PMIDOWN STATDA DCOMIS IS VI IP DP TI z

18547903 NLM MEDLINE 20080612 20081028 1528-4336 (Print) 1528-4336 (Linking) 9 3 2008 May-Jun Randomization to once-daily stavudine extended release/lamivudine/efaviren

versus a more frequent regimen improves adherence while maintaining viral suppression. PG - 164-76 AB - BACKGROUND: In antiretroviral (ARV) therapy, pill burden, dosing frequency , and regimen complexity adversely affect adherence. We sought to evaluate the e ffect of regimen simplification on maintenance of virologic suppression and trea tment adherence. METHOD: In this 48-week, open-label, randomized study, 320 HIV-1-infected adult patients with a viral load of <50 copies/mL on a twic e-daily or more frequent ARV regimen were either switched to a once-daily regimen of efavirenz, extended-release stavudine, and lamivudine (QD arm) or continue d on existing therapy (BID+ arm). Medication Event Monitoring System (MEMS) cap s, AIDS Clinical Trials Group (ACTG)-validated questionnaire, and pill counts were used to evaluate adherence. Treatment satisfaction and preference were also eva luated. RESULTS: The QD arm was noninferior to the BID+ arm in the primary efficac y measure (proportion of patients who maintained virologic suppression at We ek 48; QD arm, 80.0% vs. BID+ arm, 75.8%). Adherence and treatment satisfaction significantly favored the QD arm, in which 91.0% of patients preferred the simpler regimen. Overall, the majority of adverse events were mild to mode rate in severity and resulted in a low rate of treatment discontinuations. CONCLUS IONS: Simplifying twice-daily or more frequent ARV therapy to a once-daily efavirenz-containing regimen in virologically suppressed HIV-1-infected pa tients maintains virologic suppression while improving adherence and patient satisfaction. AD - Weill Medical College of Cornell University, New York, New York, USA. brianboylemd@yahoo.com FAU - Boyle, Brian A AU - Boyle BA FAU - Jayaweera, Dushyantha AU - Jayaweera D FAU - Witt, Mallory D AU - Witt MD FAU - Grimm, Kristy AU - Grimm K

FAU AU FAU AU LA PT PT PT PL TA JT JID RN RN RN RN RN SB MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH EDATMHDACRDTAID AID PST SO -

Maa, Jen-fue Maa JF Seekins, Daniel W Seekins DW eng Journal Article Multicenter Study Randomized Controlled Trial United States HIV Clin Trials HIV clinical trials 100936377 0 (Benzoxazines) 0 (RNA, Viral) 134678-17-4 (Lamivudine) 154635-17-3 (efavirenz) 3056-17-5 (Stavudine) IM Adult Benzoxazines/administration & dosage/*therapeutic use Drug Administration Schedule Female HIV Infections/*drug therapy HIV-1/drug effects/metabolism Humans Lamivudine/administration & dosage/*therapeutic use Male Middle Aged *Patient Compliance RNA, Viral/blood/metabolism Stavudine/administration & dosage/*therapeutic use Viral Load Virus Replication/drug effects 2008/06/13 09:00 2008/10/29 09:00 2008/06/13 09:00 8717Q06156839272 [pii] 10.1310/hct0903-164 [doi] ppublish HIV Clin Trials. 2008 May-Jun;9(3):164-76.

PMID- 18181522 OWN - NLM STAT- MEDLINE DA - 20080109 DCOM- 20080124 LR - 20101109 IS - 1530-9932 (Electronic) IS - 1530-9932 (Linking) VI - 8 IP - 4 DP - 2007 TI - Design and study of lamivudine oral controlled release tablets. PG - E101 AB - The objective of this study was to design oral controlled release matrix t ablets of lamivudine using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, and compression force on the in vitro relea

