DOCSLIB.ORG

Erik DE CLERCQ ANTI-HERPESVIRUS THERAPIES: BASIC STRATEGIES and APPLICATIONS

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Erik DE CLERCQ ANTI-HERPESVIRUS THERAPIES: BASIC STRATEGIES and APPLICATIONS ANTI-HERPESVIRUS THERAPIES: BASIC STRATEGIES AND APPLICATIONS Erik DE CLERCQ Rega Institute for Medical Research, K.U.Leuven B-3000 Leuven, Belgium Herpesviridae Human herpesviruses (HHV) HHV-1: Herpes simplex virus type 1 (HSV-1) HHV-2: Herpes simplex virus type 2 (HSV-2) HHV-3: Varicella-zoster virus (VZV) HHV-4: Epstein-Barr virus (EBV) HHV-5: Human cytomegalovirus (HCMV) HHV-6: Human herpes simplex virus type 6 (HSV-6) HHV-7: Human herpes simplex virus type 7 (HSV-7) HHV-8: Kaposi’s sarcoma herpesvirus (KSHV) O N HN N H2N N HO O Acyclovir, Aciclovir (ACV), Acycloguanosine 9-[(2-Hydroxyethoxy)methyl]guanine Zovirax® O O N N HN HN N N H2N N H2N N H2N CH CO O HO O O CH H3CCH3 Acyclovir Acyclovir valyl ester Valaciclovir O O N N HN HN N N H2N N H2N N H2N CH CO O H2N CH2 CO O O O CH3 Acyclovir glycyl ester Acyclovir alanyl ester O N HN N H2N N O H H2N C C O O CH H3CCH3 Valaciclovir Valine ester of acyclovir Valtrex®, Zelitrex® Antiviral activity spectrum of valaciclovir (acyclovir) Herpesviridae ! Herpes simplex virus type 1 (HSV-1) ! Herpes simplex virus type 2 (HSV-2) ! Varicella-zoster virus (VZV) ! Epstein-Barr virus (EBV) " Human cytomegalovirus (HCMV) " Human herpesvirus type 6 (HHV-6) " Human herpesvirus type 7 (HHV-7) " Human herpesvirus type 8 (HHV-8) " Thymidine kinase-deficient HSV (TK- HSV) " Thymidine kinase-deficient VZV (TK- VZV) Major clinical indications of valaciclovir Systemic (oral) treatment of HSV and VZV infections: • primary and recurrent genital herpes, mucocutaneous HSV-1 and HSV-2 infections in immuno-compromised and –competent patients • varicella-zoster in immuno-compromised and –competent patients O N N N HN N N H2N N H2N N O H3C O HO H3CO OH O Famciclovir Penciclovir Famvir® N N N N N N N N N H2N N H2N N H2N N O O H3C O Esterase H3C O Esterase HO H3C O OH OH O Xanthine Xanthine Xanthine oxidase oxidase oxidase O O O N N N HN HN HN N N N H2N N H2N N H2N N O O Esterase Esterase H3C O H3C O HO H3C O OH OH O Intravenous penciclovir versus acyclovir in the treatment of HSV infections in immunocompromised patients Kaplan-Meier plot of time to healing of lesions for penciclovir at 5 mg/kg q12 h (long-dashed line), penciclovir at 5 mg/kg q8h (short-dashed line), and acyclovir at 5 mg/kg q8h (solid line) Lazarus et al., Antimicrob. Agents Chemother. 43: 1192-1197 (1999) O N HN N H2N N HO O OH Ganciclovir (GCV) 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) Cymevene®, Cytovene® O N HN N H2 N N O H H2N C C O O CH H3CCH3 OH Valganciclovir Valcyte® Nucleoside kinase O O + -O P C 3 Na O- O- Foscarnet Phosphonoformate (trisodium salt) PFA Foscavir® O N NH N N NH2 HO HO HO O O OH OH Acyclovir Ganciclovir H2G HO HO HO O OH OH OH Penciclovir Lobucavir Anhydrohexitol guanine HO HO HO HO OH Synguanol A-5021 D/L-Cyclohexenyl guanine O N HN N H2N N HO OH Lobucavir O HN N N H2N N HO OH (-) 2HM-HBG H2G (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine NH2 O N N N NH HO N HO N N N NH2 Synadenol Syngenol Methylene cyclopropane nucleoside analogues O N NH N N NH2 HO OH D/L-Cyclohexenyl guanine O N NH N N NH2 HO HO A-5021 O N N N NH N N N NH2 N NH2 HO HO OH OH AV-038 A-5021 Comparative potency of different antiherpetic compounds against different herpesviruses Compound 50% Effective concentration EC50 (µM) HSV-1 HSV-2 VZV HCMV