DOCSLIB.ORG

Therapeutic Options for Herpes Simplex Infections Eugene Au and Stephen L

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Therapeutic Options for Herpes Simplex Infections Eugene Au and Stephen L Therapeutic Options for Herpes Simplex Infections Eugene Au and Stephen L. Sacks, MD Address Herpes simplex virus initiates infection through direct Department of Pharmacology and Therapeutics, The University of contact with mucosal surfaces or abraded skin. Following British Columbia, Viridae Clinical Sciences Inc.,1134 Burrard Street, infection, the virus is transported to the dorsal root gan- Vancouver, BC, Canada V6Z 1Y8. E-mail: [email protected] glion, where latent infection is established. Stimuli such as stress, fever, and exposure to ultraviolet light can cause Current Infectious Disease Reports 2003, 5:22–27 Current Science Inc. ISSN 1523-3847 reactivation from latency, upon which active infection Copyright © 2003 by Current Science Inc. occurs near the point of entry into the host [5•]. Signs of recurrent infection may include a prodrome of pain, burn- Herpes simplex viruses are responsible for a number of dis- ing, tingling, or discomfort, which precede the develop- ease states in infected individuals. Capable of establishing ment of classic herpes lesions characterized by vesicle latent infection, herpes simplex can reactivate, causing pain, formation on a red patch of skin. Classically, vesicular discomfort, and psychosocial consequences. Because no lesions evolve into erosions, although atypical presenta- cure is available, treatment modalities for herpes simplex tions are common [2]. infection are required, from both personal and public health There is no known cure for herpes simplex infections. standpoints. To date, therapy has centered around the use As the incidence of infection continues to rise, and with of antiviral drugs to control infection and suppress recur- mounting evidence that HSV-2 is a significant cofactor in rences. To expand the scope of available treatments, efforts the transmission of HIV, it may be imperative to develop have focused on the development of vaccines against her- new therapeutic options for HSV disease. This review dis- pes simplex virus and new agents such as immune response cusses the use of antiviral drugs currently used in episodic modifiers. Recent data suggest that these new agents are and suppressive therapy. In the immunocompromised promising in their therapeutic potential. host, use of antivirals may play a role in the selection of drug-resistant HSV, and therapies for resistant virus strains are discussed. In addition, vaccines against HSV are consid- ered, as well as topical treatment modalities and other Introduction potential targets for HSV chemotherapy. The Herpesviridae family, officially designated as human herpes viruses 1 through 8 (HHV-1 through HHV-8), con- sists of eight viruses capable of producing pathogenic Antivirals in the Treatment of Herpes infection in humans [1]. HHV-1 and HHV-2 are com- Simplex Infections monly referred to as herpes simplex viruses type 1 and type The major treatment modality for HSV infections is the use 2 (HSV-1 and HSV-2), respectively. HSV are enveloped, of antiviral nucleoside analogues. Common across this double-stranded DNA viruses distinguished by differences class of medication is the requirement of activation by in clinical and virologic characteristics, including differ- viral-encoded thymidine kinase (TK). The first nucleoside ences in glycoproteins expressed on the viral envelope. It is analogue shown to be effective agent in clinical trials was estimated that up to 85% of the population is seropositive acyclovir. In cells infected with HSV, acyclovir is phospho- for HSV-1 [2], and though this virus is most often associ- rylated to acyclovir monophosphate by TK, and subse- ated with herpes labialis (cold sores), the incidence of her- quently converted to its di- and triphosphate forms pes genitalis (genital herpes) caused by HSV-1 is on the rise through the actions of host cellular enzymes. The active [3]. HSV-2 is the major cause genital herpes, one of the form of the drug is acyclovir triphosphate, which inhibits most common sexually transmitted infections (STIs). HSV-encoded DNA polymerase through competition with Despite the efforts aimed at preventing the spread of AIDS deoxyguanosine triphosphate as a substrate for the and other STIs, the prevalence of HSV-2 infection has enzyme. This results in obligate termination of HSV DNA increased, as evidenced by the National Health and Nutri- replication, and thus inhibition of viral growth [6]. Oral tion Examination Surveys (NHANES) II and III, which acyclovir is approved by the US Food and Drug Adminis- showed a 30% increase in HSV-2 seroprevalence [4]. HSV-2 tration (FDA) for the treatment of genital herpes infection. is also associated with neonatal herpes. Primary infection is effectively treated with 200 mg five Therapeutic Options for Herpes Simplex Infections • Au and Sacks 23 times daily for 5 to 10 days, and episodic drug therapy with the presence of a 3' hydroxyl group, whereas acyclovir lacks 200 mg five times daily for 5 days is used for the treatment the 3' hydroxyl