Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity.
- MeSH
- adenosinmonofosfát * analogy a deriváty terapeutické užití MeSH
- alanin * analogy a deriváty terapeutické užití MeSH
- antivirové látky * terapeutické užití MeSH
- COVID-19 * virologie mortalita MeSH
- farmakoterapie COVID-19 * MeSH
- jednotky intenzivní péče MeSH
- lidé středního věku MeSH
- lidé MeSH
- péče o pacienty v kritickém stavu MeSH
- retrospektivní studie MeSH
- SARS-CoV-2 * účinky léků izolace a purifikace fyziologie MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- virová nálož * účinky léků MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Background: Remdesivir has recently been used more widely as an antiviral medication, possibly due to its potency against coronavirus.Aim: This study was aimed at detecting the toxicity of remdesivir on the liver and kidneys of albino rats at various doses, as well as the possibility of recovering to the normal structure of these tissues two weeks after drug discontinuation.Methods: Forty adult albino rats were divided into five groups (8 rats per group). The first group was the control group; the second group received 5 mg/kg remdesivir; the third group received 10 mg/kg for five days; and the fourth and fifth groups were withdrawal groups (treated as 2nd and 3rd groups then left for two weeks). After five days of treatment, the animals of the 1st, 2nd, and 3rd groups were sacrificed, while the animals of the withdrawal groups were killed after two weeks of drug discontinuation. Both the liver and kidneys were removed and prepared for histological examination.Results: Remdesivir-treated liver and kidneys showed histological alterations such as blood vessel congestion, mononuclear cell infiltration, and localized hepatocyte degeneration. Meanwhile, kidney sections revealed localized vacuolation of the tubular epithelium, focal glomerular tuft shrinkage with Bowman's space dilatation.Conclusion: Remdesivir is hepatotoxic and nephrotoxic mainly, at high doses. Even after drug withdrawal, structural alterations persist, particularly at high dosages, confirming that remdesivir toxicity is dose-dependent.
- Klíčová slova
- remdesivir,
- MeSH
- adenosinmonofosfát analogy a deriváty toxicita MeSH
- alanin analogy a deriváty toxicita MeSH
- antivirové látky * toxicita MeSH
- farmakoterapie COVID-19 škodlivé účinky MeSH
- histologické techniky MeSH
- játra účinky léků MeSH
- ledviny účinky léků MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Klíčová slova
- remdesivir, nirmatrelvir, molnupiravir,
- MeSH
- adenosinmonofosfát analogy a deriváty MeSH
- alanin analogy a deriváty MeSH
- antivirové látky aplikace a dávkování farmakologie terapeutické užití MeSH
- COVID-19 terapie MeSH
- cytidin analogy a deriváty MeSH
- farmakoterapie COVID-19 * MeSH
- heparin nízkomolekulární aplikace a dávkování terapeutické užití MeSH
- hormony kůry nadledvin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- hydroxylaminy MeSH
- inhibitory virových proteáz aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- pasivní imunizace MeSH
- Check Tag
- lidé MeSH
By December 2019, humanity was challenged by a new infectious respiratory disease named coronavirus disease of 2019 or COVID-19. This is a viral infection based on the presence of the previously non-problematic coronavirus with assigned number 2. This virus causes severe acute respiratory distress and is known now as SARS-CoV2. Since SARS-CoV2 is an RNA virus, remdesivir and favipiravir, both broad-spectrum RNA polymerase inhibitors, were repurposed for treating COVID-19 patients. Remdesivir and favipiravir are antimetabolites, and they are structurally related to the naturally occurring structural elements of RNA. Both agents are prodrugs and must be activated intracellularly to exert their effects through numerous and different mechanisms of action. Efforts have been exerted to determine their efficacy and safety against COVID-19 through clinical trials. Clinical trials have shown an association of remdesivir with increased frequency of adverse effects (in comparison to favipiravir). Nevertheless, the data obtained with remdesivir resulted in its approval by the FDA on the 22nd of October 2020 for COVID-19 treatment. At present, remdesivir is being recommended by several treatment guidelines for the treatment of COVID-19 patients. The evidence in favor of favipiravir is compromised by the small number and low-quality of trials conducted. Favipiravir has shown various benefits when administered in mild and moderate cases of COVID-19, while remdesivir was more beneficial in more severe cases of the disease. Since the two agents are suitable for different groups of patients, both drugs can play a significant role in fighting this pandemic. The goal of this work is to summarize the information available on two antimetabolites - remdesivir and favipiravir - and to compare clinical experience obtained so far with these two agents in COVID-19 patients.
- MeSH
- adenosinmonofosfát analogy a deriváty terapeutické užití MeSH
- alanin analogy a deriváty terapeutické užití MeSH
- antivirové látky terapeutické užití MeSH
- COVID-19 komplikace terapie virologie MeSH
- dospělí MeSH
- farmakoterapie COVID-19 MeSH
- hematologické nádory epidemiologie prevence a kontrola virologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- pasivní imunizace MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- SARS-CoV-2 izolace a purifikace MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- klinické zkoušky MeSH
- Geografické názvy
- Česká republika MeSH
SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.
