subsequently converted to ACV-TP by cellular enzymes.
  • Acyclovir triphosphate can be readily synthesized using known techniques or purchased commercially.
  • Acyclovir triphosphate has the chemical formula:
  • the present invention also relates to useful forms of acyclovir as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts, "J. Pharm. Sci. 1977, 66, 1-19.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • salts also include those in which acyclovir functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • an appropriate base e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of acyclovir the appropriate inorganic or organic acid via any of a number of known methods.
  • BOS2 691665.1 acidic acyclovir are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts acyclovir include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides
  • a solvate for the purpose of this invention is a complex of a solvent and acyclovir in the solid state.
  • Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water.
  • prodrug of acyclovir refers to a form of drug which is converted through metabolic processes to acyclovir.
  • exemplary prodrugs of acyclovir include, but are not limited to, valacyclovir.
  • Valacyclovir can be readily synthesized using known techniques or purchased commercially under the trade name VALTREX®.
  • HtV refers to human immunodeficiency virus, including, but not limited to, HIV-I, HIV-2, specific treatment resistant mutations of HIV-I or HIV-2, or particular isolated strains or mutations of HIV obtained from a subject to be treated by the methods of the invention.
  • herpesvirus refers to a virus, including, but not limited to, an ⁇ - herpesvirus, including HHV-I (herpes simplex viruses 1, HSV-I), HHV-2 (herpes simplex viruses 2, HSV-2), and HHV-3 (varicella zoster virus); a ⁇ -herpesvirus, including, HHV-5 (cytomegalovirus, CMV), HHV-6a, HHV-6b, and HHV-7; or a ⁇ - herpesvirus including HHV-4 (Epstein-Barr virus) and HHV-8 (Kaposi's sarcoma herpesvirus).
  • HHV-I herpes simplex viruses 1, HSV-I
  • HHV-2 herpes simplex viruses 2, HSV-2
  • HHV-3 variantcella zoster virus
  • a ⁇ -herpesvirus including, HHV-5 (cytomegalovirus, CMV), HHV-6a, HHV-6b, and
  • subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • the invention thus provides methods of treatment against HIV infections.
  • the methods also include the step of identifying that the subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate, e.g., identifying that the subject is infected with an endogenous herpesvirus and the associated kinase which converts acyclovir into acyclovir triphosphate.
  • the identification can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).
  • Tests for HHV infection are known in the art and include polymerase chain reaction-based (PCR-based) amplification and detection of viral RNA; Western blot detection of anti-HHV antibodies; agglutination assays for anti- HHV antibodies; ELISA-based detection of HHV-specific antigens (e.g., p24); line immunoassay (LIA); and other methods known to one of ordinary skill in the art.
  • a sample of biological material such as blood, plasma, semen, or saliva
  • the methods of the invention can include the step of obtaining a sample of biological material (such as a bodily fluid) from a subject; testing the sample to determine the presence or absence of detectable HHV infection, HHV particles, or HHV nucleic acids; and determining whether the subject possesses a herpesvirus infection capable of
  • BOS2 691665.1 converting acyclovir into acyclovir triphosphate, i.e., identifying whether the subject is capable of converting acyclovir into a potent HIV suppressor.
  • the method of identifying a subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is specifically designed to identify an HHV-6a or HHV-6b infection. In other embodiments, the method of identifying a subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is specifically designed to identify an HHV-I or HHV-2 infection.
  • the method of identifying a subject as possessing a herpesvirus infection capable of converting acyclovir into acyclovir triphosphate is specifically designed to identify an HHV-3, HHV-4, HHV-5, HHV-7 or HHV-8 infection.
  • the subject is identified as possessing a herpesvirus infection by quantifying the viral load for a herpesvirus present in a subject.
  • the viral load for a herpesvirus in an identified subject is determined to be from about 1 DNA copy to about 1000 DNA copies per 10 4 cells; from about 10 DNA copies to about 500 DNA copies; or from about 50 DNA copy to about 200 DNA copies per 104 cells.