se of drug. In vitro release studies were performed using US Pharmacopeia type 1 apparatus (basket method) in 900 mL of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using the zero-order model equation, Higuch i's square-root equation, and the Ritger-Peppas empirical equation. Compatibil ity of the drug with various excipients was studied. In vitro release studies rev ealed that the release rate decreased with increase in polymer proportion and vi scosity grade. Increase in compression force was found to decrease the rate of dru g release. Matrix tablets containing 60% HPMC 4000 cps were found to show go od initial release (26% in first hour) and extended the release up to 16 hour s. Matrix tablets containing 80% HPMC 4000 cps and 60% HPMC 15,000 cps showed a first-hour release of 22% but extended the release up to 20 hours. Mathema tical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets was dependent on drug diffusion and polymer relaxation and therefore followed non-Fickian or anomalous release. No incompatibility wa s observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of lamivudine, wi th good initial release (20%-25% in first hour) and extension of release up to 16 to 20 hours, can overcome the disadvantages of conventional tablets of lamivudin e. AD - Pharmacy Group, Faculty Division III, Birla Institute of Technology and Sc ience, Pilani, Rajasthan, India. FAU - Ravi, Punna Rao AU - Ravi PR FAU - Ganga, Sindhura AU - Ganga S FAU - Saha, Ranendra Narayan AU - Saha RN LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20071207 PL - United States TA - AAPS PharmSciTech JT - AAPS PharmSciTech JID - 100960111 RN - 0 (Delayed-Action Preparations) RN - 0 (Excipients) RN - 0 (Reverse Transcriptase Inhibitors) RN - 0 (Tablets) RN - 134678-17-4 (Lamivudine) RN - 8063-82-9 (hypromellose) RN - 9004-67-5 (Methylcellulose) SB - IM

MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH PMC OID EDATMHDACRDTAID PST SO PMIDOWN STATDA DCOMIS IS VI IP DP TI -naive

Administration, Oral Chemistry, Pharmaceutical Compressive Strength Delayed-Action Preparations Diffusion Drug Compounding Drug Stability Excipients/*chemistry Hardness Kinetics Lamivudine/administration & dosage/*chemistry Methylcellulose/*analogs & derivatives/chemistry Models, Chemical Porosity Reproducibility of Results Reverse Transcriptase Inhibitors/administration & dosage/*chemistry Solubility Tablets Technology, Pharmaceutical/methods Viscosity PMC2750687 NLM: PMC2750687 2008/01/10 09:00 2008/01/25 09:00 2008/01/10 09:00 10.1208/pt0804101 [doi] epublish AAPS PharmSciTech. 2007 Dec 7;8(4):E101. 17971713 NLM MEDLINE 20080128 20080318 1525-4135 (Print) 1525-4135 (Linking) 47 2 2008 Feb 1 Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral

patients. PG - 161-7 AB - BACKGROUND: Atazanavir (ATV), the first once-daily protease inhibitor appr oved for the treatment of HIV-1 infection, is recommended for use in antiretrov iral (ARV) treatment-naive and -experienced patients. Study AI424-089 was a prospective, randomized, open-label, 96-week study comparing 2 ATV-based treatment regimens in ARV-naive HIV-infected patients. METHODS: Adults wit h HIV RNA levels > or =2000 copies/mL were randomized (1:1) to once-daily ATV at a dose of 300 mg with ritonavir at a dose of 100 mg (ATV300/RTV) or ATV at a dose of 400 mg (ATV400); both regimens included lamivudine and an investigational extended-release formulation of stavudine. The primary endpoint for this noninferiority study was the proportion of patients (response rate) with a n HIV

RNA load <400 copies/mL at week 48. RESULTS: Response rates at week 48 wer e 86% and 85% on the ATV300/RTV and ATV400 regimens, respectively (difference es timate [95% confidence interval] = 1.5 [-8.2 to 11.1]). There were 3 and 10 patie nts with virologic failure in the ATV300/RTV and ATV400 groups, respectively. One patient (ATV400) developed phenotypic resistance to ATV associated with an I50L substitution. Adverse event-related discontinuations were 8% among ATV300/RTV-treated patients and <1% among ATV400-treated patients. Plasma lipid elevations were low with both regimens. Both regimens were well tolerated. CONCLUSIONS: These findings demonstrate the safety and efficacy of the ATV 300/RTV regimen and confirm the safety and efficacy of ATV400 in an ARV-naive pati ent population. AD - Triple M Research, Port Elizabeth, South Africa. nielm@iafrica.com FAU - Malan, D R AU - Malan DR FAU - Krantz, Edrich AU - Krantz E FAU - David, Neal AU - David N FAU - Wirtz, Victoria AU - Wirtz V FAU - Hammond, Janet AU - Hammond J FAU - McGrath, Donnie AU - McGrath D CN - 089 Study Group LA - eng PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - J Acquir Immune Defic Syndr JT - Journal of acquired immune deficiency syndromes (1999) JID - 100892005 RN - 0 (Anti-HIV Agents) RN - 0 (Lipids) RN - 0 (Oligopeptides) RN - 0 (Pyridines) RN - 0 (RNA, Viral) RN - 0 (Ritonavir) RN - 134678-17-4 (Lamivudine) RN - 198904-31-3 (atazanavir) RN - 3056-17-5 (Stavudine) SB - IM SB - X MH - Adult MH - Aged MH - Amino Acid Substitution/genetics MH - Anti-HIV Agents/administration & dosage/*adverse effects/*therapeutic use MH - *Antiretroviral Therapy, Highly Active MH - Drug Resistance, Viral/genetics MH - Female

MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH EDATMHDACRDTAID PST SO PMIDOWN STATDA DCOMLR IS IS VI IP DP TI a

HIV Infections/*drug therapy HIV-1/drug effects Humans Lamivudine/therapeutic use Lipids/blood Male Microbial Sensitivity Tests Middle Aged Oligopeptides/administration & dosage/*adverse effects/*therapeutic use Prospective Studies Pyridines/administration & dosage/*adverse effects/*therapeutic use RNA, Viral/blood Ritonavir/administration & dosage/*therapeutic use Stavudine/therapeutic use Viral Load Withholding Treatment 2007/11/01 09:00 2008/03/19 09:00 2007/11/01 09:00 10.1097/QAI.0b013e31815ace6a [doi] ppublish J Acquir Immune Defic Syndr. 2008 Feb 1;47(2):161-7. 17922546 NLM MEDLINE 20071123 20080123 20101118 1043-1802 (Print) 1043-1802 (Linking) 18 6 2007 Nov-Dec Synthesis, analysis, in vitro characterization, and in vivo disposition of

lamivudine-dextran conjugate for selective antiviral delivery to the liver . PG - 2097-108 AB - A liver-selective prodrug (3TCSD) of the antiviral drug lamivudine (3TC) w as developed and characterized. 3TC was coupled to dextran ( approximately 25 kDa) using a succinate linker, and the in vitro and in vivo behavior of the con jugate was studied using newly developed size-exclusion and reversed-phase analyt ical methods. Synthesized 3TCSD had a purity of >99% with a degree of substitut ion of 6.5 mg of 3TC per 100 mg of the conjugate. Furthermore, the developed assa ys were precise and accurate in the concentration ranges of 0.125-20, 0.36-18, and 1-50 microg/mL for 3TC, 3TC succinate (3TCS), and 3TCSD, respectively. In vitro , the conjugate slowly released 3TC in the presence of rat liver lysosomes, wher eas it was stable in the corresponding buffer. In vivo in rats, conjugation of 3T C to dextran resulted in 40- and 7-fold decreases in the clearance and volume o

f distribution of the drug, respectively. However, the accumulation of the conjugated 3TC in the liver was 50-fold higher than that of the parent dru g. The high accumulation of the conjugate in the liver was associated with a grad ual and sustained release of 3TC in the liver. These studies indicate the feasibil ity of the synthesis of 3TCS-dextran and its potential use for the selective deli very of 3TC to the liver. AD - Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech Univ ersity Health Sciences Center, Amarillo, TX 79106, USA. FAU - Chimalakonda, Krishna C AU - Chimalakonda KC FAU - Agarwal, Hitesh K AU - Agarwal HK FAU - Kumar, Anil AU - Kumar A FAU - Parang, Keykavous AU - Parang K FAU - Mehvar, Reza AU - Mehvar R LA - eng PT - Journal Article DEP - 20071009 PL - United States TA - Bioconjug Chem JT - Bioconjugate chemistry JID - 9010319 RN - 0 (Antiviral Agents) RN - 0 (Buffers) RN - 0 (Prodrugs) RN - 134678-17-4 (Lamivudine) RN - 9004-54-0 (Dextrans) SB - IM MH - Animals MH - Antiviral Agents/blood/*chemical synthesis/chemistry/*pharmacokinetics MH - Buffers MH - Chromatography, Gel MH - Chromatography, Liquid MH - Dextrans/blood/chemistry/*pharmacokinetics MH - Hydrophobic and Hydrophilic Interactions MH - Kidney/drug effects MH - Lamivudine/chemistry/*pharmacokinetics MH - Liver/drug effects/*metabolism MH - Male MH - Molecular Structure MH - Prodrugs/chemical synthesis/chemistry/pharmacology MH - Rats MH - Rats, Sprague-Dawley EDAT- 2007/10/10 09:00 MHDA- 2008/01/24 09:00 CRDT- 2007/10/10 09:00 PHST- 2007/10/09 [aheadofprint] AID - 10.1021/bc700193d [doi] PST - ppublish SO - Bioconjug Chem. 2007 Nov-Dec;18(6):2097-108. Epub 2007 Oct 9.