group making its chain termination "obli- of recurrent infection [7••]. An alternative regimen recom- gate." It has been shown that the active drug form, penci- mended by the Centers for Disease Control and Prevention clovir triphosphate, is made in excess and has a much (CDC) is 400 mg three times daily for the treatment of longer intracellular half-life (20 hours) than acyclovir both primary and recurrent infections [8]. A 2-day regimen triphosphate (1 hour) in cells infected with HSV-2. How- of acyclovir has also been successfully used for episodic ever, penciclovir triphosphate is proportionally less potent treatment of recurrent infection [9]. For patients with fre- against viral DNA polymerase [20]. A topical 1% cream quent recurrences, 400 mg twice daily is effective in contin- preparation of penciclovir, applied once every 2 hours for 4 uous suppressive therapy of genital herpes [7], although days, is approved by the FDA for the treatment of recurrent dosages of 200 mg two to five times daily have also been herpes labialis. effectively used [10,11]. Acyclovir may also be of minimal Famciclovir, administered at 125 mg twice daily for 5 benefit in the treatment of herpes labialis. Acyclovir is not days, is approved for the episodic treatment of recurrent FDA-approved for treatment of HSV labialis [12–14]. genital herpes. It is also effective in the suppression of Though acyclovir has been demonstrated to be both effec- recurrent infection, approved at a dose of 250 mg twice tive and safe, its inconvenient dosing schedule, which leads daily [7••]. The dosing of famciclovir is often confusing to to issues in compliance, and low bioavailability (approxi- clinicians, but results from the intracellular pharmacoki- mately 15%) have fostered the development of the nucleo- netic advantage in its conversion to its triphosphate. This side prodrugs valaciclovir and famciclovir, which exhibit provides a dosing advantage during active treatment, but improved absorption characteristics. that advantage disappears between active episodes, when Valaciclovir, the 1-valyl ester prodrug of acyclovir, is viral TK is not expressed. The use of famciclovir in the metabolized to L-valine and acyclovir. Its safety and phar- treatment of primary genital herpes infection has been macokinetics are essentially identical to those of acyclovir investigated in clinical studies. It was determined that as the parent nucleoside, but valaciclovir is much better when administered at 250 mg, 500 mg, and 750 mg three absorbed than acyclovir, with an oral bioavailability of times daily for 5 days, famciclovir was as efficacious as about 55%. The peak plasma concentrations of acyclovir acyclovir at doses approved for the treatment of primary achieved are approximately four times greater when valaci- infection [21], and has the practical advantage of reduced clovir is administered in similar doses to acyclovir [15]. dosing frequency. Oral valaciclovir is efficacious in the treatment of genital In assessing the advantages of the antivirals currently herpes, and is indicated for primary (1000 mg twice daily available for the treatment of HSV infection, acyclovir and for 10 days) and recurrent (500 mg twice daily for 3 days) valaciclovir are favored for the potency of acyclovir triphos- infections [7••]. It is also approved for continuous sup- phate, whereas famciclovir has a dosing advantage only pressive therapy of genital herpes at a dosage of 500 mg during episodic therapy due to its long intracellular half- once daily for patients with 10 or fewer recurrences per life. These differences in drug characteristics may be indi- year, and 1000 mg once daily for patients with greater than vidually optimized to select treatment regimens according 10 recurrences annually [7••]. Doses of 250 to 500 mg to each individual’s needs. twice daily have also been shown to be effective in suppres- sive therapy [16,17]. Recent studies have demonstrated the therapeutic Resistance to Antivirals potential of valaciclovir for the treatment of herpes labia- A concern regarding the use of antiviral medications for lis. High-dose valaciclovir at the first prodromal symptom the treatment of HSV infections has been the development for 1 day (2000 mg twice) or 2 days (2000 mg twice on of drug resistance. Strains of HSV that are resistant to acy- the first day, followed by 1000 mg twice on the second clovir have been identified, with a far higher rate of occur- day) was effective in reducing episode duration and rence in immunocompromised individuals (4% to 11%) lesion healing time [18]. It has also been recently compared with the general population (0.4%) [2]. Resis- reported that suppressive valaciclovir therapy is effective tance may be conferred by viral mutations resulting in in reducing transmission of genital herpes among hetero- strains of HSV that are deficient in TK [22], or strains that sexual HSV-2 discordant couples, a significant finding in exhibit altered TK activity without loss of virulence [23]. that it is the first controlled trial demonstrating the ability Strains lacking TK are resistant, but also frequently subviru- of antiviral therapy to reduce sexual transmission of viral lent.
