INTRODUCTION: Zidovudine (AZT) and emtricitabine (FTC) are effective and well tolerated antiretroviral drugs, routinely used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in their transfer from mother to fetus are not fully elucidated. Since both drugs are nucleoside analogues, we hypothesized that the mechanisms of their transplacental passage might include equilibrative nucleoside transporters, ENT1 and/or ENT2. METHODS: To address this issue, we performed in vitro accumulation assays in the BeWo placental trophoblast cell line, ex vivo uptake studies in fresh villous fragments isolated from human placenta and in situ dually perfused rat term placenta experiments. RESULTS: Applying this complex array of methods, we did not prove that ENTs play a significant role in transfer of AZT or FTC across the placenta. DISCUSSION: We conclude that the transplacental passage of AZT and FTC is independent of ENTs. Disposition of either compound into the fetal circulation should thus not be affected by ENT-mediated drug-drug interactions or placental expression of the transporters.

• Klíčová slova
• ENTs, Emtricitabine, Nucleoside transporters, Placenta, Pregnancy, Zidovudine,
• MeSH
• ekvilibrační proteiny přenášející nukleosidy metabolismus   MeSH
• emtricitabin farmakokinetika   MeSH
• inhibitory reverzní transkriptasy farmakokinetika   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• těhotenství MeSH
• zidovudin farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ekvilibrační proteiny přenášející nukleosidy MeSH
• emtricitabin MeSH
• inhibitory reverzní transkriptasy MeSH
• zidovudin MeSH

Zidovudine (AZT) is one of the most frequently used antiretroviral drugs in prevention of perinatal transmission of HIV. However, safety concerns on AZT use in pregnancy still persist as severe side effects are associated with AZT exposure in children. In our study we aimed to contribute to current knowledge on AZT transplacental transport and to evaluate potential involvement of the main human drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins 2 and 5 (ABCC2 and ABCC5) in the disposition of AZT between mother and fetus. In order to elucidate this issue we investigated the effect of selected ABC transporters on AZT transepithelial transport across MDCKII cell monolayers. In addition we used the in situ method of dually perfused rat term placenta to further study the role of ABC transporters in AZT transplacental transport. In vitro studies revealed significant effect of ABCB1 and ABCG2 on AZT transport which was subsequently confirmed also on organ level. Lamivudine, an antiretroviral agent commonly co-administered with AZT, did not affect ABC transporter-mediated AZT transfer.

• Klíčová slova
• breast cancer resistance protein, multidrug resistance-associated protein 2, multidrug resistance-associated protein 5, p-glycoprotein, zidovudine,
• MeSH
• ABC transportéry antagonisté a inhibitory   metabolismus   MeSH
• akridiny farmakologie   MeSH
• buňky MDCK MeSH
• indomethacin farmakologie   MeSH
• lamivudin farmakologie   MeSH
• látky proti HIV farmakokinetika   MeSH
• lékové interakce MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• psi MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• zidovudin farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCC2 protein, human MeSH Prohlížeč
• akridiny MeSH
• Elacridar MeSH Prohlížeč
• indomethacin MeSH
• lamivudin MeSH
• látky proti HIV MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• tetrahydroisochinoliny MeSH
• zidovudin MeSH

Apple hammerhead viroid (AHVd) was detected in the apple cultivar 'Šampion' and in mixed infection with Solanum nigrum ilarvirus 1 (SnIV-1) in the cultivars 'Selena' and 'Jonagored Supra', using a high-throughput sequencing method. Experiments were conducted to eliminate both pathogens in apples using meristem tip cultures in combination with the antivirotics ribavirin, rimantadine, and zidovudine. Elimination of both pathogens was verified by repeated RT-PCR and qRT-PCR assays after 7-11 months. Elimination of SnIV-1 from all cultivars was successful with each of the three antivirotics at concentrations of 20, 40, and 80 mg L-1. Elimination of AHVd was also achieved, although less effectively and only with ribavirin in the concentration range of 20-160 mg L-1.