Acyclovir +++ +++ ++ + Penciclovir +++ ++ ++ (+) Ganciclovir +++++ +++++ ++ ++ Lobucavir ++++ ++++ +++ ++ H2G ++++ ++++ ++++ (+) A-5021 ++++ +++ +++ + Synguanol + - + ++ Anhydrohexitol G ++(+) +++(+) ++ ++ D-Cyclohexenyl G ++++ +++ ++ ++ L-Cyclohexenyl G +++(+) +++ ++ ++ EC50 (µM)= 10-100 (+), 1-10 (++), 0.1-1 (+++), 0.01-0.1 (++++), 0.001-0.01 (+++++) H2N N N N N HO O OH S2242 2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine O OH CH3 OH C O O OCH3 CH3 Mycophenolic acid O OH CH3 O C N O O O OCH3 CH3 Mycophenylate mofetil (Cellcept®) 2-Morpholinoethyl ester of mycophenolic acid MPA-IMPDH interactions Sintchak et al., Cell 85: 921-930 (1996) Phosphoribosylamine (PRA) + Mycophenolic acid H2O + NAD IMP IMP dehydrogenase + NADH + H XMP Deoxyguanosine Guanosine analogues GMP dGMP dGMP analogues GDP dGDP dGDP analogues GTP dGTP dGTP analogues RNA DNA synthesis synthesis Inhibitory effects of mycophenolate mofetil (MMF) and lobucavir (LBV) on cytopathicity of HCMV in human embryonic lung (HEL) cells Virus Control 2.5 µg/ml MMF 1 µg/ml LBV 1 µg/ml LBV + 2.5 µg/ml MMF Inhibitory effects of topical mycophenolate mofetil (MMF) 5% and topical acyclovir (ACV) 0.1% on HSV-1-induced lesions in hairless mice Virus Control MMF ACV MMF + ACV O I HN O N HO O OH Idoxuridine 5-iodo-2’-deoxyuridine (IDU) Stoxil® O CF3 HN O N HO O OH Trifluridine, Trifluorothymidine (TFT) 5-Trifluoromethyl-2’-deoxyuridine Viroptic®, TFT-Ophthiol® O Br HN O N HO O HO Brivudin, Bromovinyldeoxyuridine (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU) Zostex®, Zonavir® Antiviral activity spectrum of BVDU De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002) O O O Br Br Br HN HN HN O N O N O N HO HO HO O O HO HO HO OH HO BVaraU BVriboU C-BVDU De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002) O NH2 O Br Br Br HN N HN O N O N O N HO HO S O HO OH O HO HO S-BVDU BVDC L-BVDU De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002) N O N N Br O HN Br N Br HN O N O N O N HO S HO O HO O HO O HO S-BVMU Triazolyl BVDC L-BVODDU derivative De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002) O O O Br Br Br HN HN HN O N O N O N HO O HO O H3C HO HO OH OH BMS-181165 4’-methyl BVDU AV-100 De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002) Mechanism of action of BVDU HSV-1 dThd kinase DNA polymerase BVDU BVDUMP BVDUDP BVDUTP DNA BVDU BVDUMP HSV-2 dThd kinase O O H Br H Br C C C C HN H HN H O N O N H HO HO O O O P + Pi BVU + Thymidine phosphorylase HO HO BVDU BVU O O F F HN HN Dihydrothymine O N O N H H dehydrogenase 5-Fluorouracil 5-Fluorodihydrouracil Major clinical indications of BVDU (Brivudin) Topical: - herpetic keratitis (BVDU eyedrops) - herpes labialis (BVDU cream) Systemic: - mucocutaneous HSV-1 and VZV infections (oral) - immunocompromised patients - immunocompetent patients Oral brivudin versus intravenous acyclovir in the treatment of severe herpes zoster in cancer patients BRIVUDIN: BVDU: (E)-5-(2-bromovinyl)-2’-deoxyuridine orally 125 mg x 4 per day for 5 days ACYCLOVIR: ACV: 9-(2-hydroxyethoxymethyl)guanine intravenously 10 mg/kg x 3 per day for 5 days Multicentered, double-blind, randomized BVDU group (24 patients) also received placebo i.v. ACV group (23 patients) also received placebo p.o. Wutzler et al., J. Med. Virol. 