Load more

Recommended publications
  • Newer Trends in the Management of Genital Herpes
    Review NNewerewer trendstrends inin thethe mmanagementanagement ofof genitalgenital herpesherpes Article AAmiyamiya KKumarumar NNath,ath, DDevinderevinder MohanMohan ThappaThappa Department of Dermatology ABSTRACT and STD, Jawaharlal Institute of Postgraduate Medical Management of genital herpes is complex. Apart from using the standard antivirals, an Education and Research (JIPMER), Pondicherry - 605 ideal management protocol also needs to address various aspects of the disease, including 006, India the psychological morbidity. Oral acyclovir, valacyclovir or famciclovir are recommended for routine use. Long-term suppressive therapy is effective in reducing the number of AAddressddress forfor ccorrespondence:orrespondence: recurrences and the risk of transmission to others. Severe or disseminated disease may Dr. Devinder Mohan Thappa, require intravenous therapy. Resistant cases are managed with foscarnet or cidofovir. Genital Department of Dermatology herpes in human immunodeÞ ciency virus-infected individuals usually needs a longer duration and STD, JIPMER, of antiviral therapy along with continuation of highly active anti retroviral therapy (HAART). Pondicherry - 605 006, India. E-mail: [email protected] Genital herpes in late pregnancy increases the risk of neonatal herpes. Antiviral therapy and/or cesarean delivery are indicated depending on the clinical circumstance. Acyclovir appears to be safe in pregnancy. But, there is limited data regarding the use of valacyclovir and famciclovir in pregnancy. Neonatal herpes requires a higher dose of acyclovir given intravenously for a longer duration. Management of the sex partner, counseling and prevention advice are equally important in appropriate management of genital herpes. Vaccines till date have been marginally effective. Helicase–primase inhibitors, needle-free mucosal vaccine and a new microbicide product named VivaGel may become promising treatment options in the future.
    [Show full text]
  • The Effects of Atopy and Asthma on in Vivo Human Nasal Responses to Toll
    The effects of atopy and asthma on in vivo human nasal responses to Toll-like receptor agonists Dr Akhilesh Jha A thesis submitted for the degree of Doctor of Philosophy (PhD) Centre for Respiratory Infection National Heart and Lung Institute (NHLI), St Mary’s Campus Imperial College London, Norfolk Place, London W2 1PG July 2018 Abstract Acute respiratory viral infections cause significant morbidity and mortality, especially in vulnerable individuals, and it is important to study viral pathogenesis and the host immune response in humans. Toll-like receptors (TLRs) play a critical role in the detection of viral nucleic acids, and airway TLR receptors respond to nucleic acid patterns in the RNA viruses that cause respiratory infections. However, a reliable method of measuring mucosal innate immune responses to viral infections is lacking. TLR3 agonists (poly(I:C) and poly-ICLC) and the combined TLR7/8 agonist (resiquimod, R848) are synthetic analogues of double stranded RNA (dsRNA) and single stranded RNA (ssRNA) respectively. Nasal challenge with these TLR agonists was carried out, and serial sampling using nasosorption and nasal curettage was performed. Mucosal immune responses were measured and the effect of different host factors (e.g. asthma) on these responses was studied. Poly(I:C) and poly-ICLC were well tolerated but failed to induce significant and reliable nasal mucosal innate immune responses. R848 at a higher dose (10 µg/100 µL per nostril) induced significant mucosal interferon and cytokine responses but caused mild to moderate flu-like symptoms in three out of nine volunteers. A lower dose of R848 (0.02 µg/kg/100 µL, mean dose 1.5 µg/100 µL) was subsequently utilised in three groups of volunteers: healthy non-atopic (n=12), allergic rhinitis (n=12) and allergic asthma (n=11).