PMID- 17276009 OWN - NLM STAT- MEDLINE DA - 20070226 DCOM- 20070417 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1770 IP - 4 DP - 2007 Apr TI - Targeting potential and anti-HIV activity of lamivudine loaded mannosylate d poly (propyleneimine) dendrimer. PG - 681-6 AB - T-lymphocytes, dendritic cells and macrophages are the target cells for HI V. The infected macrophages are considered as reservoirs for spreading the virus. Treatment of HIV infection therefore must reach these cells in addition to the organs like brain, liver and bone marrow. Lectin receptors, which act as molecular targets for sugar molecules, are found on the surface of these c ells of the phagocytic system. The purpose of the present study is to investigate the targeting potential and anti HIV activity of lamivudine (3TC) loaded manno sylated fifth generation Poly (propyleneimine) dendrimers (MPPI). The entrapment efficiency of 3TC loaded MPPI and 5th generation poly(propyleneimine) dend rimer (PPI) were found to be 43.27+/-0.13% and 35.69+/-0.2% respectively. The in vitro drug release profile shows that while PPI releases the drug by 24 h, the M PPI slows down and hence prolongs the release up to 144 h (96.89+/-1.8% in cas e of MPPI). The results of in vitro ligand agglutination assay indicated that e ven after conjugation with PPI, mannose displayed binding specificity towards Con A. The subtoxic concentrations of free 3TC, blank PPI, blank MPPI, drug loade d PPI and drug loaded MPPI, determined on MT2 cells, were found to be 0.625, 0.0 39, 0.156, 0.039 and 0.156 nM/ml respectively. Significant increase in cellula r uptake of 3TC was observed when MPPI was used, which was 21 and 8.3 times higher than that of free drug (p<0.001) and PPI (p<0.001) at 48 h respectively. Antiretroviral activity was determined using MT2 cell lines by estimating p24 antigen by ELISA. 3TC loaded PPI and MPPI formulations were found to posse ss higher anti-HIV activity at a concentration as low as 0.019 nM/ml, as comp ared to that of free drug, which was found to be extremely significant (p<0.001). The significantly higher anti-HIV activity of PPI and MPPI is due to the enhan ced cellular uptake of 3TC in formulation as compared to that of free drug Res ults

suggest that the proposed carrier hold potential to increase the efficacy and reduce the toxicity of antiretroviral therapy. AD - Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sag ar (M.P.) 470 003, India. duttatathababu@yahoo.com FAU - Dutta, Tathagata AU - Dutta T FAU - Jain, Narendra K AU - Jain NK LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20061221 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Anti-HIV Agents) RN - 0 (Calmodulin) RN - 0 (Cam2 protein, S pombe) RN - 0 (Delayed-Action Preparations) RN - 0 (Drug Carriers) RN - 0 (HIV Core Protein p24) RN - 0 (Reverse Transcriptase Inhibitors) RN - 0 (Schizosaccharomyces pombe Proteins) RN - 134678-17-4 (Lamivudine) SB - IM MH - Agglutination/drug effects MH - Anti-HIV Agents/chemistry/metabolism/*pharmacology MH - Calmodulin/analysis/*metabolism MH - Cell Line MH - Cell Survival/drug effects MH - Chemistry, Pharmaceutical MH - Delayed-Action Preparations MH - Dose-Response Relationship, Drug MH - *Drug Carriers MH - Drug Compounding MH - HIV Core Protein p24/metabolism MH - HIV-1/*drug effects/immunology MH - Humans MH - Lamivudine/chemistry/metabolism/*pharmacology MH - Lymphocytes/*drug effects/metabolism/virology MH - Reverse Transcriptase Inhibitors/chemistry/metabolism/*pharmacology MH - Schizosaccharomyces pombe Proteins/analysis/*metabolism MH - Solubility MH - Time Factors EDAT- 2007/02/06 09:00 MHDA- 2007/04/18 09:00 CRDT- 2007/02/06 09:00 PHST- 2006/09/26 [received] PHST- 2006/12/11 [revised] PHST- 2006/12/14 [accepted] PHST- 2006/12/21 [aheadofprint] AID - S0304-4165(06)00384-9 [pii] AID - 10.1016/j.bbagen.2006.12.007 [doi] PST - ppublish SO - Biochim Biophys Acta. 2007 Apr;1770(4):681-6. Epub 2006 Dec 21.

