scholarly journals In Vitro Benznidazole and Nifurtimox Susceptibility Profile of Trypanosoma cruzi Strains Belonging to Discrete Typing Units TcI, TcII and TcV

2019 ◽  
Author(s):  
Suzana Revollo ◽  
Bruno Oury ◽  
Andrea Vela ◽  
Michel Tibayrenc ◽  
Denis Sereno
Keyword(s):  
Genetic Background ◽  
Geographic Origin ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Wild Type ◽  
Triatomine Bugs ◽  
History Of ◽  
The Individual ◽  
Susceptibility Status

We ascertain the in vitro Benznidazole (BZN) and Nifurtimox (NFX) susceptibility pattern of epimastigotes, trypomastigotes, and amastigotes of 21 T. cruzi strains, from patients, reservoir and triatomine bugs of various geographic origin. Using this panel of isolates, we compute the Epidemiological cut off value (COwt). Then, the frequency of the susceptible phenotype (Wild type) towards BZN and nifurtimox (NFX) within this set of strains belonging to 3 discrete typing units (DTUs), TcI, TcII, and TcV was deduced. We have observed that the susceptibility status of individual T. cruzi isolates toward BZN and NFX is related to the genetic background and to underlying factors probably related to the individual life trait history of each strain. Analyzing drug susceptibility in this conceptual framework would offers the possibility to evidence a link between isolates expressing a low susceptibility level (not wild-type) as define by the COwt value and none-curative treatment. It will also permit to tract drug-resistant parasites in T. cruzi population.

scholarly journals In Vitro Benznidazole and Nifurtimox Susceptibility Profile of Trypanosoma cruzi Strains Belonging to Discrete Typing Units TcI, TcII, and TcV

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 197 ◽  
Author(s):  
Susana Revollo ◽  
Bruno Oury ◽  
Andrea Vela ◽  
Michel Tibayrenc ◽  
Denis Sereno
Keyword(s):  
Genetic Background ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Wild Type ◽  
Triatomine Bugs ◽  
Geographic Origins ◽  
History Of ◽  
The Individual ◽  
Susceptibility Status

We ascertain the in vitro Benznidazole (BZN) and Nifurtimox (NFX) susceptibility pattern of epimastigotes, trypomastigotes, and amastigotes of 21 T. cruzi strains, from patients, reservoir, and triatomine bugs of various geographic origins. Using this panel of isolates, we compute the Epidemiological cut off value (COwt). Then, the frequency of the susceptible phenotype (Wild type) towards benznidazole (BZN) and nifurtimox (NFX) within this set of strains belonging to three discrete typing units (DTUs), TcI, TcII, and TcV, was deduced. We observed that the susceptibility status of individual T. cruzi isolates toward BZN and NFX is related to the genetic background and underlying factors that are probably related to the individual life trait history of each strain. Analyzing drug susceptibility in this conceptual framework would offer the possibility to evidence a link between isolates expressing a low susceptibility level (not wild-type) as defined by the COwt value and none-curative treatment. It will also permit us to track drug-resistant parasites in the T. cruzi population.

scholarly journals Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants

2021 ◽  
Author(s):  
Michael Stumpp
Keyword(s):  
Single Agent ◽  
Standard Of Care ◽  
Cooperative Binding ◽  
Wild Type ◽  
Inhibitory Potency ◽  
Alpha Variant ◽  
The Individual ◽  
Very High ◽  
Comprehensive Study

Abstract SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron, as of December 2021. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.

scholarly journals Domain II plays a crucial role in the function of ribosome recycling factor

2006 ◽  
Vol 393 (3) ◽  
pp. 767-777 ◽  
Author(s):  
Peng Guo ◽  
Liqiang Zhang ◽  
Hongjie Zhang ◽  
Yanming Feng ◽  
Guozhong Jing
Keyword(s):  
Crucial Role ◽  
Specific Interaction ◽  
Elongation Factor ◽  
Wild Type ◽  
Ribosome Recycling Factor ◽  
E Coli ◽  
Thermoanaerobacter Tengcongensis ◽  
The Individual