    [Show full text]
  • Inclusion and Exclusion Criteria for Each Key Question
    Supplemental Table 1: Inclusion and exclusion criteria for each key question Chronic HBV infection in adults ≥ 18 year old (detectable HBsAg in serum for >6 months) Definition of disease Q1 Q2 Q3 Q4 Q5 Q6 Q7 HBV HBV infection with infection and persistent compensated Immunoactive Immunotolerant Seroconverted HBeAg HBV mono-infected viral load cirrhosis with Population chronic HBV chronic HBV from HBeAg to negative population under low level infection infection anti-HBe entecavir or viremia tenofovir (<2000 treatment IU/ml) Adding 2nd Stopped antiviral therapy antiviral drug Interventions and Entecavir compared Antiviral Antiviral therapy compared to continued compared to comparisons to tenofovir therapy therapy continued monotherapy Q1-2: Clinical outcomes: Cirrhosis, decompensated liver disease, HCC and death Intermediate outcomes (if evidence on clinical outcomes is limited or unavailable): HBsAg loss, HBeAg seroconversion and Outcomes HBeAg loss Q3-4: Cirrhosis, decompensated liver disease, HCC, relapse (viral and clinical) and HBsAg loss Q5: Renal function, hypophosphatemia and bone density Q6: Resistance, flare/decompensation and HBeAg loss Q7: Clinical outcomes: Cirrhosis, decompensated liver disease, HCC and death Study design RCT and controlled observational studies Acute HBV infection, children and pregnant women, HIV (+), HCV (+) or HDV (+) persons or other special populations Exclusions such as hemodialysis, transplant, and treatment failure populations. Co treatment with steroids and uncontrolled studies. Supplemental Table 2: Detailed Search Strategy: Ovid Database(s): Embase 1988 to 2014 Week 37, Ovid MEDLINE(R) In-Process & Other Non- Indexed Citations and Ovid MEDLINE(R) 1946 to Present, EBM Reviews - Cochrane Central Register of Controlled Trials August 2014, EBM Reviews - Cochrane Database of Systematic Reviews 2005 to July 2014 Search Strategy: # Searches Results 1 exp Hepatitis B/dt 26410 ("hepatitis B" or "serum hepatitis" or "hippie hepatitis" or "injection hepatitis" or 2 178548 "hepatitis type B").mp.
    [Show full text]
  • Bioinformatics Review of the Role of HSV-1 in Alzheimer's Disease
    Advances in Alzheimer’s Disease, 2020, 9, 57-75 https://www.scirp.org/journal/aad ISSN Online: 2169-2467 ISSN Print: 2169-2459 Bioinformatics Review of the Role of HSV-1 in Alzheimer’s Disease Brian T. Reiss1, Meade C. Eggleston1, Arah C. Godbole1, Julia A. Marut1, Cecelia M. McCann1, Jessica A. Cottrell1, Tinchun Chu1, Sulie L. Chang1,2* 1Department of Biological Sciences, Seton Hall University, South Orange, NJ, USA 2Institute of Neuroimmune Pharmacology, Seton Hall University, South Orange, NJ, USA How to cite this paper: Reiss, B.T., Eg- Abstract gleston, M.C., Godbole, A.C., Marut, J.A., McCann, C.M., Cottrell, J.A., Chu, T.C. and Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the Chang, S.L. (2020) Bioinformatics Review progressive loss of cognitive functions in affected individuals. Brain tissue of the Role of HSV-1 in Alzheimer’s Dis- pathology is associated with the formation of senile plaques which result from ease. Advances in Alzheimer’s Disease, 9, 57-75. the over-production of amyloid β (Aβ), due to the cleavage of a membrane https://doi.org/10.4236/aad.2020.93005 bound glycoprotein. It is unclear what causes AD and its associated patholo- gies, but age and genetic predisposition play an import role in the likelihood Received: June 11, 2020 Accepted: September 6, 2020 of disease development. Studies have shown that the reactivation of latent Published: September 9, 2020 herpes simplex virus 1 (HSV-1) infection can lead to the neuropathy of acute herpes simplex encephalitis (HSE), which causes similar symptoms to AD.
