US2007190558A1PendingUtilityA1

Cationic Steroid Antimicrobial Compositions and Methods of Use

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Assignee: SAVAGE PAUL BPriority: Feb 1, 2006Filed: Jan 31, 2007Published: Aug 16, 2007
Est. expiryFeb 1, 2026(expired)· nominal 20-yr term from priority
Inventors:Paul B. SavageDonald Y.M. Leung
A61P 31/16A61K 45/06C12Q 1/18A61K 31/57A61K 31/568A61P 31/22A61K 31/575G01N 2333/03A61K 31/56
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Claims

Abstract

The invention provides methods for decreasing or inhibiting herpesviridae (HV) infection or pathogenesis of a cell in vitro, ex vivo or in vivo, a symptom or pathology associated with a herpesviridae (HV) infection or pathogenesis in vitro, ex vivo or in vivo, or an adverse side effect of herpesviridae (HV) infection or pathogenesis in vitro, ex vivo or in vivo. In one embodiment, a method of the invention includes treating a subject with an invention compound (e.g., cationic steroid antimicrobial or CSA).

Claims

exact text as granted — not AI-modified
1 . A method for providing a subject with protection against a herpesviridae (HV) infection or pathogenesis, comprising administering a sufficient amount of cationic steroid antimicrobial (CSA) to provide the subject with protection against herpesviridae (HV) infection or pathogenesis.  
   
   
       2 . A method for treating a subject in need of treatment for herpesviridae (HV) infection or pathogenesis, comprising administering a sufficient amount of cationic steroid antimicrobial (CSA) to treat the subject for the herpesviridae (HV) infection or pathogenesis.  
   
   
       3 . A method for decreasing susceptibility or inhibiting herpesviridae (HV) reactivation from latency in a subject, comprising administering a sufficient amount of cationic steroid antimicrobial (CSA) to decrease susceptibility or inhibit herpesviridae (HV) reactivation from latency in the subject.  
   
   
       4 . The method of any of  claims 1  to  3 , wherein the CSA is administered prior to, concurrently with, or following infection of the subject with HV, exposure to or contact of the subject with HV, or reactivation of HV.  
   
   
       5 . The method of any of  claims 1  to  3 , wherein the CSA is administered prior to, concurrently with, or following development of a symptom or pathology of acute or chronic HV infection, or reactivation of HV from latency.  
   
   
       6 . The method of any of  claims 1  to  3 , wherein the CSA is administered to a biological fluid, an immune cell or tissue, mucosal cell or tissue, neural cell or tissue, or epithelial cell or tissue.  
   
   
       7 . The method of any of  claims 1  to  3 , wherein the HV is present in a biological fluid, cell, tissue or organ.  
   
   
       8 . The method of  claim 7 , wherein the biological fluid comprises mucus, saliva, blood, serum, plasma, cerebrospinal fluid, urine, or placenta.  
   
   
       9 . The method of  claim 7 , wherein the tissue or organ comprises a transplant.  
   
   
       10 . The method of any of  claims 1  to  3 , wherein the HV is present in an immune cell tissue or organ, mucosal cell, tissue or organ, neural cell, tissue or organ, or epithelial cell, tissue or organ.  
   
   
       11 . The method of  claim 10 , wherein the immune cell comprises a T cell or a B cell.  
   
   
       12 . The method of  claim 10 , wherein the mucosal cell or tissue comprises mouth, buccal cavity, labia, nasopharynx, esophagus, trachea, lung, stomach, small intestine, vagina, rectum, or colon.  
   
   
       13 . The method of  claim 10 , wherein the neural cell or tissue comprises ganglia, motor or sensory neurons.  
   
   
       14 . The method of  claim 10 , wherein the epithelial cell or tissue comprises nose, fingers, ears, cornea, conjunctiva, skin or dermis.  
   
   
       15 . The method of any of  claims 1  to  3 , wherein the HV comprises an alpha-herpesvirus, beta-herpesvirus or gamma-herpesvirus.  
   
   
       16 . The method of  claim 15 , wherein the alpha herpes virus comprises herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2) or varicella zoster virus (VZV/HHV-3).  
   
   
       17 . The method of  claim 15 , wherein the beta or gamma-herpesvirus comprises cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus-6, -7 or -8 (HHV-6, HHV-7, or HHV-8/Kaposi's sarcoma herpesvirus/KSHV).  
   
   
       18 . The method of any of  claims 1  to  3 , wherein the CSA is selected from CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 .  
   