RRF (ribosome recycling factor) consists of two domains, and in concert with EF-G (elongation factor-G), triggers dissociation of the post-termination ribosomal complex. However, the function of the individual domains of RRF remains unclear. To clarify this, two RRF chimaeras, EcoDI/TteDII and TteDI/EcoDII, were created by domain swaps between the proteins from Escherichia coli and Thermoanaerobacter tengcongensis. The ribosome recycling activity of the RRF chimaeras was compared with their wild-type RRFs by using in vivo and in vitro activity assays. Like wild-type TteRRF (T. tengcongensis RRF), the EcoDI/TteDII chimaera is non-functional in E. coli, but both wild-type TteRRF, and EcoDI/TteDII can be activated by coexpression of T. tengcongensis EF-G in E. coli. By contrast, like wild-type E. coli RRF (EcoRRF), TteDI/EcoDII is fully functional in E. coli. These findings suggest that domain II of RRF plays a crucial role in the concerted action of RRF and EF-G for the post-termination complex disassembly, and the specific interaction between RRF and EF-G on ribosomes mainly depends on the interaction between domain II of RRF and EF-G. This study provides direct genetic and biochemical evidence for the function of the individual domains of RRF.

Population pharmacokinetic analysis of S-1 including the CYP2A6 genotype in patients with advanced cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2507-2507
Author(s):  
T. Hirose ◽  
K. Nishimura ◽  
K. Fujita ◽  
M. Adachi ◽  
Y. Sasaki ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Advanced Cancer ◽  
Variant Allele ◽  
Population Pharmacokinetic ◽  
Wild Type ◽  
Chain Reaction ◽  
History Of ◽  
Polymerase Chain ◽  
Variant Alleles ◽  
The Individual

2507 Background: S-1 is an oral anticancer agent composed of tegafur, CDHP, and potassium oxonate. Tegafur is a prodrug of fluorouracil (5-FU), and CDHP prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase and enhances the anticancer activity of 5-FU. The biotransformation of tegafur to 5-FU is demonstrated to be catalyzed by CYP2A6. CYP2A6 polymorphisms are seen more frequently in Japanese people than Caucasian. Therefore, we performed a population pharmacokinetic (PPK) analysis of S-1 including the CYP2A6 genotype in Japanese patients with advanced cancer and developed a model describing the disposition kinetics of tegafur, CDHP, and 5-FU after oral administration of S-1. Methods: Fifty-eight patients with advanced cancer were eligible if they had a performance status of 0 to 3 and had adequate organ function. A dose of 80 mg/m2 of S-1 was given orally twice daily for 28 consecutive days, followed by 14 days of rest. The PPK analysis was performed with plasma concentration data for tegafur, CDHP, and 5-FU. The CYP2A6 genotype was analyzed with the polymerase chain reaction-restriction fragment length polymorphism method or an allele-specific polymerase chain reaction-based method. On the basis of the CYP2A6 genotype, all patients were classified into 1 of 3 groups: wild type, 1 variant allele, and 2 variant alleles. Results: Creatinine clearance correlated with the individual clearance of CDHP. Body surface area correlated with the individual clearance and volumes of CDHP and tegafur. In patients with 2 variant alleles of CYP2A6, tegafur clearance was 58% less than that in patients with wild type or 1 variant allele of CYP2A6. In addition, in patients with a history of gastrectomy, the absorption rate constant of tegafur was 66% higher than that in patients with no history of gastrectomy. The time-varying concentration of CDHP was the most appropriate model component describing the inhibitory effect on 5-FU catabolism. The individual Bayesian predictions of CDHP, tegafur, and 5-FU concentrations based on the present PPK model were in good agreement with the observed data. Conclusions: This is the first PPK model of S-1 including the CYP2A6 genotype. No significant financial relationships to disclose.

scholarly journals Phenotypic Drug Susceptibility Assay for Influenza Virus Neuraminidase Inhibitors