    [Show full text]
  • Activation of Anti-Hepatitis C Virus Responses Via Toll-Like Receptor 7
    Activation of anti-hepatitis C virus responses via Toll-like receptor 7 Jongdae Lee*, Christina C. N. Wu*†, Ki Jeong Lee‡, Tsung-Hsien Chuang§, Kyoko Katakura*, Yu-Tsueng Liu*†, Michael Chan†, Rommel Tawatao†, Michelle Chung*, Carol Shen*, Howard B. Cottam†, Michael M. C. Lai‡, Eyal Raz*, and Dennis A. Carson†¶ *Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0663; †Moores Cancer Center, University of California at San Diego Medical Center, La Jolla, CA 92093-0820; ‡Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; and §Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 Contributed by Dennis A. Carson, December 15, 2005 IFN-␣ is used to suppress the replication of hepatitis C virus (HCV) in HCV replicon cells. The IRFs can both foster type I IFN in chronically infected patients with partial success. Here we production (18) and enhance the antiviral activity of these present evidence showing that a ligand of Toll-like receptor 7 cytokines (19). Thus, pharmacologic agents that activate IRFs in (TLR7) can induce anti-HCV immunity not only by IFN induction, but hepatocytes may exert direct anti-HCV effects, as well as po- also through an IFN-independent mechanism. Human hepatocyte tentiate IFN action. line Huh-7 carrying an HCV replicon expressed TLR7, and activation Pharmacologic inhibitors of the enzyme inosine monophos- of the receptor induced several antiviral genes including IFN phate dehydrogenase (IMPDH), including ribavirin and mizor- regulatory factor-7. Inhibitors of the enzyme inosine monophos- ibine, have been reported to have activity against RNA viruses phate dehydrogenase augmented both IFN-dependent and -inde- (18–20).
    [Show full text]
  • Annual Report 2016
    Annexes to the annual report of the European Medicines Agency 2016 Annex 1 – Members of the Management Board ............................................................... 2 Annex 2 - Members of the Committee for Medicinal Products for Human Use ...................... 4 Annex 3 – Members of the Pharmacovigilance Risk Assessment Committee ........................ 6 Annex 4 – Members of the Committee for Medicinal Products for Veterinary Use ................. 8 Annex 5 – Members of the Committee on Orphan Medicinal Products .............................. 10 Annex 6 – Members of the Committee on Herbal Medicinal Products ................................ 12 Annex 7 – Committee for Advanced Therapies .............................................................. 14 Annex 8 – Members of the Paediatric Committee .......................................................... 16 Annex 9 – Working parties and working groups ............................................................ 18 Annex 10 – CHMP opinions: initial evaluations and extensions of therapeutic indication ..... 24 Annex 10a – Guidelines and concept papers adopted by CHMP in 2016 ............................ 25 Annex 11 – CVMP opinions in 2016 on medicinal products for veterinary use .................... 33 Annex 11a – 2016 CVMP opinions on extensions of indication for medicinal products for veterinary use .......................................................................................................... 39 Annex 11b – Guidelines and concept papers adopted by CVMP in 2016 ...........................