46: 252-257 (1995) Double-blind study BVDU versus ACV 100 ---- ACV (n = 23) — BVDU (n = 24) 80 60 40 % Patients with new vesicles new with Patients % 20 0 1 2 3 4 5 6 7 Number of days following start of therapy Current antiviral therapy for zoster Valaciclovir oral 1000 mg 3 x daily 7 days Acyclovir oral 800 mg 5 x daily 7 days Acyclovir intravenous 5-10 mg/kg 3 x daily 7-10 days Famciclovir oral 250 mg 3 x daily 7 days Brivudin oral 125 mg 1 x daily 7 days Gross et al., J. Clin. Virol., in press (2003) Brivudin compared to acyclovir Incidence of postherpetic pain A randomized, double-blind post-study survey on the effect of brivudin in the prevention of postherpetic pain in comparison with acyclovir Survey patients (n = 608) Brivudin Acyclovir (n = 309) (n = 299) Patients with postherpetic pain n(%) 101 (32.7) 130 (43.5) Odds ratio (95% Cl) 1.61 (1.15 – 2.25) p value for difference 0.006 Prof. Dr. S.W. Wassilew Brivudin compared to famciclovir Brivudin compared to famciclovir in the prevention of postherpetic neuralgia: a prospective randomized, double-blind multicenter trial Prevalence of postherpetic pain ITT (n = 1954) Brivudin Famciclovir (n = 980) (n = 974) Patients with postherpetic pain n(%) 109 (11.1) 90 (9.2) Odds ratio (95% Cl) 1.23 (0.92 – 1.65) p value for non-inferiority 0.0102 Prof. Dr. S.W. Wassilew Brivudin compared to famciclovir Brivudin compared to famciclovir in the prevention of postherpetic neuralgia: a prospective randomized, double-blind multicenter trial Duration of postherpetic pain ITT (n = 199) Brivudin Famciclovir (n = 109) (n = 90) Duration of postherpetic pain Mean ± SD 69.3 ± 62.8 72.9 ± 63.7 Median 47.0 54.0 Risk ratio (95% Cl) 1.05 (0.76 – 1.45) p value for non-inferiority 0.049 Prof. Dr. S.W. Wassilew Brivudin compared to famciclovir Duration of ZAP (Zoster-Associated Pain), n = 1712 1 0,9 Brivud in 0,8 Fam ciclovir 0,7 0,6 0,5 Probability 0,4 0,3 0,2 0,1 0 0 30 60 90 120 150 180 210 240 270 Duration of ZA P [days, after start of tre a tment] Prof.
Load more

Recommended publications
  • Interbiotech Entecavir
    InterBioTech FT-XLS250 Entecavir Product Description Catalog #: XLS250, 5mg XLS251, 10mg XLS252, 50mg XLS253, 100mg AXAIV0, 1ml 10mM in DMSO. Catalog #: Name: Entecavir, Monohydrate Syn: BMS200475 monohydrate; SQ34676 monohydrate CAS : 209216-23-9 MW : 295.29 Formula : C12H17N5O4 Properties : DMSO : ≥ 50 mg/mL (169.33 mM) H2O : 2.8 mg/mL (9.48 mM) >99.5% Storage: Powder: -20°C (long term; possible at +4°C (2 years) (M) Also available: In solvent: -80°C (6 months) -20°C (1 month) Entecavir free form #RO893P/Q/R (Syn.: BMS200475; SQ34676) CAS No. : 142217-69-4; MW: 277.2 For Research Use Only Introduction Entecavir monohydrate (BMS200475 monohydrate; SQ34676 monohydrate) is a potent and selective inhibitor of HBV, with an EC50 of 3.75 nM in HepG2 cell. IC50 & Target EC50：3.75 nM (anti-HBV, HepG2 cell)[1] In Vitro *Solubility : DMSO : ≥ 50 mg/mL (169.33 mM) H2O : 2.8 mg/mL (9.48 mM; Need ultrasonic and warming) *Preparation : 1mM = 1mg in 3.3865 mL Entecavir monohydrate (BMS200475 monohydrate; SQ34676 monohydrate) has a EC50 of 3.75 nM against HBV. It is incorporated into the protein primer of HBV and subsequently inhibits the priming step of the reverse transcriptase. The antiviral activity of BMS-200475 is significantly less against the other RNA and DNA viruses[1]. Entecavir monohydrate is more readily phosphorylated to its active metabolites than other deoxyguanosine analogs (penciclovir, ganciclovir, lobucavir, and aciclovir) or lamivudine. The intracellular half-life of entecavir is 15 h[2]. P.1 InterBioTech FT-XLS250 In Vivo *Preparation : 1. Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% saline Solubility: ≥ 3 mg/mL (10.16 mM); Clear solution 2.