PMIDOWN STATDA DCOMLR IS IS VI IP DP TI erapy udine

15876285 NLM MEDLINE 20050506 20050920 20071115 1464-2662 (Print) 1464-2662 (Linking) 6 3 2005 May Better maintained adherence on switching from twice-daily to once-daily th for HIV: a 24-week randomized trial of treatment simplification using stav

prolonged-release capsules. PG - 185-90 AB - BACKGROUND: Adherence to antiretroviral therapy is critical to treatment outcomes. Adherence studies in other therapeutic areas of medicine suggest that once-daily regimens support improved adherence when compared to twice-dail y therapy. An expansion in the range of once-daily antiretrovirals is making once-daily therapy possible for persons with HIV infection. METHODS: A 24week randomized open-label simplification study of twice-daily regimens based o n stavudine immediate release or zidovudine to an all once-daily regimen bas ed on the stavudine prolonged-release capsule (PRC), in persons with complete virological suppression on regimens also including efavirenz and lamivudin e, was carried out. Subjects were assessed for adherence [using the Medication Ev ent Monitoring System (MEMS) cap; Aardex Corporation, Union City, CA, USA], qu ality of life, tolerability and efficacy. RESULTS: Forty-three patients were ran domly assigned: 21 remained on their original regimen and 22 switched to once-da ily therapy with stavudine PRC. Although high levels of adherence and good qua lity of life were present at study enrollment, adherence declined to a significant ly lesser extent at week 24 in the group that switched to once-daily therapy. Efficacy was maintained in both groups and there were no differences in tolerability or toxicity. CONCLUSIONS: Subjects switching from twice-daily therapy to once-daily therapy demonstrate less of a decline in adherence o ver 24 weeks. A once-daily regimen including stavudine PRC is as effective and to lerable as a regimen containing the twice-daily formulation. AD - Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK. FAU - Portsmouth, S D AU - Portsmouth SD FAU - Osorio, J AU - Osorio J FAU - McCormick, K AU - McCormick K FAU - Gazzard, B G

AU FAU AU LA PT PT PT PT PL TA JT JID RN RN RN RN RN RN RN SB MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH MH EDATMHDACRDTAID AID PST SO PMIDOWN STATDA DCOMLR IS IS VI IP DP TI -

Gazzard BG Moyle, G J Moyle GJ eng Clinical Trial Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't England HIV Med HIV medicine 100897392 0 (Benzoxazines) 0 (Delayed-Action Preparations) 0 (Oxazines) 0 (Reverse Transcriptase Inhibitors) 134678-17-4 (Lamivudine) 154635-17-3 (efavirenz) 3056-17-5 (Stavudine) IM Adult Antiretroviral Therapy, Highly Active Benzoxazines CD4 Lymphocyte Count Delayed-Action Preparations Drug Administration Schedule Female HIV Infections/*drug therapy/immunology/virology *HIV-1 Humans Lamivudine/therapeutic use Male Middle Aged Oxazines/therapeutic use *Patient Compliance Quality of Life Reverse Transcriptase Inhibitors/*administration & dosage/therapeutic use Statistics, Nonparametric Stavudine/*administration & dosage/therapeutic use Viral Load 2005/05/07 09:00 2005/09/21 09:00 2005/05/07 09:00 HIV287 [pii] 10.1111/j.1468-1293.2005.00287.x [doi] ppublish HIV Med. 2005 May;6(3):185-90. 12885880 NLM MEDLINE 20030729 20030923 20091118 0022-538X (Print) 0022-538X (Linking) 77 16 2003 Aug Diminished RNA primer usage associated with the L74V and M184V mutations i