  • the methods can further include the step of reporting the results of such analyzing to the subject or other health care professional.
  • the method can further include additional steps wherein (such that) the subject is treated for the indicated disease or disease symptom.
  • the subject may be identified as possessing a herpesvirus infection by measuring the presence of anti-herpesvirus antibodies.
  • antibodies are tested for non-latent forms of herpes virus, such as HHV-I, HHV-2, and HHV-5.
  • the antibodies are present in such an amount as to indicate the presence of a herpesvirus capable of converting acyclovir into acyclovir triphosphate
  • BOS2 691665 1 The invention thus provides methods of treatment against HIV infections, which methods in general comprise administration of a therapeutically effective amount of amount of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof such that said acyclovir is converted into an effective amount of acyclovir triphosphate.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a mammal, preferably, a human concurrently with one or more other biologically active agents.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and the other agent are administered to a mammal in a sequence and within a time interval such that acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can act together with the other agent to provide an increased or synergistic benefit than if they were administered otherwise.
  • each component may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently closely in time so as to provide the desired treatment effect.
  • all components are administered at the same time, and if not administered at the same time, preferably, they are all administered from about 6 hours to about 12 hours apart from one another.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and the therapeutic agent can act additively or, more preferably, synergistically.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered concurrently with another therapeutic agent in the same pharmaceutical composition.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered concurrently with another therapeutic agent in separate pharmaceutical compositions.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered prior or subsequent to administration of another therapeutic agent.
  • combination therapy involves
  • BOS2 691665.1 alternating between administering acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and a pharmaceutical composition comprising another therapeutic agent, e.g., to minimize the toxicity associated with a particular drug.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof when administered concurrently with another therapeutic agent that potentially produces adverse side effects including, but not limited to toxicity, the therapeutic agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof may be used in combination with other medicaments such as nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, or HIV integrase inhibitors or combinations thereof.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof may be used in therapy in conjuction with reverse transcriptase inhibitors such as a dideoxynucleoside including AZT, ddl, ddC, d4T, 3TC or 1592U89; TAT antagonists such as Ro 3-3335 and Ro 24-7429; protease inhibitors such as saquinavir, ritonavir, indinavir or AHGl 343 (Viracept); and other agents such as , ganciclovir or pencyclovir, interferon, e.g., alpha-interon or interleukin II, or in conjunction with other immune modulation agents including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate.
  • reverse transcriptase inhibitors such as a dideoxynucleoside including AZT, ddl
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with antibiotics.
  • they can be formulated with a macrolide (e.g., tobramycin (TOBI®)), a cephalosporin (e.g., cephalexin (KEFLEX®), cephradine (VELOSEF®), cefuroxime (CEFTIN®), cefprozil (CEFZIL®), cefaclor (CECLOR®), cefixime (SUPRAX®) or cefadroxil (DURICEF®)), a clarithromycin (e.g., clarithromycin (BIAXIN®)), an erythromycin (e.g., erythromycin (Emycin®)), a penicillin (e.g., penicillin V (V-
  • a macrolide e.g., tobramycin (TOBI®)
  • a cephalosporin e.g., cephal
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can also be administered or formulated in combination with an antiemetic agent.
  • Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine,
  • BOS2 691665.1 nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with an antidepressant.
  • Suitable antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitript
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with an antifungal agent.
  • Suitable antifungal agents include but are not limited to amphotericin B, itraconazole, ketoconazole, fluconazole, intrathecal, flucytosine, miconazole, butoconazole, clotrimazole, nystatin, terconazole, tioconazole, ciclopirox, econazole, haloprogrin, naftif ⁇ ne, terbinafine, undecylenate, and griseofuldin.
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with an anti-inflammatory agent.
  • anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate,
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with an immunomodulatory agent.