    [Show full text]
  • Chemical Properties Biological Description Solubility Information
    Data Sheet (Cat.No.T0085L) Entecavir Chemical Properties CAS No.: 142217-69-4 Formula： C12H15N5O3 Molecular Weight： 277.28 Appearance： Solid Storage： 0-4℃ for short term (days to weeks), or -20℃ for long term (months). Biological Description Description Entecavir is a guanosine nucleoside analogue used in the treatment of chronic hepatitis B virus (HBV) infection. Entecavir therapy can be associated with flares of the underlying hepatitis B during or after therapy, but has not been linked to cases of clinically apparent liver injury. Targets(IC50) HBV( HepG2 cell): EC50:3.75nM In vitro BMS-200475 has a EC50 of 3.75 nM against HBV. It is incorporated into the protein primer of HBV and subsequently inhibits the priming step of the reverse transcriptase. The antiviral activity of BMS-200475 is significantly less against the other RNA and DNA viruses[1]. Entecavir is more readily phosphorylated to its active metabolites than other deoxyguanosine analogs (penciclovir, ganciclovir, lobucavir, and aciclovir) or lamivudine. The intracellular half-life of entecavir is 15 h[2]. In vivo Daily oral treatment with BMS-200475 at doses ranging from 0.02 to 0.5 mg/kg of body weight for 1 to 3 months effectively reduces the level of woodchuck hepatitis virus (WHV) viremia in chronically infected woodchucks[3]. Cell Research BMS 200475 is prepared in phosphate-buffered saline (PBS) and diluted with appropriate medium containing 2% fetal bovine serum. HepG2 2.2.15 cells are plated at a density of 5×105 cells per well on 12-well Biocoat collagen-coated plates and are maintained in a confluent state for 2 to 3 days before being overlaid with 1 mL of medium spiked with BMS 200475.
    [Show full text]
  • Direct Acting Antivirals for the Treatment of Chronic Viral Hepatitis
    Hindawi Publishing Corporation Scienti�ca Volume 2012, Article ID 478631, 22 pages http://dx.doi.org/10.6064/2012/478631 Review Article Direct Acting Antivirals for the Treatment of Chronic Viral Hepatitis Peter Karayiannis Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College, St Mary’s Campus, London W2 1PG, UK Correspondence should be addressed to Peter Karayiannis; [email protected] Received 17 September 2012; Accepted 8 October 2012 Academic Editors: M. Clementi and W. Vogel Copyright © 2012 Peter Karayiannis. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. e development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). e introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long- term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in signi�cant breakthroughs.is paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives. 1. Introduction recombinant subsequently, both of which have more recently been superceded by the pegylated form (PegIFN), which Conservative estimates of the number of individuals world- requires intramuscular injection only once a week as opposed wide who are thought to be chronically infected with either to three times a week with the previous forms.