    [Show full text]
  • Naive Alum | IMQ-Cpg
    US010485861B2 United States Patent (10 ) Patent No.: US 10,485,861 B2 Stary et al. (45 ) Date of Patent : Nov. 26 , 2019 (54 ) NANOPARTICLE -BASED COMPOSITIONS Related U.S. Application Data ( 71) Applicants : President and Fellows of Harvard (60 ) Provisional application No. 61/ 783,439 , filed on Mar. College , Cambridge , MA (US ) : 14 , 2013 . Massachusetts Institute of (51 ) Int. CI. Technology , Cambridge , MA (US ); The A61K 39/118 (2006.01 ) Brigham and Women's Hospital, Inc., A61K 45/06 ( 2006.01) Boston , MA (US ) (Continued ) (52 ) U.S. CI. (72 ) Inventors : Georg Stary, Brookline, MA (US ) ; CPC A61K 39/118 (2013.01 ) ; A61K 31/4745 Aleksandar Filip Radovic -Moreno , ( 2013.01 ) ; A61K 31/711 ( 2013.01) ; State College , PA (US ) ; Pamela A. (Continued ) Basto , Cambridge, MA (US ) ; Michael ( 58 ) Field of Classification Search N. Starnbach , Needham , MA (US ) ; CPC A61K 9/10 ; A61K 35/74 ; A61K 39/39 ; Robert S. Langer , Newton , MA (US ) ; A61K 39/522 ; A61K 39/55555 ; Omid C. Farokhzad , Waban , MA (US ) ; Ulrich Von Andrian , Chestnut (Continued ) Hill , MA (US ) ( 56 ) References Cited (73 ) Assignees: President and Fellows of Harvard U.S. PATENT DOCUMENTS College, Cambridge , MA (US ) ; Massachusetts Institute of 3,960,757 A 6/1976 Morishita et al . Technology , Cambridge, MA (US ) ; The 4,638,045 A 11/1987 Kohn et al . Brigham and Women's Hospital, Inc. , (Continued ) Boston , MA (US ) FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this WO WO1997028259 8/1997 patent is extended or adjusted under 35 WO WO1998016247 4/1998 U.S.C. 154 ( b ) by 0 days .
    [Show full text]
  • Breast Cancer Treatment with Imiquimod: Applying an Old Lotion to a New Disease
    Author Manuscript Published OnlineFirst on November 21, 2012; DOI: 10.1158/1078-0432.CCR-12-3138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Breast cancer treatment with imiquimod: Applying an old lotion to a new disease Holbrook Kohrt, MD PhD Stanford University Cancer Institute Department of Medicine, Division of Oncology Stanford, CA 94305 Title: 79 characters Abstract: 49 words Text: 1200 words References: 12 references The author has no conflicts of interest. Running Title: Applying an old lotion to a new disease Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 21, 2012; DOI: 10.1158/1078-0432.CCR-12-3138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Over the prior two decades, imiquimod, a toll-like receptor 7 agonist, has been applied to nearly fifty clinical settings. Due to its immunomodulatory role, the topical cream today for the first time, is being applied to cutaneous breast cancer in pre-clinical models and in a Phase 2 clinical trial. Manuscript In this issue of Clinical Cancer Research, two sets of authors from Demaria’s group, Dewan et al. (1) and Adams et al. (2) detail in companion papers the anti-tumor efficacy of imiquimod in first, a preclinical breast cancer model in combination with radiation (1), and second, a Phase 2, breast cancer clinical trial assessing safety and immunologic activity (2). Fifteen years after first approval by the Food and Drug Administration (FDA), imiquimod remains the only approved, active toll-like receptor (TLR) agonist (3).
    [Show full text]
  • Time-Resolved Effect of Interferon-Alpha 2A on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes
    pharmaceutics Article Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes Dirk Theile , Lelia Wagner , Cindy Bay, Walter Emil Haefeli and Johanna Weiss * Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; [email protected] (D.T.); [email protected] (L.W.); [email protected] (C.B.); [email protected] (W.E.H.) * Correspondence: [email protected]; Tel.: +49-6221-5639402 Abstract: Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-kB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-kB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross- talk between NF-kB activation and PXR suppression was evaluated by NF-kB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-kB activity 2-fold and suppressed PXR Citation: Theile, D.; Wagner, L.; activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after Bay, C.; Haefeli, W.E.; Weiss, J.