  • Immunomodulatory agents include, but are not limited to, methothrexate, leflunomide, cyclophosphamide, cyclosporine A, mycophenolate mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar, malononitriloamindes (e.g., leflunamide), T cell receptor modulators, and cytokine receptor modulators, peptide mimetics, and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or epitope binding fragments), nucleic acid molecules (e.g., antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds.
  • T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (e.g., anti- CD4 antibodies (e.g., cM-T412 (Boeringer), IDEC-CE9.1® (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (e.g., anti-CD4 antibodies (e.g., anti- CD4 antibodies (e.g., cM-T412 (Boeringer), IDEC-CE9.1® (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (e.g.,
  • BOS2 691665.1 Nuvion (Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)
  • anti-CD5 antibodies e.g., an anti-CD5 ricin-linked immunoconjugate
  • anti-CD7 antibodies e.g., CHH-380 (Novartis)
  • anti-CD8 antibodies anti-CD40 ligand monoclonal antibodies
  • anti-CD52 antibodies e.g., CAMPATH IH (Ilex)
  • anti-CD2 antibodies anti-CDl Ia antibodies (e.g., Xanelim (Genentech)
  • anti-B7 antibodies e.g., IDEC-114 (IDEC)
  • CTLA4- immunoglobulin e.g., CTLA4- immunoglobulin.
  • cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (e.g., the extracellular domain of a TNF-.alpha. receptor or a fragment thereof, the extracellular domain of an IL-I .beta, receptor or a fragment thereof, and the extracellular domain of an IL-6 receptor or a fragment thereof), cytokines or fragments thereof (e.g., interleukin (IL)-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-9, IL-IO, IL-11, IL-12, IL-15, TNF-.alpha., interferon (IFN)-.alpha., IFN-.beta., IFN-.gamma., and GM-CSF), anti-cytokine receptor antibodies (e.g., anti- IFN receptor antibodies, anti-IL-2 receptor antibodies (e.g., Zenapax (Protein Design Labs)), anti-IL-4 receptor
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with cytokines.
  • cytokines include, but are not limited to, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin- 10 (IL-IO), interleukin- 12 (IL-12), interleukin 15 (IL- 15), interleukin 18 (IL-18), platelet derived growth factor (PDGF), erythropoietin (Epo), epidermal growth factor (EGF), fibroblast growth factor (FGF), granulocyte macrophage stimulating factor (GM-CSF), granulocyte colony stimulating factor (G- CSF), macrophage colony stimulating factor (M-CSF), prolactin, and interferon (IFN), e.g., IFN-alpha, and IFN-gamma).
  • IL-2 interleukin-2
  • IL-3 interleukin-3
  • BOS2 691665.1 Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with hormones.
  • hormones include, but are not limited to, luteinizing hormone releasing hormone (LHRH), growth hormone (GH), growth hormone releasing hormone, ACTH, somatostatin, somatotropin, somatomedin, parathyroid hormone, hypothalamic releasing factors, insulin, glucagon, enkephalins, vasopressin, calcitonin, heparin, low molecular weight heparins, heparinoids, synthetic and natural opioids, insulin thyroid stimulating hormones, and endorphins.
  • LHRH luteinizing hormone releasing hormone
  • GH growth hormone
  • ACTH ACTH
  • somatostatin somatotropin
  • somatomedin parathyroid hormone
  • hypothalamic releasing factors insulin
  • glucagon enkephalins
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with .beta.-interferons which include, but are not limited to, interferon beta- Ia and interferon beta- Ib.
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be administered or formulated in combination with an alkylating agent.
  • alkylating agents include, but are not limited to nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelaine, thiotepa, busulfan, carmustine, streptozocin, dacarbazine and temozolomide.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject in a pharmaceutically-acceptable formulation.
  • acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof or an acyclovir pharmaceutical composition is suitable for topical, intravenous, parental, or oral administration.
  • the methods of the invention further include administering to a subject a therapeutically effective amount of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof or acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof in combination with another
  • BOS2691665.1 pharmaceutically active compound.