• Klíčová slova
• HTS, apple, chemotherapy, viroid, virus,
• MeSH
• antivirové látky farmakologie   MeSH
• Ilarvirus * MeSH
• Malus * MeSH
• ribavirin farmakologie   MeSH
• rimantadin MeSH
• Solanum nigrum * MeSH
• viroidy * MeSH
• zidovudin MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• ribavirin MeSH
• rimantadin MeSH
• zidovudin MeSH

Azidothymidine (AZT, 3'-azido-3'-deoxythymidine, Zidovudine, Retrovir) is an approved and widely used antiretroviral drug for the treatment of human immunodeficiency virus (HIV) infection. Dynamic electrochemical methods have been employed for the fast and inexpensive determination of this drug in natural samples. The electrochemical signal of AZT, resulting from the reduction of azido group, was studied by square wave voltammetry (SWV), linear sweep voltammetry (LSV) and elimination voltammetry with linear scan (EVLS) using a hanging mercury drop electrode (HMDE). This paper explores the possibility of determining AZT in the presence of native (dsDNA) or denatured calf thymus DNA (ssDNA), and/or some synthetic oligodeoxynucleotides (ODNs). The detection limit of AZT in the absence and in the presence of ssDNA (10 microg/ml) is 1 and 250 nM, respectively. It was found that the signal of AZT is not substantially affected by the presence of DNA. We can therefore assume that the electrons are transferred through the adsorption layer of nucleic acids. By using the elimination procedure, both irreversible reduction signals of AZT and DNA are augmented. Moreover, the elimination signal in the peak-counterpeak form may indicate the adsorption of the analytes on the electrode surface preceding an electron transfer.

• MeSH
• chromozomy chemie   MeSH
• DNA analýza   chemie   MeSH
• elektrochemie metody   MeSH
• komplexní směsi analýza   chemie   MeSH
• oligonukleotidy analýza   chemie   MeSH
• senzitivita a specificita MeSH
• zidovudin analýza   chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• validační studie MeSH
• Názvy látek
• calf thymus DNA MeSH Prohlížeč
• DNA MeSH
• komplexní směsi MeSH
• oligonukleotidy MeSH
• zidovudin MeSH

The main advantage of the use of electrochemical methods is that the object studied is under conditions very close to the natural ones. Next advantage is that the same information about the sample can be received with lower costs than other methods. The electrode double layer impedance measurement is effective electrochemical method of the study of interaction of the substances on electrode surface. It is much more sensitive on adsorption processes than other electrochemical methods. After the mathematical evaluation of the results of the electrode double layer impedance measurements it was found, that the adsorption energies of xanthine are much higher than those of adenine and for hypoxanthine are close to adenine. This result could be connected with the role of these two adenine metabolites in nucleic acids. The measurements in the solutions, containing different methyl derivatives of xanthine showed that the adsorption behaviour of every substance is strongly dependent on the position of the methyl group in the molecule. From the dependence of the electrode double layer impedance on the potential and frequency in the solution containing 3'-azido-2'3'-dideoxythymidine (AZT) it was found, that under conditions studied a reduction process occurs in the sample near-IV vs. AgCl. The adsorption behaviour of AZT is the same as that of thymidine both at room temperature and at lower ones (near 0 degree C). The measurement of the electrode double layer impedance is the sensitive method for the study of the properties of the nucleic acids components that could be used in the field of new antiviral agents development.

• MeSH
• adenin analogy a deriváty   farmakokinetika   MeSH
• adsorpce MeSH
• elektrická impedance MeSH
• elektrochemie MeSH
• elektrody MeSH
• nukleosidy farmakokinetika   MeSH
• xanthiny farmakokinetika   MeSH
• zidovudin farmakokinetika   MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• nukleosidy MeSH
• xanthiny MeSH
• zidovudin MeSH

1-(2-O-Acetyl-3,5,6-tri-O-benzoyl-beta-D-glucofuranosyl)thymine (1) was converted into the 2,2'-anhydro derivative 4 by selective deacetylation, mesylation, and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Cleavage of the 2,2'-anhydro ring in 4 with hydrogen bromide or hydrogen chloride led to the 2'-bromo (5) or 2'-chloro (6) derivative, respectively. Dehalogenation of 6 with tributylstannane and then debenzoylation gave 1-(2-deoxy-beta-D-arabino-hexofuranosyl)thymine (8). Isopropylidenation of 8 followed by mesylation, azide displacement, and deprotection gave 1-(3-azido-2,3-dideoxy-beta-D-ribo-hexofuranosyl)thymine (12). Oxidation of 12 with Dowex 1 (IO4-) resin followed by reduction with Dowex 1 (BH4-) resin gave 1-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (AZT). Catalytic hydrogenation of 5 afforded a mixture of 1-(5,6-di-O-benzoyl-2,3-dideoxy-beta-D-erythro-hexofuranosyl)thymi ne (13) and 1-(3,5,6-tri-O-benzoyl-2-deoxy-beta-D-arabino-hexofuranosyl)thymin e (7). Reaction of 5 with a Cu/Zn couple gave 1-(5,6-di-O-benzoyl-2,3-dideoxy-beta-D-erythro-hex-2-enofuranosyl) thymine (15). 1-(2,3-Dideoxy-beta-D-erythro-hexofuranosyl)thymine (14) and 1-(2,3-dideoxy-beta-D-erythro-hex-2-enofuranosyl)thymine (16) were obtained by debenzoylation.

• MeSH
• antivirové látky chemická syntéza   farmakologie   MeSH
• dideoxynukleosidy chemická syntéza   farmakologie   MeSH
• HIV účinky léků   MeSH
• molekulární struktura MeSH
• zidovudin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• dideoxynukleosidy MeSH
• zidovudin MeSH

The inhibition of HSV-1 DNA polymerase and HeLa DNA polymerases alpha and beta by diphosphoryl derivatives of acyclic phosphonylmethoxyalkyl nucleotide analogues was studied and compared with the inhibition by ACV-TP, araCTP, ddTTP and AZT-TP. In the series of phosphonylmethoxyethyl (PME-) derivatives of heterocyclic bases, the inhibitory effect of their diphosphates on HSV-1 DNA polymerase decreased in the order 2-amino-PMEApp (Ki = 0.03 microM) much greater than PMEGpp greater than PMEApp greater than PMETpp much greater than PMECpp much greater than n8z7PMEApp greater than PMEUpp. The diphosphate derivative of the antiherpes agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine (HPMPA) proved to be a relatively weak inhibitor of HSV-1 DNA polymerase (Ki = 1.4 microM). The inhibitors could be divided into three groups: (a) the diphosphoryl derivatives of acyclic nucleotide analogues (PME-type and HPMPA) and ACV-TP specifically inhibit HSV-1 DNA polymerase and DNA polymerase alpha and do not significantly inhibit DNA polymerase beta; (b) AZT-TP and ddTTP are effective only against DNA polymerase beta, and (c) araCTP inhibits all three enzymes. When dATP was omitted from the reaction mixture, the addition of HPMPApp stimulated DNA synthesis by HSV-1 DNA polymerase indicating that HPMPApp is an alternative substrate for in vitro DNA synthesis catalyzed by this enzyme.

• MeSH
• acyklovir analogy a deriváty   chemická syntéza   farmakologie   MeSH
• adenin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• antivirové látky chemická syntéza   farmakologie   MeSH
• arabinofuranosylcytosintrifosfát farmakologie   MeSH
• dideoxynukleotidy MeSH
• DNA-polymerasa I antagonisté a inhibitory   MeSH
• DNA-polymerasa II antagonisté a inhibitory   MeSH
• HeLa buňky MeSH
• inhibitory syntézy nukleových kyselin * MeSH
• kinetika MeSH
• lidé MeSH
• organofosfonáty * MeSH
• organofosforové sloučeniny chemická syntéza   farmakologie   MeSH
• replikace DNA účinky léků   MeSH
• Simplexvirus účinky léků   enzymologie   MeSH
• thiminnukleotidy farmakologie   MeSH
• zidovudin analogy a deriváty   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• 2',3'-dideoxythymidine triphosphate MeSH Prohlížeč
• 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine MeSH Prohlížeč
• acyclovir triphosphate MeSH Prohlížeč
• acyklovir MeSH
• adefovir MeSH Prohlížeč
• adenin MeSH
• antivirové látky MeSH
• arabinofuranosylcytosintrifosfát MeSH
• dideoxynukleotidy MeSH
• DNA-polymerasa I MeSH
• DNA-polymerasa II MeSH
• inhibitory syntézy nukleových kyselin * MeSH
• organofosfonáty * MeSH
• organofosforové sloučeniny MeSH
• thiminnukleotidy MeSH
• zidovudin MeSH
• zidovudine triphosphate MeSH Prohlížeč

The genetic resistance to nucleoside inhibitors of the reverse transcriptase (RT) of human immunodeficiency virus I (HIV-1) isolates in the Czech Republic was examined by a line probe assay (LiPA) and nucleotide sequencing. The results of LiPA analysis of 294 blood specimens obtained from 156 patients revealed a high incidence of mutations in the RT gene related to resistance to various drugs (67.3%) in various combinations. Mutations in RT gene (M41L, K70R and T215Y/F) conferring the resistance to zidovudine (ZDV) were most frequent (62.6%), that (M184V) responsible for the resistance to lamivudine (3TC) was less frequent (33.7%), while those linked to the resistance to dideoxyinosine (ddl) and dideoxyinosine together with dideoxycytidine (ddl/ddC) were rather rare (6.5% and 5.1%, respectively). LiPA gave a high rate of uninterpretable results due to codon hybridization failure, especially in HIV-1 isolates of non-B subtype. Thirty-two specimens were analyzed also by direct sequencing of a part of RT gene. The results obtained by LiPA and the sequencing were highly concordant for codons successfully analyzed by both methods, but the sequencing provided information also about the codons that could not be analyzed by LiPA. A high prevalence of resistant strains in the Czech Republic and their heterogeneity justifies a regular HIV-1 resistance testing. LiPA turned out as a fast, powerful and most reliable tool for such a purpose. However, due to an increasing diversity of HIV-1 strains circulating in the Czech Republic, LiPA cannot replace the nucleotide sequence analysis.

• MeSH
• dideoxycytidin farmakologie   terapeutické užití   MeSH
• dideoxyinosin farmakologie   terapeutické užití   MeSH
• fylogeneze MeSH
• HIV infekce farmakoterapie   genetika   imunologie   MeSH
• HIV reverzní transkriptasa antagonisté a inhibitory   MeSH
• HIV-1 účinky léků   genetika   izolace a purifikace   MeSH
• inhibitory reverzní transkriptasy farmakologie   terapeutické užití   MeSH
• kodon MeSH
• lamivudin farmakologie   terapeutické užití   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• molekulární sondy - techniky * MeSH
• mutace MeSH
• prevalence MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• virová léková rezistence genetika   MeSH
• zidovudin farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• dideoxycytidin MeSH
• dideoxyinosin MeSH
• HIV reverzní transkriptasa MeSH
• inhibitory reverzní transkriptasy MeSH
• kodon MeSH
• lamivudin MeSH
• zidovudin MeSH

P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.

• Klíčová slova
• Caco-2 cells, P-glycoprotein, antiviral drugs, drug-drug interactions, intestinal absorption, precision-cut intestinal slices, rhodamine 123,
• MeSH
• antivirové látky farmakologie   MeSH
• atazanavir sulfát farmakologie   MeSH
• benzimidazoly farmakologie   MeSH
• Caco-2 buňky účinky léků   metabolismus   MeSH
• fluoreny farmakologie   MeSH
• hepatitida C komplikace   farmakoterapie   virologie   MeSH
• HIV infekce komplikace   farmakoterapie   virologie   MeSH
• imidazoly farmakologie   MeSH
• karbamáty MeSH
• krysa rodu Rattus MeSH
• látky proti HIV farmakologie   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• Lopinavir farmakologie   MeSH
• maravirok farmakologie   MeSH
• P-glykoprotein antagonisté a inhibitory   metabolismus   MeSH
• potkani Wistar MeSH
• pyrrolidiny MeSH
• ritonavir farmakologie   MeSH
• saquinavir farmakologie   MeSH
• senioři MeSH
• střeva účinky léků   MeSH
• valin analogy a deriváty   MeSH
• zidovudin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• atazanavir sulfát MeSH
• benzimidazoly MeSH
• daclatasvir MeSH Prohlížeč
• fluoreny MeSH
• imidazoly MeSH
• karbamáty MeSH
• látky proti HIV MeSH
• ledipasvir MeSH Prohlížeč
• Lopinavir MeSH
• maravirok MeSH
• P-glykoprotein MeSH
• pyrrolidiny MeSH
• ritonavir MeSH
• saquinavir MeSH
• valin MeSH
• zidovudin MeSH

The previously developed mathematical model simulates the CD4+ lymphocyte dynamics in HIV infection very well. As the number of these cells is a good indicator of the infection progression, it was used to evaluate the effectiveness of different therapeutic interventions. For chemotherapy simulation, both permanent and temporary zinovudine (AZT) administration were considered and the induced return of the CD4+ lymphocyte counts was analysed. Similar analysis was performed for active and passive immunotherapy. The model offers also the possibility of stimulating the CD4+ dynamics after depletion of CD8+ lymphocytes by antibodies. Even one simulated administration of anti-CD8 antibodies increases the CD4+ lymphocyte counts and prolongs the survival of the patient. However, if cells involved in protective immunity are assumed to belong to the CD8+ category, anti-CD8 antibodies accelerate the decrease of CD4- cells and thus shorten the patient's survival.

• MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• HIV infekce imunologie   terapie   MeSH
• lidé MeSH
• lymfocytární deplece MeSH
• teoretické modely MeSH
• zidovudin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• zidovudin MeSH