- MeSH
- adenosinmonofosfát analogy a deriváty farmakologie MeSH
- alanin analogy a deriváty farmakologie MeSH
- antivirové látky farmakologie MeSH
- benzothiazoly farmakologie MeSH
- buněčné linie MeSH
- inhibitory enzymů farmakologie MeSH
- koronavirová RNA-replikasa antagonisté a inhibitory MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- replikace viru účinky léků MeSH
- SARS-CoV-2 účinky léků enzymologie fyziologie MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
V článku jsou přehledně shrnuty základní poznatky o klinicky nejdůležitějších látkách s potenciálním účinkem na SARS‑CoV‑2. Nejvíce pozornosti je věnováno remdesiviru, který je jako jediný lék registrován k léčbě covid‑19 v České republice. Zmíněna jsou antivirotika favipiravir a lopinavir/ritonavir, antimala‑ rikum hydroxychlorochin a antibiotikum azithromycin. Dále jsou uvedeny relevantní informace o použití rekonvalescentní plazmy.
This review describes the current knowledge of the most clinically relevant agents with potential acti‑ vity against SARS‑CoV‑2. The main focus is on remdesivir, the only medicine currently registered in the Czech Republic for the treatment of COVID‑19. Other candidate drugs are mentioned as well, including favipiravir, lopinavir/ritonavir, hydroxychloroquine and azithromycin. Also, relevant information on convalescent plasma is reviewed.
- Klíčová slova
- remdesivir, favipiravir, rekonvalescentní plazma,
- MeSH
- adenosinmonofosfát analogy a deriváty farmakologie terapeutické užití MeSH
- alanin analogy a deriváty farmakologie terapeutické užití MeSH
- antivirové látky farmakologie škodlivé účinky terapeutické užití MeSH
- azithromycin škodlivé účinky terapeutické užití MeSH
- Betacoronavirus * MeSH
- COVID-19 MeSH
- fixní kombinace léků MeSH
- hydroxychlorochin škodlivé účinky terapeutické užití MeSH
- koronavirové infekce * farmakoterapie MeSH
- lidé MeSH
- převod jednotlivých krevních složek metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Klíčová slova
- Remdesivir,
- MeSH
- adenosinmonofosfát analogy a deriváty MeSH
- alanin analogy a deriváty MeSH
- amidy terapeutické užití MeSH
- antivirové látky terapeutické užití MeSH
- azithromycin terapeutické užití MeSH
- chlorochin terapeutické užití MeSH
- Coronavirus * patogenita účinky léků MeSH
- hydroxychlorochin terapeutické užití MeSH
- lidé MeSH
- pyraziny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- remdesivir,
- MeSH
- adenosin analogy a deriváty terapeutické užití MeSH
- alanin analogy a deriváty terapeutické užití MeSH
- antivirové látky * terapeutické užití MeSH
- COVID-19 * MeSH
- farmakoterapie COVID-19 MeSH
- klinická studie jako téma MeSH
- koronavirové infekce farmakoterapie MeSH
- lidé MeSH
- ribonukleotidy terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- zprávy MeSH
- Geografické názvy
- Spojené státy americké MeSH
Brivanib, a promising tyrosine kinase inhibitor, is currently undergoing advanced stages of clinical evaluation for solid tumor therapy. In this work, we investigated possible interactions of this novel drug candidate with ABC drug efflux transporters and cytochrome P450 (CYP450) drug-metabolizing enzymes that participate in cancer multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). First, in accumulation experiments with various model substrates, we identified brivanib as an inhibitor of the ABCB1, ABCG2, and ABCC1 transporters. However, in subsequent combination studies employing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide proliferation assays in both Madin-Darby canine kidney II (MDCKII) and A431 cellular models, only ABCG2 inhibition was revealed to be able to synergistically potentiate mitoxantrone effects. Advantageous to its possible use as MDR antagonist, brivanib's chemosensitizing properties were not impaired by activity of any of the MDR-associated ABC transporters, as observed in comparative viability assay in the MDCKII cell sublines. In incubation experiments with eight recombinant CYP450s, we found that brivanib potently inhibited CYP2C subfamily members and the CYP2B6 isoform. Finally, in induction studies, we demonstrated that brivanib upregulated ABCB1 and CYP1A2 messenger RNA levels in systemic cell models, although this interaction was not significantly manifested at a functional level. In conclusion, brivanib exhibits potential to cause clinically relevant pharmacokinetic DDIs and act as a modulator of ABCG2-mediated MDR. Our findings might be used as an important background for subsequent in vivo investigations and pave the way for the safe and effective use of brivanib in oncological patients.
- MeSH
- ABC transportér z rodiny G, člen 2 antagonisté a inhibitory MeSH
- alanin analogy a deriváty farmakologie MeSH
- biotransformace účinky léků MeSH
- buněčné linie MeSH
- buňky MDCK MeSH
- chemorezistence účinky léků MeSH
- inhibitory cytochromu P450 farmakologie MeSH
- lékové interakce fyziologie MeSH
- lidé MeSH
- mnohočetná léková rezistence účinky léků MeSH
- nádorové proteiny antagonisté a inhibitory MeSH
- P-glykoproteiny metabolismus MeSH
- psi MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- triaziny farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