  • Pharmaceutically active compounds that may be used can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T.R. Harrison et al. McGraw-Hill N.Y., NY; and the Physicians Desk Reference 50th Edition 1997, Oradell New Jersey, Medical Economics Co., the complete contents of which are expressly incorporated herein by reference.
  • phrases "pharmaceutically acceptable” refers to acyclovir, compositions containing acyclovir, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically- acceptable material, composition or vehicle, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • compositions include the step of bringing into association acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof with the carrier and, optionally, one or more accessory ingredients.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • acyclovir which may be used in a suitable salt, solvate, or hydrate form, and/or the pharmaceutical compositions of acyclovir, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Formulations are provided to a subject in an effective amount.
  • an effective amount or “therapeutically effective amount” or other similar term includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
  • An effective amount of acyclovir may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the
  • BOS2 691665.1 compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • the effective amount is generally determined by the physician on a case-by- case basis and is within the skill of one in the art.
  • the dosage for in vivo therapeutics or diagnostics will vary. Several factors are typically taken into account when determining an appropriate dosage. These factors include age, sex and weight of the patient, the condition being treated, and the severity of the condition.
  • Suitable dosages and formulations of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be empirically determined by the administering physician. Standard texts, such as Remington: The Science and Practice of Pharmacy, 17th edition, Mack Publishing Company, and the Physician's Desk Reference, each of which are incorporated herein by reference, can be consulted to prepare suitable compositions and doses for administration. A determination of the appropriate dosage is within the skill of one in the art given the parameters for use described herein.
  • Suitable dosages can also be based upon the text and documents cited herein. A determination of the appropriate dosages is within the skill of one in the art given the parameters herein.
  • an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of an enveloped virus infection, HIV infection, AIDS or the symptoms thereof.
  • a therapeutically effective amount can be provided in one or a series of administrations.
  • an effective amount is one sufficient to enhance the immune response to the immunogen. The effective amount is generally determined by the physician on a case-by-case basis and is within the skill of one in the art.
  • the dosage for in vivo therapeutics or diagnostics will vary. Several factors are typically taken into account when determining an appropriate dosage. These factors include age, sex and weight of the patient, the condition being treated, the severity of the condition and the form of the antibody being administered.
  • the dosage of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can vary e.g. suitably from about 10 mg to about 5,000 mg per day, preferably about 100 mg to about 4000 mg per day, more preferably about 1000 mg to about 3000 mg per day. Ascertaining dosage ranges is well within the skill of one in the art.
  • the dosage of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can range from about 0.1 to 70 mg/kg of body weight. Such dosages may vary, for example, depending on whether multiple administrations are given, tissue type and route of administration, the condition of the individual, the desired objective and other factors known to those of skill in the art. Administrations can be conducted infrequently, or on a regular weekly basis until a desired, measurable parameter is detected, such as diminution of disease symptoms. Administration can then be diminished, such as to a biweekly or monthly basis, as appropriate.
  • a therapeutically effective amount can be administered in one or more doses.
  • administration or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • BOS2 691665.1 administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • Such dosages may vary, for example, depending on whether multiple administrations are given, tissue type and route of administration, the condition of the individual, the desired objective and other factors known to those of skill in the art.
  • Available routes of administration include subcutaneous, intramuscular, intraperitoneal, intradermal, oral, intranasal, intrapulmonary (i.e., by aerosol), intravenously, intramuscularly, subcutaneously, intracavity, intrathecally or transdermally, alone or in combination with other pharmaceutical agents.
  • Acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and compositions comprising acyclovir that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
  • Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms e.g., powders, tablets, capsules, and caplets
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • talc calcium carbonate
  • microcrystalline cellulose e.g., powdere., powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is
  • BOS2 691665.1 typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH- 101, AVICEL-PH-103 AVICEL RC-581, AVICEL- PH- 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC- 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH- 103. TM and Starch 1500 LM.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional
  • BOS2 691665.1 lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 manufactured by W. R. Grace Co. of Baltimore, Md.