n the reverse transcriptase of human immunodeficiency virus type 1 provides a po ssible mechanism for diminished viral replication capacity. PG - 8621-32 AB - The emergence of drug resistance-conferring mutations can severely comprom ise the success of chemotherapy directed against human immunodeficiency virus type 1 (HIV-1). The M184V and/or L74V mutation in the reverse transcriptase (RT) gene are frequently found in viral isolates from patients treated with the nucl eoside RT inhibitors lamivudine (3TC), abacavir (ABC), and didanosine (ddI). Howe ver, the effectiveness of combination therapy with regimens containing these co mpounds is often not abolished in the presence of these mutations; it has been conjectured that diminished fitness of HIV-1 variants containing L74V and M184V may contribute to sustained antiviral effects in such cases. We have deter mined that viruses containing both L74V and M184V are more impaired in replicati on capacity than viruses containing either mutation alone. To understand the biochemical mechanisms responsible for this diminished fitness, we generat ed a series of recombinant mutated enzymes containing either or both of the L74 V and M184V substitutions. These enzymes were tested for their abilities to bypa ss important rate-limiting steps during the complex process of reverse transcription. We studied both the initiation of minus-strand DNA synthesi s with the cognate replication primer human tRNA(3)(Lys) and the initiation of plus-strand DNA synthesis, using a short RNA primer derived from the viral polypurine tract. We observed that the efficiencies of both reactions were diminished with enzymes containing either L74V or M184V and that these eff ects were significantly amplified with the double mutant. We also show that rel ease from intrinsic pausing sites during reverse transcription appears to be a major obstacle that cannot be efficiently bypassed. Our data suggest that the efficiency of RNA-primed DNA synthesis represents an important considerati on that can affect viral replication kinetics. AD - McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospita l, McGill University, Montreal, Quebec, Canada. FAU - Diallo, Karidia AU - Diallo K FAU - Marchand, Bruno AU - Marchand B FAU - Wei, Xin AU - Wei X FAU - Cellai, Luciano AU - Cellai L FAU - Gotte, Matthias AU - Gotte M

FAU AU LA PT PT PL TA JT JID RN RN RN RN SB MH MH MH MH MH MH MH MH MH MH PMC OID EDATMHDACRDTPST SO PMIDOWN STATDA DCOMLR IS IS VI IP DP TI -

Wainberg, Mark A Wainberg MA eng Journal Article Research Support, Non-U.S. Gov't United States J Virol Journal of virology 0113724 0 (DNA, Single-Stranded) 0 (RNA primers) 63231-63-0 (RNA) EC 2.7.7.49 (HIV Reverse Transcriptase) IM Animals Base Sequence COS Cells Cell-Free System DNA, Single-Stranded/genetics HIV Reverse Transcriptase/*genetics HIV-1/enzymology/*physiology *Mutation *RNA *Virus Replication PMC167213 NLM: PMC167213 2003/07/30 05:00 2003/09/25 05:00 2003/07/30 05:00 ppublish J Virol. 2003 Aug;77(16):8621-32.

11796353 NLM MEDLINE 20020117 20020508 20091118 0066-4804 (Print) 0066-4804 (Linking) 46 2 2002 Feb Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus-infected hepatocytes in v ivo and in vitro. PG - 425-33 AB - The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus of infected hepatocytes is an obstacle to achieving sustained vira l clearance during antiviral therapy of chronic hepatitis B virus (HBV) infe ction. The aim of our study was to determine whether treatment with adefovir, a n ew acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and i n vivo using the duck HBV (DHBV) model. First, the effect of adefovir on viral CC

C DNA synthesis was examined with primary cultures of DHBV-infected fetal hepato cytes. Adefovir was administered for six consecutive days starting one day before or four days after DHBV inoculation. Dose-dependent inhibition of both virion release in culture supernatants and synthesis of intracellular viral DNA w as observed. Although CCC DNA amplification was inhibited by adefovir, CCC DN A was not eliminated by antiviral treatment and the de novo formation of CCC DNA was not prevented by pretreatment of the cells. Next, preventive treatment of experimentally infected ducklings with lamivudine or adefovir revealed tha t both efficiently suppressed viremia and intrahepatic DNA. However, persistence of viral DNA even when detectable only by PCR was associated with a recurrenc e of viral replication following drug withdrawal. Taken together, our results demonstrate that adefovir is a potent inhibitor of DHBV replication that i nhibits CCC DNA amplification but does not effectively prevent the formation of CC C DNA from incoming viral genomes. AD - INSERM Unit 271, 69003 Lyon, France. FAU - Delmas, Julien AU - Delmas J FAU - Schorr, Olivier AU - Schorr O FAU - Jamard, Catherine AU - Jamard C FAU - Gibbs, Craig AU - Gibbs C FAU - Trepo, Christian AU - Trepo C FAU - Hantz, Olivier AU - Hantz O FAU - Zoulim, Fabien AU - Zoulim F LA - eng PT - Journal Article PL - United States TA - Antimicrob Agents Chemother JT - Antimicrobial agents and chemotherapy JID - 0315061 RN - 0 (Antiviral Agents) RN - 0 (DNA, Circular) RN - 0 (DNA, Viral) RN - 0 (Phosphonic Acids) RN - 106941-25-7 (adefovir) RN - 73-24-5 (Adenine) SB - IM MH - Adenine/*analogs & derivatives/*pharmacology/therapeutic use MH - Animals MH - Antiviral Agents/*pharmacology/therapeutic use MH - DNA, Circular/biosynthesis/*drug effects MH - DNA, Viral/biosynthesis/*drug effects MH - Disease Models, Animal MH - Ducks