   
       19 . The method of any of  claims 1  to  3 , wherein the CSA does not have a charged group at position C24.  
   
   
       20 . The method of any of  claims 1  to  3 , wherein the CSA has a hydrophobic moiety at position C24.  
   
   
       21 . The method of  claim 20 , wherein the hydrophobic moiety at position C24 comprises a lipid.  
   
   
       22 . The method of any of  claims 1  to  3 , wherein the CSA has a charged group at position C7.  
   
   
       23 . The method of any of  claims 1  to  3 , wherein the CSA comprises a multimer.  
   
   
       24 . The method of any of  claims 1  to  3 , wherein the CSA multimer comprises a dimer, trimer, or tetramer.  
   
   
       25 . The method of any of  claims 1  to  3 , wherein the CSA has a shorter tether length between the steroid scaffold and the amine groups at positions C3, C7 and C12, relative to the tether length of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 or CSA-59, as set forth in  FIG. 10 .  
   
   
       26 . The method of any of  claims 1  to  3 , wherein the CSA comprises a pharmaceutically acceptable carrier or excipent.  
   
   
       27 . The method of any of  claims 1  to  3 , wherein the CSA comprises a sterile formulation.  
   
   
       28 . The method of any of  claims 1  to  3 , wherein the CSA comprises a composition comprising one or more additional CSAs or biologically active ingredients.  
   
   
       29 . The method of any of  claims 1  to  28 , wherein the subject is symptomatic or asymptomatic for HV infection, reactivation or pathogenesis.  
   
   
       30 . The method of any of  claims 1  to  28 , wherein the HV infection is in a latent state, active state or reactivated state.  
   
   
       31 . The method of any of  claims 1  to  28 , wherein the subject produces an antibody against a HV.  
   
   
       32 . The method of any of  claims 1  to  28 , wherein the subject is provided with partial or complete protection against HV infection or pathogenesis, a symptom or pathology caused by HV infection or pathogenesis or reactivation of HV from latency.  
   
   
       33 . The method of any of  claims 1  to  28 , wherein the method reduces, decreases, inhibits, ameliorates or prevents onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by HV infection or pathogenesis, or reactivation of HV from latency, in a subject.  
   
   
       34 . The method of  claim 33 , wherein the symptoms or pathologies are selected from: lesions, ulcers, canker sore, close sore, rash, boils, Gingivostomatitis, Herpetic whitlow Traumatic herpes ( herpes gladiatorum ), Eczema herpeticum, fever, fatigue, headache, sore throat, swollen lymph nodes, pneumonitis, pneumonia, hepatitis, meningitis, myelitis, Encephalitis, keratitis, Genital herpes, esophagitis, dysphasia, hemiparesis, coma, shingles, chicken pox, mononucleosis, chronic or acute pelvic inflammatory disease (PID), proctitis, colitis and nerve damage.  
   
   
       35 . The method of any of  claims 1  to  28 , wherein the method prevents or inhibits a worsening or progression of HV infection or one or more symptoms or pathologies associated with HV infection or pathogenesis or reactivation of HV from latency.  
   
   
       36 . The method of any of  claims 1  to  28 , wherein the method stabilizes the HV infection or one or more symptoms or pathologies associated with the HV infection or pathogenesis or reactivation of HV from latency.  
   
   
       37 . The method of any of  claims 1  to  28 , wherein the method reduces or decreases HV titer, viral load, viral replication, viral proliferation or a viral protein, or inhibits or prevents increases in HV titer, viral load, viral replication, viral proliferation or a viral protein.  
   
   
       38 . The method of any of  claims 1  to  28 , wherein the method reduces or decreases susceptibility of the subject to HV infection or one or more symptoms or pathologies associated with HV infection or pathogenesis or reactivation of HV from latency.  
   
   
       39 . The method of any of  claims 1  to  28 , wherein the subject has not been infected with or exposed to HV.  
   
   
       40 . The method of any of  claims 1  to  28 , wherein the subject has been infected with or exposed to HV.  
   
   
       41 . The method of any of  claims 1  to  28 , wherein the subject has been diagnosed as HV+ or has experienced a symptom or pathology caused by HV infection or pathogenesis or reactivation of HV from latency.  
   
   
       42 . The method of any of  claims 1  to  28 , wherein the subject is immunocompromised.  
   
   
       43 . The method of any of  claims 1  to  28 , wherein the subject is a candidate for or has received an immunosuppressant treatment.  
   
   
       44 . The method of any of  claims 1  to  28 , wherein the subject is a candidate for or has received a tissue or organ transplant.  
   