    [Show full text]
  • Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Scaffold †
    Proceeding Paper 1′-Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Scaffold † Constantin I. Tănase 1,*, Constantin Drăghici 2, Anamaria Hanganu 2, Lucia Pintilie 1, Maria Maganu 2, Vladimir V. Zarubaev 3, Alexandrina Volobueva 3 and Ekaterina Sinegubova 3 1 National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Av., 031299 Bucharest 3, Romania; [email protected] 2 Organic Chemistry Center “C.D.Nenitescu”, 202 B Splaiul Independentei, 060023 Bucharest, Romania; [email protected] (C.D.); [email protected] (A.H.); [email protected] (M.M.) 3 Department of Virology, Pasteur Institute of Epidemiology and Microbiology, 197101 St. Petersburg, Russia; [email protected] (V.V.Z.); [email protected] (A.V.); [email protected] (E.S.) * Correspondence: [email protected] † Presented at the 24th International Electronic Conference on Synthetic Organic Chemistry, 15 November–15 December 2020; Available online: https://ecsoc-24.sciforum.net/. Abstract: An optically active bicyclo[2.2.0]heptane fragment was introduced in the molecule of new 1′-homonucleosides on a 2- 6-chloro-amino-purine scaffold to obtain 6-substituted carbocyclicnu- cleozide analogs as antiviral compounds. The synthesis was realized by a Mitsunobu reaction of the base with the corresponding bicyclo[2.2.0]heptane intermediate, and then the nucleoside analogs were obtained by substitution of the 6-chlorime with selected pharmaceutically accepted amines. A molecular docking study of the compounds on influenza, HSV and low active coronavirus was re- alized. Experimental screening of the compounds on the same viruses is being developed and soon Citation: Tănase, C.I.; Drăghici, C.; will be finished.
    [Show full text]
  • Rash with Entecavir - Case Report Xiong Khee Cheong1, Zhiqin Wong2*, Norazirah Md Nor3 and Bang Rom Lee4
    Cheong et al. BMC Gastroenterology (2020) 20:305 https://doi.org/10.1186/s12876-020-01452-3 CASE REPORT Open Access “Black box warning” rash with entecavir - case report Xiong Khee Cheong1, Zhiqin Wong2*, Norazirah Md Nor3 and Bang Rom Lee4 Abstract Background: Hepatitis B infection is a significant worldwide health issue, predispose to the development of liver cirrhosis and hepatocellular carcinoma. Entecavir is a potent oral antiviral agent of high genetic barrier for the treatment of chronic hepatitis B infection. Cutaneous adverse reaction associated with entecavir has rarely been reported in literature. As our knowledge, this case was the first case reported on entecavir induced lichenoid drug eruption. Case presentation: 55 year old gentlemen presented with generalised pruritic erythematous rash on trunk and extremities. Six weeks prior to his consultation, antiviral agent entecavir was commenced for his chronic hepatitis B infection. Skin biopsy revealed acanthosis and focal lymphocytes with moderate perivascular lymphocyte infiltration. Skin condition recovered completely after caesation of offending drug and short course of oral corticosteroids. Conclusion: This case highlight the awareness of clinicians on the spectrum of cutaneous drug reaction related to entecavir therapy. Keywords: Drug eruption, Entecavir, Hepatitis B Background Case presentation Hepatitis B infection is a global health issue, contribut- A 55 years old gentlemen, background of chronic ing to approximately 887,000 deaths in 2015 due to he- hepatitis B (treatment naïve), was referred for 2 patocellular carcinoma and liver cirrhosis [1, 2]. weeks of generalised itchy erythematous rash. His Entecavir is a nucleoside analogue reverse transcriptase other medical illnesses were ischemic heart disease, inhibitor that is widely used in the treatment of chronic chronic kidney disease stage 3, diabetes mellitus and hepatitis B (HBV) infection.