MH MH MH MH PMC OID EDATMHDACRDTPST SO PMIDOWN STATDA DCOMLR IS IS VI IP DP TI tic

Hepatitis B/*prevention & control Hepatitis B Virus, Duck/*drug effects/physiology Hepatocytes/*virology *Phosphonic Acids PMC127044 NLM: PMC127044 2002/01/18 10:00 2002/05/09 10:01 2002/01/18 10:00 ppublish Antimicrob Agents Chemother. 2002 Feb;46(2):425-33. 11485138 NLM MEDLINE 20010803 20011211 20041117 1060-0280 (Print) 1060-0280 (Linking) 35 7-8 2001 Jul-Aug Metformin in an HIV-infected patient with protease inhibitor-induced diabe

ketoacidosis. PG - 877-80 AB - OBJECTIVE: To describe a case of diabetes mellitus and diabetic ketoacidos is in a patient receiving protease inhibitor therapy and to describe the patient's response to treatment with metformin. CASE SUMMARY: A 49-year-old HIV-posi tive white man who was receiving indinavir, stavudine, and lamivudine for more than two years presented with shortness of breath and significant weight loss o ver the previous month. On admission, he had a pH of 7.11 and PaCO2 of 12.9 mm Hg. Laboratory investigations revealed glucose 420 mg/dL, a total carbon dioxi de 5 mEq/L, and anion gap of 32. Beta-hydroxybutyrate was 5.9 mmol/L (normal va lue <0.4 mmol/L). Urine was highly positive for glucose and ketones. The patie nt was given intravenous fluids and an insulin infusion was started. Five days la ter, he was discharged on 60 units of insulin per day. Following discharge, efavir enz was substituted for indinavir. Metformin was added and six months following di scharge the patient's blood glucose was well controlled with 36 units of insulin p er day. DISCUSSION: New-onset diabetes mellitus has been reported in HIV-infected patients receiving protease inhibitors. To date, diabetic ketoacidosis has been an infrequent acute complication. The mechanism by which protease inhibito rs cause diabetes is unclear; however, studies have noted insulin resistance and increased proinsulin. Metformin increases the sensitivity of peripheral ti ssues

to insulin and appeared to be useful in this patient. However, further cli nical research is needed. CONCLUSIONS: Monitoring glucose concentrations in HIV-positive patients receiving protease inhibitors is important to preven t the development of acute complications, including diabetic ketoacidosis. We re commend that these patients have their fasting serum glucose concentration measure d at baseline, with follow-up every three months. The role of metformin and the thiazolidinedione antidiabetic agents in the management of protease inhibitor-induced diabetes requires further study. AD - Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmo nton, Canada. christine.hughes@ualberta.ca FAU - Hughes, C A AU - Hughes CA FAU - Taylor, G D AU - Taylor GD LA - eng PT - Case Reports PT - Journal Article PL - United States TA - Ann Pharmacother JT - The Annals of pharmacotherapy JID - 9203131 RN - 0 (HIV Protease Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 657-24-9 (Metformin) SB - IM MH - Diabetes Mellitus, Type 1/*drug therapy MH - Diabetic Ketoacidosis/*chemically induced MH - HIV Protease Inhibitors/*adverse effects MH - HIV Seropositivity/*drug therapy MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Metformin/*therapeutic use MH - Middle Aged MH - Treatment Outcome EDAT- 2001/08/04 10:00 MHDA- 2002/01/05 10:01 CRDT- 2001/08/04 10:00 PST - ppublish SO - Ann Pharmacother. 2001 Jul-Aug;35(7-8):877-80.