2004 ◽  
Vol 11 (1) ◽  
pp. 21-28 ◽  
Author(s):  
James J. McSharry ◽  
Ann C. McDonough ◽  
Betty A. Olson ◽  
George L. Drusano
Keyword(s):  
Influenza A ◽  
Influenza Viruses ◽  
Virus Yield ◽  
Drug Resistant ◽  
Wild Type ◽  
Vitro Assay ◽  
Drug Concentrations ◽  
Clinical Resistance ◽  
Na Gene

ABSTRACT A flow cytometric (fluorescence-activated cell sorter [FACS]) assay was developed for analysis of the drug susceptibilities of wild-type and drug-resistant influenza A and B virus laboratory strains and clinical isolates for the neuraminidase (NA) inhibitors oseltamivir carboxylate, zanamivir, and peramivir. The drug susceptibilities of wild-type influenza viruses and those with mutations in the hemagglutinin (HA) and/or NA genes rendering them resistant to one or more of the NA inhibitors were easily determined with the FACS assay. The drug concentrations that reduced the number of virus-infected cells or the number of PFU by 50% as determined by the FACS assay were similar to those obtained with the more time-consuming and labor-intensive virus yield reduction assay. The NA inhibition (NAI) assay confirmed the resistance patterns demonstrated by the FACS and virus yield assays for drug-resistant influenza viruses with mutations in the NA gene. However, only the FACS and virus yield assays detected NA inhibitor-resistant influenza viruses with mutations in the HA gene but not in the NA gene. The FACS assay is more rapid and less labor-intensive than the virus yield assay and just as quantitative. The FACS assay determines the drug susceptibilities of influenza viruses with mutations in either the HA or NA genes, making the assay more broadly useful than the NAI assay for measuring the in vitro susceptibilities of influenza viruses for NA inhibitors. However, since only viruses with mutations in the NA gene that lead to resistance to the NA inhibitors correlate with clinical resistance, this in vitro assay should not be used in the clinical setting to determine resistance to NA inhibitors. The assay may be useful for determining the in vivo susceptibilities of other compounds effective against influenza A and B viruses.

scholarly journals Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-12
Author(s):  
Fei Chu ◽  
Jessica A. Naiditch ◽  
Sandra Clark ◽  
Yi-Yong Qiu ◽  
Xin Zheng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chemotherapy Resistance ◽  
Neuroblastoma Cells ◽  
Cytotoxic Agents ◽  
Drug Resistant ◽  
Wild Type ◽  
Cytoprotective Effect ◽  
Acquired Drug Resistance

Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide. Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.

scholarly journals Favipiravir-resistant influenza A virus shows potential for transmission

2020 ◽  
Author(s):  
Daniel H. Goldhill ◽  
Ada Yan ◽  
Rebecca Frise ◽  
Jie Zhou ◽  
Jennifer Shelley ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Genetic Background ◽  
Influenza A ◽  
Resistance Mutation ◽  
Polymerase Activity ◽  
Resistant Virus ◽  
Wild Type ◽  
Fitness Advantage