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
  • Parenteral and intravascular dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection and constant infusion), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral and intravascular dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products (including, but not limited to lyophilized powders, pellets, and tablets) ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • water for Injection USP Water for Injection USP
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride
  • B0S2 691665.1 For intravascular administration, for instance by direct injection into the blood vessel, or surrounding area, it may be desirable to administer the compositions locally to the area in need of treatment. This can be achieved, for example, by local infusion during surgery, by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers.
  • membranes such as silastic membranes, or fibers.
  • Gliadel® provided by Guilford Pharmaceuticals Inc.
  • Transdermal, Topical, And Mucosal Dosage Forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • kits which, when used by the medical practitioner, can simplify the identification of subjects and the administration of appropriate amounts of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to a patient.
  • a typical kit of the invention comprises one or more unit dosage forms of acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and instructions for identification of a subject.
  • Kits of the invention can further comprise materials that are used to quantify the viral load for a herpes virus by quantitative real-time PCR or other methods known to those of skill in the art.
  • materials include, primers for HHV-I, HHV-2, HHV-3, HHV-4, HHV-5 HHV-6a, HHV-6b, HHV-7, HHV-8 and combinations thereof; Reagents for performing a nucleic acid amplification reaction, for example, buffers, additional primers, positive and negative controls, nucleoside triphosphates, enzymes; and one or more suitable positive controls.
  • Kits of the invention can further comprise devices that are used to administer acyclovir or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof of the invention.
  • devices include, but are not limited to, intravenous cannulation devices, syringes, drip bags, patches, topical gels, pumps, containers that provide protection from photodegredation, autoinjectors, and inhalers.
  • Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but
  • BOS2 691665.1 not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Tonsillar, lymph node, colorectal and cervicovaginal tissues were obtained from routine surgery or from cadavers under IRB-approved protocols. Tissues were dissected, cultured and inoculated with viruses as described[2,l I].
  • MT- 4 T-cell line was obtained from the American Type Culture Collection (ATCC, Manassas, VA). HIV-I stocks were obtained from the Rush University Virology Quality Assurance Laboratory (Chicago, IL). HSV-2 strain G was obtained from ATCC.
  • HIV-I replication was measured by the p24 accumulation in the medium as assessed with ELISA.
  • HSV-2 viral replication was evaluated by viral DNA accumulation as assessed by real-time PCR.
  • Quantification of herpesvirus, proviral HIV-I and of cellular DNA in tissue blocks was evaluated by real-time PCR. Flow cytometry of isolated tissue cells stained for various markers was performed as described earlier 12 .
  • ACV Bedford Laboratories, Bedford, OH
  • ACV-TP Merasek, Brea, CA
  • BOS2 691665.1 Statistical analysis. Each data point is the result of analysis of sets of 9-to-27 tissue blocks derived from each of n donors, where n is indicated in the text. There was significant donor-to-donor variability in the absolute levels of HIV-I replication[2, 4, 11, 12]. Therefore, to pool data from different donors, for each experiment we normalized these levels to those in matched control blocks. Depending on normality of data distributions, parametric (Student's t) or non-parametric (Wilcoxon Match- Pairs-Signed-Ranks and Mann-Whitney-U) tests were applied. Pooled data are presented as mean ⁇ standard error of the mean or as median and interquartile range. All the hypotheses tests were two tailed, and ap value ⁇ 0.05 defines statistical significance.
  • the recommended therapeutic doses for the different clinical indications of ACV prodrug valacyclovir range between 1 and 3 g per day
  • the IC 50 for inhibition of HIV-I replication (9 ⁇ M) are within the range of the plasma concentration of ACV therapeutic doses in vivo [13].