    [Show full text]
  • Recent Advances in Antiviral Therapy J Clin Pathol: First Published As 10.1136/Jcp.52.2.89 on 1 February 1999
    J Clin Pathol 1999;52:89–94 89 Recent advances in antiviral therapy J Clin Pathol: first published as 10.1136/jcp.52.2.89 on 1 February 1999. Downloaded from Derek Kinchington Abstract indicated that using a combination of drugs In the early 1980s many institutions in might overcome this problem. The only Britain were seriously considering available drugs during the late 1980s were two whether there was a need for specialist other nucleotide reverse transcriptase inhibi- departments of virology. The arrival of tors (NRTI) which also targeted HIV reverse HIV changed that perception and since transcriptase (HIV-RT): 2',3'-dideoxycytidine then virology and antiviral chemotherapy (ddC) and 2',3'-dideoxyinosine (ddI).56 In have become two very active areas of bio- vitro combination studies gave surprising medical research. Cloning and sequencing results: those viruses that became highly resist- have provided tools to identify viral en- ant to ZDV remained sensitive to both ddC zymes and have brought the day of the and ddI.7 Furthermore, neither cross resistance “designer drug” nearer to reality. At the nor interference between the drugs was an other end of the spectrum of drug discov- issue, and subsequent clinical experience ery, huge numbers of compounds for showed that patients benefited when these two screening can now be generated by combi- compounds were used in combination with natorial chemistry. The impetus to find ZDV.8 It was also found by in vitro studies that drugs eVective against HIV has also virus isolated from patients on long term ZDV stimulated research into novel treatments monotherapy had become insensitive to ZDV, for other virus infections including her- but regained sensitivity when these patients pesvirus, respiratory infections, and were switched to ddI monotherapy.
    [Show full text]
  • Investigating Synergy Between Ribonucleotide Reductase Inhibitors and Cmv Antivirals
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 INVESTIGATING SYNERGY BETWEEN RIBONUCLEOTIDE REDUCTASE INHIBITORS AND CMV ANTIVIRALS Sukhada Bhave Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medicine and Health Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2838 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Sukhada Milind Bhave August 2012 All Rights Reserved INVESTIGATING SYNERGY BETWEEN RIBONUCLEOTIDE REDUCTASE INHIBITORS AND CMV ANTIVIRALS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Sukhada Milind Bhave Bachelor of Pharmacy, Bombay College of Pharmacy, India, 2010 Major Director: Michael McVoy, Ph.D. Professor, Department of Microbiology and Immunology Virginia Commonwealth University Richmond, Virginia August 2012 ACKNOWLEDGEMENTS It is a pleasure to thank everyone who made this thesis possible. First, I would like to thank Dr. McVoy for accepting me as a graduate student in his lab and for his guidance and support through this project. I would also like to thank the other members of the McVoy lab: Frances Saccoccio, Anne Sauer, Xiao Cui, Ronzo Lee, Ben Wang, and Sabrina Prescott for sharing their expertise and helping me through various steps in the project. All of them indeed create a very cheerful and pleasant atmosphere in the lab.
    [Show full text]
  • A Granulomatous Drug Eruption Induced by Entecavir Ann Dermatol Vol
    A Granulomatous Drug Eruption Induced by Entecavir Ann Dermatol Vol. 25, No. 4, 2013 http://dx.doi.org/10.5021/ad.2013.25.4.493 CASE REPORT A Granulomatous Drug Eruption Induced by Entecavir Jimi Yoon1, Donghwa Park1, Chiyeon Kim1,2 1Department of Dermatology, Gyeongsang National University Hospital, 2Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea Entecavir (BaracludeⓇ, Bristol-Myers Squibb) is a potent and effective for treating chronic hepatitis B when admini- selective antiviral agent that has demonstrated efficacy in stered for the short1,2. The current phase II dose-ranging patients with chronic hepatitis B. The most frequent adverse trial evaluated the good tolerability of 0.1 mg and 0.5 mg events attributed to entecavir include increased alanine entecavir daily for 52 weeks in nucleoside-naive chronic aminotransferase, upper respiratory tract infection, head- hepatitis B patients3. Common entecavir-related toxicities ache, abdominal pain, cough, pyrexia, fatigue, and diarrhea. are known to be diverse and include increased alanine Although quite a few randomized double-blind studies aminotransferase, upper respiratory tract infections, head- including ones investigating adverse events along with these ache, abdominal pain, cough, pyrexia, fever, fatigue, dia- general symptoms have been reported, few cases of rrhea, and dizziness4. We present a female patient who cutaneous adverse events have been described in detail. We developed a granulomatous drug eruption induced by demonstrate a case of granulomatous drug eruption as a entecavir. cutaneous adverse event induced by entecavir. (Ann Dermatol 25(4) 493∼495, 2013) CASE REPORT -Keywords- A 65-year-old woman was referred for consultation of a Drug eruptions, Entecavir facial granulomatous facial eruption.