    [Show full text]
  • Immunosuppressant Ingredients, Immunostimulant Ingredients
    Immunosuppressant Ingredients, Immunostimulant Ingredients Immunosuppressant Ingredients Immunosuppressant ingredients are chemical and medicinal agents used for the suppression and regulation of immune responses. Pharmacologically speaking, these agents have varied mecha- nisms of action, such as regulation of inflammatory gene expression, suppression of lymphocyte signal transduction, neutralization of cytokine activity, and inhibition lymphocyte proliferation by agent-induced cytotoxicity. Common agents include glucocorticoids, alkylating agents, metabolic antagonists, calcineurin inhibitors, T-cell suppressive agents, and cytokine inhibitors. 5-Aminosalicylic Acid 25g / 500g [A0317] 5-Aminosalicylic acid (5-ASA) is commonly used as a gastrointestinal anti-inflammatory agent. It has in vitro and in vivo pharmacologic effects that decrease leukotriene production, scavenge for free radicals, and inhibits leukocyte chemotaxis et al. Azathioprine 5g / 25g [A2069] Azathioprine is a prodrug of 6-mercaptopurine (6-MP), which inhibits the synthesis of purine ribonucleotides and DNA/RNA. Cyclophosphamide Monohydrate 5g / 25g [C2236] Cyclophosphamide is an antitumor alkylating reagent involved in the cross-linking of tumor cell DNA. Cyclosporin A 100mg / 1g [C2408] Cyclosporin A is a cyclic polypeptide immunosuppressant. It inhibits the activity of T-lymphocytes, and the phosphatase activity of calcineurin. Dimethyl Fumarate 25g / 500g [F0069] Dimethyl fumarate has neuroprotective and immunomodulating effects. Fingolimod Hydrochloride 200mg / 1g [F1018] Fingolimod (FTY720) is an immunomodulatory agent. It is an agonist at sphingosine 1-phosphate (S1P) receptors, and inhibits lymphocyte emigra- tion from lymphoid organs. Iguratimod 25mg / 250mg [I0945] Iguratimod (T-614) is an agent with anti-inflammatory and immunomodulatory activities. Its activity functions by the inhibiting production of immune globulin and inflammatory cytokines such as TNF-α, IL-1β and IL-6, and used as a disease modifying anti-rheumatic drug (DMARD).
    [Show full text]
  • Rapid Host Immune Response and Viral Dynamics in Herpes Simplex Virus-2 Infection
    PERSPECTIVE Rapid host immune response and viral dynamics in herpes simplex virus-2 infection Joshua T Schiffer1,2 & Lawrence Corey1–3 Herpes simplex virus-2 (HSV-2) is periodically shed throughout rate of HIV five- to tenfold14. Men and women who have acquired the human genital tract. Although a high viral load correlates HSV-2 have a two- to threefold increased risk of HIV-1 infection15,16. with the development of genital ulcers, shedding also In countries in which sexually active adults have a high prevalence commonly occurs even when ulcers are absent, allowing for of HSV-2 infection, or in subpopulations such as men who have silent transmission during coitus and contributing to high sex with men where HSV-2 infection is common, HSV-2 is a major seroprevalence of HSV-2 worldwide. Frequent viral reactivation epidemiological driver of HIV-1 epidemics16–18. occurs within ganglia despite diverse and complementary Here we describe how frequent reactivation and release of HSV-2 host and viral mechanisms that predispose toward latency, from latency within neurons, as well as highly dynamic interactions suggesting that viral replication may be constantly occurring between replicating HSV-2 and the host cell-mediated immune in a small minority of neurons at these sites. Within genital response in genital tissues, contribute to observed disease manifes- mucosa, the in vivo expansion and clearance rates of HSV-2 are tations, high global prevalence and enhanced HIV acquisition risk. extremely rapid. Resident dendritic cells and memory HSV-2 We also highlight the unique challenges that the kinetics of these specific T cells persist at prior sites of genital tract reactivation viral-host interactions pose for antiviral and vaccine development.
    [Show full text]
  • Wo 2010/059253 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 27 May 2010 (27.05.2010) WO 2010/059253 A2 (51) International Patent Classification: 02140 (US). BERSHTEYN, Anna [US/US]; 25 Linden A61K 9/16 (2006.01) A61K 31/711 (2006.01) Avenue, Apartment 6, Somerville, MA 02143 (US). A61K 9/127 (2006.01) A61P 35/00 (2006.01) A61K 31/7105 (2006.01) (74) Agent: TREVISAN, Maria, A.; Wolf, Greenfield & Sacks, P.C , Federal Reserve Plaza, 600 Atlantic Avenue, (21) International Application Number: Boston, MA 02210-2206 (US). PCT/US2009/006290 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 24 November 2009 (24.1 1.2009) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/200,1 60 24 November 2008 (24.1 1.2008) US NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (71) Applicant (for all designated States except US): MAS- SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, SACHUSETS INSTITUTE OF TECHNOLOGY [US/ TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]