   
       45 . The method of any of  claims 1  to  28 , wherein the subject is a newborn, infant, toddler or child.  
   
   
       46 . The method of any of  claims 1  to  28 , wherein the subject is 50 years or older.  
   
   
       47 . The method of any of  claims 1  to  28 , further comprising administering to the subject an additional CSA or treatment.  
   
   
       48 . The method of  claim 47 , wherein the additional treatment is for HV, or a side effect of an HV treatment.  
   
   
       49 . The method of  claim 47 , wherein the additional treatment comprises a protease inhibitor, a reverse transcriptase inhibitor, a virus fusion inhibitor or a virus entry inhibitor.  
   
   
       50 . The method of  claim 47 , wherein the additional treatment comprises administering: AK602, AMD070, APV, ATV, ATZ, AVX754, AZT, Abacavir, Acyclovir, Adefovir dipivoxil, Adriamycin, Agenerase, Aldesleukin, Alovudine, AmBisome, Amdoxovir, Amphocin, Amphotec, Amphotericin B, Ampligen, Amprenavir, Androderm, Androgel, Aptivus, Atazanavir, Azithromycin, BMS-488043, Bactrim, Baraclude, Biaxin, BufferGel, C31G, CD 4 -IgG2, CPV, CS, Calanolide A, Capravirine, Carbopol 974P, Carrageenan, Carraguard, Cellulose sulfate, Cidofovir, Clarithromycin, Combivir, Copegus, Cotrimoxazole, Crixivan, Cyanovirin-N, Cytovene, DAPD, DLV, DPC 817, DS, Delavirdine, Depo-Testosterone, Dextran sulfate, Didanosine, Diflucan, Docosanol, Doxil, Doxorubicin, Dronabinol, EFV, Efavirenz, Elvucitabine, Emtricitabine, Emtriva, Enfuvirtide, Entecavir, Epivir, Epoetin alfa, Epogen, Epzicom, Etopophos (phosphate salt), Etoposide, Etravirine, Famcyclovir, Fluconazole, Foscarnet, Fortovase, Fosamprenavir, Fungizone, Fuzeon, GSK-873,140 (aplaviroc), GW433908, Gammar-P, Ganciclovir, Growth hormone, Human growth hormone, HEC, Hepsera, Hivid, Hydroxyethyl cellulose, IDV, IGIV, Interleukin-2 (IL-2), INH, Immune Globulin, Indinavir, Interferon alfa-2, Intron A (2b), Invirase, Isoniazid, Isoprinosine, Itraconazole, KP-1461, Kaletra, L-000870810, LPV/RTV, Lamivudine, Lexiva, Marinol, Megace, Megestrol, Mycobutin, NFV, NVP, Naphthalene 2-sulfonate polymer, Nebupent, Nelfinavir, Neutrexin, Nevirapine, New-Fill, Norvir, Nydrazid, Onxol, PA-457, PMPA, PRO2000, PRO542, Paclitaxel, Paxene, Pegasys (2a), Pentamidine, Peptide T, Poly(I)-Poly(C12U), Poly-L-lactic acid, Polygam S/D, Procrit, Proleukin, RCV, RTV, RVT, Racivir, Rebetol, Rescriptor, Retrovir, Reverset, Reyataz, Ribavirin, Rifabutin, Rifadin, Rifampin, Rimactane, Ritonavir, Roferon-A (2a), SCH-C, SCH-D (vicriviroc), SQV, Saquinavir, Savvy, Sculptra, Septra, Serostim, Somatropin, Sporanox, Stavudine, Sulfamethoxazole, Sustanon, Sustiva, T-20, TDF, THC, TMC114, TMC125, TNX-355, Taxol, Tenofovir, Tenofovir disoproxil fumarate, Testosterone, Tipranavir, Toposar, Trimethoprim, Trimetrexate, Trizivir, Truvada, UC-781, UK-427,857 (maraviroc), Ushercell, Valacyclovir, Valcyte, Valganciclovir, Valproic acid, VePesid, Vicriviroc, Vidabrine, Videx, Viracept, Viramune, Virazole, Viread, Vitrasert, ZDV, Zalcitabine, Zerit, Ziagen, Zidovudine, Zithromax, Zovirax, D4T, ddC, β-LFddC, P-LFd4C, DDI, f-APV, 3TC, or human erythropoietin (EPO).  
   
   
       51 . The method of  claim 47 , wherein the additional treatment comprises a cytokine, chemokine, interferon or interleukin.  
   