    [Show full text]
  • “Entecavir in Severe Acute Hepatitis B” Pervaiz Majeed Zunga* Department of Internal Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
    al of urn Li o ve J r Zunga, J Liver 2014, 3:2 Journal of Liver DOI: 10.4172/2167-0889.1000149 ISSN: 2167-0889 Hypothesis Open Access “Entecavir in Severe Acute Hepatitis B” Pervaiz Majeed Zunga* Department of internal medicine, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India Introduction be a possible mechanism for the progressive liver damage [13]. Viral hepatitis is the commonest cause of acute and subacute hepatic failure An estimated 350 million persons worldwide are chronically and among viruses Non-A, Non-B is considered to be the major cause infected with HBV [1]. The average estimated carrier rate of Hepatitis followed by hepatitis B virus [13]. B Virus (HBV) in India is 4%, with a total pool of approximately 36 million carriers. Hepatitis B Virus (HBV) is successfully cleared in more than 95% of adult patients with acute infection. Acute HBV infection can cause Most of India’s carrier pool is established in early childhood, severe acute hepatitis B that can progress to liver failure. Death may predominantly by horizontal spread due to crowded living conditions result in up to 80% of people who develop severe acute hepatitis B [14]. and poor hygiene. Acute and subacute liver failure is common Thus it becomes important to find out if any available therapy can play complications of viral hepatitis in India and HBV is reckoned to be a role in preventing the progression of severe acute hepatitis B to liver the etiological agent in 42% and 45% of adult cases, respectively. In failure. The pathogenesis of severe acute hepatitis B is still unclear.
    [Show full text]
  • Mechanisms of Action of Drugs with Dual Or Multiple Antiviral Activities
    NOTE TO USERS This reproduction is the best copy available. MECHANISMS OF ACTION OF DRUGS WITH DUAL OR MULTIPLE ANTIVIRAL ACTIVITIES Egor Petrovitch Tchesnokov Department of Microbiology & Immunology McGill University, Montreal June, 2009 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Egor Petrovitch Tchesnokov i Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-61818-9 Our file Notre référence ISBN: 978-0-494-61818-9 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation.
    [Show full text]
  • Ep001156797b1*
    (19) *EP001156797B1* (11) EP 1 156 797 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61P 31/22 (2006.01) A61P 31/20 (2006.01) 24.10.2007 Bulletin 2007/43 A61P 31/16 (2006.01) A61P 31/14 (2006.01) A61P 31/12 (2006.01) A61P 35/00 (2006.01) (2006.01) (2006.01) (21) Application number: 00912195.5 A61K 45/06 A61K 31/70 A61K 31/522 (2006.01) A61K 31/045 (2006.01) (22) Date of filing: 08.03.2000 (86) International application number: PCT/US2000/005965 (87) International publication number: WO 2000/053167 (14.09.2000 Gazette 2000/37) (54) SYNERGISTIC INHIBITION OF VIRAL REPLICATION BY LONG-CHAIN HYDROCARBONS AND NUCLEOSIDE ANALOGS SYNERGISTISCHE HEMMUNG VON VIRALREPLIKATION DURCH LANGKETTIGEN KOHLENWASSERSTOFFE UND NUCLEOSID-ANALOGE INHIBITION SYNERGIQUE DE REPLICATION VIRALE PAR DES HYDROCARBURES ET ANALOGUES NUCLEOSIDIQUES A CHAINE LONGUE (84) Designated Contracting States: • KATZ, David, H. AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU La Jolla, CA 92037 (US) MC NL PT SE • KATZ, Lee, R. Designated Extension States: La Jolla, CA 92037 (US) AL LT LV MK RO SI (74) Representative: W.P. Thompson & Co. (30) Priority: 10.03.1999 US 265922 Coopers Building Church Street (43) Date of publication of application: Liverpool L1 3AB (GB) 28.11.2001 Bulletin 2001/48 (56) References cited: (73) Proprietor: AVANIR PHARMACEUTICALS WO-A-95/16434 WO-A-96/40144 San Diego, California 92121 (US) WO-A-97/13528 WO-A-98/11887 WO-A-98/30244 US-A- 5 484 911 (72) Inventors: • MARCELLETTI, John, F.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]