  • the anti-HIV activity of ACV was not restricted to secondary lymphoid tissue (tonsils or lymph nodes), as a similar phenomenon was observed in cervicovaginal and colorectal tissues infected ex vivo with HIV-I (Fig. 2a).
  • ACV suppression of HIV replication in various tissues was observed for both CCR5- and CXCR4-tropic HIV-I variants (X4 LAI .O 4 , R5SF I 6 2 , R5 Ba L, and R5ADS) (Fig. 2c).
  • HSV-2 is an HHV that is known for its highest sensitivity to ACV
  • the absence of HSV-2 in the tissues used in this study was expected since HSV-2 is acquired
  • BOS2 691665.1 predominantly through sexual activity and these samples came from pediatric cases. Further real-time PCR analysis revealed that these tissues were also negative for HSV-I, HHV-3 and HHV-8. However, the tested tonsillar tissues carried other HHVs, including HHV-5 (15%), HHV-4 (33%), HHV-7 (89%), and HHV-6 (96%). HHV-6 was found in all tissues except one. As with immunocompromised patients [14], in the tissue explants no longer subjected to systemic immune control, virus replication increased with time.
  • ACV-TP to which ACV is converted in HHV- infected cells [6] suppresses HIV-I replication by interfering with the activity of the HIV-I reverse transcriptase (RT).
  • RT HIV-I reverse transcriptase
  • ACV-TP is a guanidine triphosphate analogue
  • its role as a nucleotide RT inhibitor was investigated by testing whether dGTP prevents ACV-TP inhibition of RT.
  • ACV-TP concentrations 3.37 ⁇ M or 33.7 ⁇ M
  • HIV-I RT inhibition was inversely dependent on the dGTP concentration.
  • no competition with dGTP was observed (Fig. 3b).
  • ACV-TP suppresses HIV in tissues as well.
  • HIV-I is efficiently suppressed by ACV in various human tissues infected with HSV-2, HHV-6, HHV-7, and other HHVs;
  • ACV in an HHV- negative tissue and in an HHV-free cell line, ACV does not inhibit HIV infection;
  • the final product of ACV phosphorylation, ACV-TP does inhibit HIV-I RT activity in a cell-free system, and its potency is inversely proportional to the amount of dGTP;
  • exogenous ACV-TP suppresses HIV-I in human tonsillar tissue ex vivo.
  • HIV-I pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5- and CXCR4-tropic HIV-I . Aids 21, 1263- 1272 (2007).

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Abstract

L'invention porte sur un traitement du VIH chez un sujet avec de l'acyclovir ou un sel, un solvate, un hydrate ou un promédicament pharmaceutiquement acceptables de celui-ci, comprenant l'étape d'identification du sujet comme possédant une infection par le virus de l'herpès apte à convertir l'acyclovir en triphosphate d'acyclovir.
PCT/US2008/010316 2007-08-30 2008-08-30 Procédé pour le traitement d'une infection par le virus du vih/le sida par utilisation d'acyclovir chez des sujets identifiés Ceased WO2009032244A1 (fr)

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PCT/US2008/010316 Ceased WO2009032244A1 (fr) 2007-08-30 2008-08-30 Procédé pour le traitement d'une infection par le virus du vih/le sida par utilisation d'acyclovir chez des sujets identifiés

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAGOT NICOLAS ET AL: "Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus", NEW ENGLAND JOURNAL OF MEDICINE, vol. 356, no. 8, February 2007 (2007-02-01), pages 790 - 799, XP002509748, ISSN: 0028-4793 *
STRICK LARA B ET AL: "Management of herpes simplex virus type 2 infection in HIV type 1-infected persons.", CLINICAL INFECTIOUS DISEASES : AN OFFICIAL PUBLICATION OF THE INFECTIOUS DISEASES SOCIETY OF AMERICA 1 AUG 2006, vol. 43, no. 3, 1 August 2006 (2006-08-01), pages 347 - 356, XP002509747, ISSN: 1537-6591 *

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