AbstractFavipiravir is a nucleoside analogue which has been licensed to treat influenza in the event of a new pandemic. We previously described a favipiravir resistant influenza A virus generated by in vitro passage in presence of drug with two mutations: K229R in PB1, which conferred resistance at a cost to polymerase activity, and P653L in PA, which compensated for the cost of polymerase activity. However, the clinical relevance of these mutations is unclear as the mutations have not been found in natural isolates and it is unknown whether viruses harbouring these mutations would replicate or transmit in vivo. Here, we infected ferrets with a mix of wild type p(H1N1) 2009 and corresponding favipiravir-resistant virus and tested for replication and transmission in the absence of drug. Favipiravir-resistant virus successfully infected ferrets and was transmitted by both contact transmission and respiratory droplet routes. However, sequencing revealed the mutation that conferred resistance, K229R, decreased in frequency over time within ferrets. Modelling revealed that due to a fitness advantage for the PA P653L mutant, reassortment with the wild-type virus to gain wild-type PB1 segment in vivo resulted in the loss of the PB1 resistance mutation K229R. We demonstrated that this fitness advantage of PA P653L in the background of our starting virus A/England/195/2009 was due to a maladapted PA in first wave isolates from the 2009 pandemic. We show there is no fitness advantage of P653L in more recent pH1N1 influenza A viruses. Therefore, whilst favipiravir-resistant virus can transmit in vivo, the likelihood that the resistance mutation is retained in the absence of drug pressure may vary depending on the genetic background of the starting viral strain.Author SummaryIn the event of a new influenza pandemic, drugs will be our first line of defence against the virus. However, drug resistance has proven to be particularly problematic to drugs against influenza. Favipiravir is a novel drug which might be used against influenza virus in the event of a new pandemic. Is resistance likely to be a problem for the use of favipiravir? Our previous work has shown that resistance to favipiravir can be generated in cell culture but we don’t know whether there will be a cost preventing the spread of resistance in whole organisms. Here, we used a mix of wild-type and resistant influenza viruses from early in the 2009 pandemic to test whether viruses resistant to favipiravir could transmit between ferrets. We found that the resistant viruses could transmit but that the resistance mutation was selected against within some ferrets. Using modelling and in vitro experiments, we found that the resistant mutation was selected against in the influenza strain from our experiment but not in more recently evolved strains. Our results show that favipiravir resistant viruses could spread if resistance is generated but the probability will depend on the genetic background of the virus.

scholarly journals SEARCH FOR NEW ANTILEISHMANIAL CHEMOTHERAPEUTICS

2018 ◽  
Vol 10 (1) ◽  
pp. 46
Author(s):  
Nabanita Kar ◽  
Santanu Ghosh ◽  
Leena Kumari ◽  
Shreyasi Chakraborty ◽  
Tanmoy Bera
Keyword(s):  
Betulinic Acid ◽  
Leishmania Donovani ◽  
Antileishmanial Activity ◽  
Gas Chromatography Mass Spectrometry ◽  
Drug Resistant ◽  
Wild Type ◽  
Leaf Oil ◽  
Resistant Strains ◽  
Type Strains

Objective: The objective of this work was to screen a number of compounds for their antileishmanial efficacy and cytotoxicity profiling.Methods: Curry leaf oil, cypress oil and spikenard oil were identified by gas chromatography-mass spectrometry (GC/MS) analysis. Betulinic acid, spikenard oil, cypress oil and curry leaf oil were evaluated for their in vitro antileishmanial activity against Leishmania donovani AG83 wild-type, sodium stibogluconate resistant (SSG-resistant), paromomycin (PMM-resistant) and GE1 field type strains on axenic and cellular amastigote model and compared the results with standard drugs used to treat leishmaniasis.Results: Betulinic acid showed strong antileishmanial activity against wild-type (SI= 192.8), SSG-resistant (SI= 19.3) and GE1 strains (SI= 100), whereas cypress oil has produced highest antileishmanial activity against PMM-resistant strains (SI= 15.09) among all the tested drugs. The data obtained also revealed that cypress oil had the maximum CC50 value of 452.9 μl among all standard and tested drugs.Conclusion: All tested drugs had antileishmanial property but among them, betulinic acid possess strong antileishmanial activity in case of both wild-type and drug-resistant leishmaniasis.

АЛЛЕРГИЯ К ЛИМОНУ: ОПИСАНИЕ СЛУЧАЯ ОРАЛЬНОГО АЛЛЕРГИЧЕСКОГО СИНДРОМА В СОЧЕТАНИИ С АЛЛЕРГИЧЕСКИМ СРЕДНИМ ОТИТОМ И ЛАБИРИНТИТОМ У БОЛЬНОЙ С ПОЛИСЕНСИБИЛИЗАЦИЕЙ И МНОЖЕСТВЕННЫМИ ПРОЯВЛЕНИЯМИ АЛЛЕРГИИ

2019 ◽  
pp. 25-32
Author(s):  
O.S. Prilutskiy ◽  
Yu.A. Lyhina
Keyword(s):  
Drug Allergy ◽  
Allergic Rhinoconjunctivitis ◽  
Oral Allergy Syndrome ◽  
Plant Origin ◽  
Pollen Allergens ◽  
History Of ