Antivirals
Dotaz
Zobrazit nápovědu
Článek podává přehled o současném stavu a perspektivách vývoje preparátů používaných pro terapii nejvážnějších lidských virových patogenů. Většina současných schválených léků je zaměřena na terapii AIDS a další jsou určeny proti chorobám vyvolaným DNA viry (zvláště herpesviry a hepatitida B). Situace je výrazně horší u nemocí vyvolávaných RNA viry, s výjimkou nedávno schválených protichřipkových preparátů. Nové látky v klinické fázi vývoje jsou určeny především proti enterovirům a hepatitidě C, a proti rezistentním mutantům HIV, HBV a VZV.
The present situation in the antiviral chemotherapy is discussed from the point of view of drugs available for treatment of the most important human pathogens. While the existing battery of approved drugs is aimed mainly at the therapy of AIDS, there are several drugs available for treatment of diseases caused by DNA viruses (herpesviruses, hepatitis B). The prospect is much worse in the therapy of infections caused by RNA viruses except for the recently approved anti-influenza preparations. Drugs in clinical development are aimed at enteroviruses and hepatitis C, as well as at resistant mutants of HIV, HBV and VZV.
Ebola hemorrhagic fever is a deadly disease caused by infection with one of the Ebola virus species. Although a significant progress has recently been made in understanding of Ebola virus biology and pathogenesis, development of effective anti-Ebola treatments has not been very productive, compared to other areas of antiviral research (e.g., HIV and HCV infections). No approved vaccine or medicine is available for Ebola but several are currently under development. This review summarises attempts in identification, evaluation, and development of small-molecule candidates for treatment of Ebola viral disease, including the most promising experimental drugs brincidofovir (CMX001), BCX4430, and favipiravir (T-705).
- MeSH
- antivirové látky chemická syntéza terapeutické užití MeSH
- epidemický výskyt choroby MeSH
- hemoragická horečka Ebola farmakoterapie epidemiologie MeSH
- lidé MeSH
- rychlé screeningové testy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- západní Afrika MeSH
This review is a Part II of the series aiming to provide comprehensive overview of currently used antiviral drugs and to show modern approaches to their analysis. While in the Part I antivirals against herpes viruses and antivirals against respiratory viruses were addressed, this part concerns antivirals against hepatitis viruses (B and C) and human immunodeficiency virus (HIV). Many novel antivirals against hepatitis C virus (HCV) and HIV have been introduced into the clinical practice over the last decade. The recent broadening portfolio of these groups of antivirals is reflected in increasing number of developed analytical methods required to meet the needs of clinical terrain. Part II summarizes the mechanisms of action of antivirals against hepatitis B virus (HBV), HCV, and HIV, their use in clinical practice, and analytical methods for individual classes. It also provides expert opinion on state of art in the field of bioanalysis of these drugs. Analytical methods reflect novelty of these chemical structures and use by far the most current approaches, such as simple and high-throughput sample preparation and fast separation, often by means of UHPLC-MS/MS. Proper method validation based on requirements of bioanalytical guidelines is an inherent part of the developed methods.
- MeSH
- antivirové látky analýza farmakologie terapeutické užití MeSH
- biologické faktory analýza metabolismus MeSH
- hepatitida farmakoterapie metabolismus MeSH
- HIV infekce farmakoterapie metabolismus MeSH
- HIV-1 účinky léků metabolismus MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Covid-19 je respirační onemocnění, jehož průběh je obvykle mírný, může však být spojeno se závažnými, potenciálně fatálními komplikacemi, a to především u pacientů vyššího věku a/nebo s komorbiditami, jako jsou obezita, hypertenze, diabetes mellitus, chronická onemocnění či malignity. Pacientům s prokázaným mírným a středně těžkým COVID-19, kteří jsou ve vysokém riziku progrese onemocnění do závažné formy s potřebou hospitalizace, by měla být nabídnuta antivirotika působící proti SARS-CoV-2, z nichž jsou v současné době v ČR k dispozici remdesivir, molnupiravir a nirmatrelvir/ritonavir. Tato antivirotika se mezi sebou liší mechanismem působení, aplikační formou i účinností.
COVID-19 is a respiratory disease whose course is usually mild, but can be associated with serious, potentially fatal complications, especially in elderly patients and/or those with comorbidities such as obesity, hypertension, diabetes mellitus, chronic diseases or malignancies. Patients with mild and moderate COVID-19 who are at high risk of disease progression to a severe form requiring hospitalisation should be offered antiviral agents active against SARS- CoV-2, of which remdesivir, molnupiravir and nirmatrelvir/ ritonavir are currently available in the Czech Republic. These antivirals differ in their mechanism of action, form of administration and efficacy.
This review article is the first in the series providing an overview of currently used antiviral drugs and presenting contemporary approaches to their analysis. Large number of available antivirals and their structural variability makes this task very challenging. Trying to cover this topic comprehensively while maintaining reasonable size of the article, the review is presented in two parts. For the purpose of the overall review, antivirals were divided into four groups: (i) antivirals against herpes viruses, (ii) antivirals against respiratory viruses, (iii) antivirals against hepatitis viruses, and (iv) antivirals against HIV. Part one is devoted to the groups (i) and (ii) and also concerns the key features of the bioanalytical method. The mechanisms of action of antivirals against respiratory and herpes viruses and their use in clinical practice are briefly outlined, and the analytical methods for selected representatives of each class are described in more detail. The methods developed for the determination of drugs from these classes mostly include conventional procedures. In contrast, current trends such as UHPLC are used rarely and proper method validation based on requirements of bioanalytical guidelines can be often considered insufficient.
- MeSH
- antivirové látky analýza terapeutické užití MeSH
- biologické faktory analýza MeSH
- Herpesviridae účinky léků metabolismus MeSH
- herpetické infekce farmakoterapie metabolismus MeSH
- infekce dýchací soustavy farmakoterapie metabolismus MeSH
- lidé MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- virové nemoci farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: The review covers basic principles of the prodrug strategy applied to antiviral nucleoside drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the most important representatives (compounds under clinical investigations or available on the market) are described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine, valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides. METHOD: A special attention is paid to acyclic nucleoside phosphonates, where the phosphonic acid residue is esterified with a side-chain hydroxyl group of appropriate amino acid (serine, tyrosine) which can be used as single amino acid or as a part of dipeptides further modified on the terminal carboxyl function. The most advantageous pharmacokinetic profile and the best oral bioavailability were found in tyrosinebased prodrugs. RESULTS & CONCLUSION: Studies were performed successfully on 1-(S)-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (cidofovir), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine and some (R)-2- (phosphonomethoxy)propyl and 2-(phosphonomethoxy)ethyl derivatives including adefovir.
- MeSH
- adenin analogy a deriváty chemie farmakologie MeSH
- antivirové látky chemie farmakologie MeSH
- Cytomegalovirus účinky léků MeSH
- cytosin analogy a deriváty chemie farmakologie MeSH
- lidé MeSH
- nukleosidy chemie farmakologie MeSH
- nukleotidy chemie farmakologie MeSH
- organofosfonáty chemie farmakologie MeSH
- prekurzory léčiv chemie farmakologie MeSH
- virus varicella zoster účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Acyclic nucleoside phosphonates (ANPs) are potent antiviral agents effective against replication of DNA viruses and retroviruses including human immunodeficiency virus (HIV). Prototype compound 9-(R)-[2-(phosphonomethoxy)propyl]adenine (tenofovir) is a principal component of drugs widely used in the treatment of HIV infection (Viread, Truvada). Besides their antimetabolic mode of action, ANPs possess immunomodulatory properties. A number of them have been previously found to stimulate secretion of cytokines and anti-HIV effective chemokines. In the present pilot experiments we analysed the in vitro effects of ANPs on the expression of chemokine receptors CCR5 and CXCR4 that are co-receptors of HIV-1 entry in cells. The impact of ANPs was investigated at the level of gene transcription of mRNA in mouse lymphocytes and macrophages using the RT-PCR method. The following compounds were included in the study: 9-(R)-[2-(phosphonomethoxy) propyl]adenine (tenofovir), N6-cyclopropyl-(R)- 9-[2-(phosphonomethoxy)-propyl]2,6-diaminopurine, N6-cyclopentyl-(R)-9-[2-(phosphonomethoxy) propyl]2,6-diaminopurine, N6-dimethylaminoethyl-(R)-9-[2-(phosphonomethoxy)propyl]2,6-diaminopurine, N6-cyclopentyl-9-[2-(phosphonomethoxy) ethyl]2,6-diaminopurine, N6-isobutyl-9-[2-(phosphonomethoxy) ethyl]2,6-diaminopurine. Gene transcription of chemokine receptors CCR5 and CXCR4 was not affected after application of these acyclic nucleoside phosphonate antivirals.
- MeSH
- antivirové látky chemie farmakologie MeSH
- lymfocyty účinky léků metabolismus MeSH
- messenger RNA genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- nukleosidy chemie farmakologie MeSH
- receptory CCR5 genetika metabolismus MeSH
- receptory CXCR4 genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
AIMS: Antiviral drugs are considered as potentially cardiotoxic, due to prolongation of QT interval which may affect incidence of severe ventricular arrhythmias. The main aim of this retrospective study was to assess the influence of treatment by three antiviral drugs on QT interval and to find patients who are at an increased risk of developing malignant ventricular arrhythmias. METHODS: The study included 23 patients (14 men, 9 women) who were treated with a combination of interferon alpha, ribavirin, and an NS3/4A protease inhibitor. The parameters from the 12 leads electrocardiograms were evaluated before treatment, and then 3 ± 1 and 6 ± 1 months after treatment. RESULTS: Heart rate (HR) 69 ± 12 / min and corrected QT interval (QTc) 412 ± 35 ms were obtained before the treatment and there was not observed a significant prolongation of intervals after 3 months (HR 72 ± 11 / min, QTc 412 ± 33 ms) and after 6 months (HR 64 ± 12 / min, QTc 405 ± 28 ms) respectively. In total QTc interval was prolonged from the baseline in 53% and in 43% of the patients 3 months respectively 6 months after treatment. A QTc prolongation over of 450 ms and new treatment-related repolarization change was noted in 1 (4%) patient. CONCLUSION: The study demonstrates that a combination therapy of 3 antiviral drugs does not significantly prolong the QTc interval and does not cause severe pathological changes on the ECG. Patients undergoing this treatment are not at risk of developing heart disease as an undesirable side effect.
- MeSH
- antivirové látky škodlivé účinky MeSH
- chronická hepatitida C * farmakoterapie MeSH
- elektrokardiografie MeSH
- hepatitida C * farmakoterapie MeSH
- lidé MeSH
- retrospektivní studie MeSH
- srdeční arytmie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Antiviral drugs are considered as potentially cardiotoxic, due to prolongation of QT interval which may affect incidence of severe ventricular arrhythmias. The main aim of this retrospective study was to assess the influence of treatment by three antiviral drugs on QT interval and to find patients who are at an increased risk of developing malignant ventricular arrhythmias. METHODS: The study included 23 patients (14 men, 9 women) who were treated with a combination of interferon alpha, ribavirin, and an NS3/4A protease inhibitor. The parameters from the 12 leads electrocardiograms were evaluated before treatment, and then 3 ± 1 and 6 ± 1 months after treatment. RESULTS: Heart rate (HR) 69 ± 12 / min and corrected QT interval (QTc) 412 ± 35 ms were obtained before the treatment and there was not observed a significant prolongation of intervals after 3 months (HR 72 ± 11 / min, QTc 412 ± 33 ms) and after 6 months (HR 64 ± 12 / min, QTc 405 ± 28 ms) respectively. In total QTc interval was prolonged from the baseline in 53% and in 43% of the patients 3 months respectively 6 months after treatment. A QTc prolongation over of 450 ms and new treatment-related repolarization change was noted in 1 (4%) patient. CONCLUSION: The study demonstrates that a combination therapy of 3 antiviral drugs does not significantly prolong the QTc interval and does not cause severe pathological changes on the ECG. Patients undergoing this treatment are not at risk of developing heart disease as an undesirable side effect.
- MeSH
- antivirové látky škodlivé účinky MeSH
- chronická hepatitida C * farmakoterapie MeSH
- elektrokardiografie MeSH
- hepatitida C * farmakoterapie MeSH
- lidé MeSH
- retrospektivní studie MeSH
- srdeční arytmie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