   
       52 . The method of  claim 47 , wherein the additional treatment is for human immunodeficiency virus (HV).  
   
   
       53 . The method of  claim 47 , wherein the additional treatment comprises an antibody that binds to an HV protein.  
   
   
       54 . The method of  claim 53 , wherein the HV protein is selected from: envelope protein, tegument protein, capsid protein, core protein and polymerase.  
   
   
       55 . The method of  claim 54 , wherein the envelope protein comprises glycoprotein gp42, gp350, gpK8.1A, B, C, D, E, H, L (gB, gC, gD, gE, gH, gL).  
   
   
       56 . The method of  claim 54 , wherein the tegument protein comprises: UL17, UL36, UL37, UL48, UL49, US11, UL11, UL14, UL16, UL21, UL41, UL46, UL47, VP13/14, VP16 and VP22.  
   
   
       57 . The method of  claim 54 , wherein the capsid protein comprises: VP5, VP19c, VP21, VP23, VP24, VP26.  
   
   
       58 . The method of  claim 53 , wherein the antibody is human, humanized or chimeric.  
   
   
       59 . The method of  claim 53 , wherein the antibody is monoclonal or polyclonal.  
   
   
       60 . A method for decreasing or inhibiting herpesviridae (HV) infection of a cell or herpesviridae (HV) reactivation from latency, in vitro or in vivo, comprising administering a composition comprising a sufficient amount of cationic steroid antimicrobial (CSA) to inhibit herpesviridae (HV) infection of the cell.  
   
   
       61 . The method of  claim 60 , wherein the cell is mammalian.  
   
   
       62 . The method of  claim 60 , wherein the cell is human.  
   
   
       63 . A method for providing a subject with protection against herpesviridae (HV) infection or pathogenesis, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-1, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to provide the subject with protection against the herpesviridae (HV) infection or pathogenesis.  
   
   
       64 . A method for treating a subject in need of treatment for herpesviridae (HV) infection or pathogenesis, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to treat the subject for the herpesviridae (HV) infection or pathogenesis.  
   
   
       65 . A method for decreasing susceptibility or inhibiting herpesviridae (HV) reactivation from latency in a subject, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to decrease susceptibility or inhibit herpesviridae (HV) reactivation from latency of the subject.  
   
   
       66 . A method for reducing, decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by herpesviridae (HV) infection or pathogenesis, or reactivation of herpesviridae (HV) from latency, in a subject, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to decrease, inhibit, ameliorate or prevent onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by herpesviridae (HV) infection or pathogenesis, or reactivation of herpesviridae (HV) from latency in the subject.  
   
   
       67 . A kit, said kit comprising packaging material, a cationic steroid antimicrobial (CSA) and instructions, said instructions comprising administering said CSA to: 
 a) provide a subject with protection against an HV infection, reactivation or pathogenesis;    b) treat a subject for HV infection, reactivation or pathogenesis;    c) decrease susceptibility or inhibit HV reactivation from latency in a subject; or    d) decrease, inhibit, ameliorate or prevent onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by HV infection, reactivation or pathogenesis.    
   
   
       68 . A method for identifying a candidate agent for treating a subject for an HV infection or pathogenesis, or reactivation from latency, comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) contacting said test agent with HV and ascertaining whether the test agent inhibits HV infection or pathogenesis, or reactivation from latency, wherein a test agent identified as inhibiting HV infection or pathogenesis or reactivation from latency is a candidate agent for treating a subject for HV infection or pathogenesis.    
   
   
       69 . A method for identifying a candidate agent for decreasing susceptibility or inhibiting HV reactivation from latency, comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) contacting said test agent with HV and ascertaining whether the test agent decreases susceptibility or inhibits HV reactivation from latency, wherein a test agent identified as decreasing susceptibility or inhibiting HV reactivation from latency is a candidate agent for decreasing susceptibility or inhibiting HV reactivation from latency.    
   
   
       70 . A method for identifying a candidate agent for decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies caused by or associated with HV infection or pathogenesis or reactivation from latency comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) administering said test agent to a subject infected with or exposed to HV and ascertaining whether the test agent decreases, inhibits, ameliorates or prevents onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by HV infection or pathogenesis, or reactivation from latency, wherein a test agent identified is a candidate agent for decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with or caused by HV infection or pathogenesis or reactivation from latency.    
   
   
       71 . The method of  claim 70 , wherein the subject comprises a mammal.  
   
   
       72 . The method of  claim 71 , wherein the mammal comprises an animal model for HV infection, reactivation or pathogenesis.

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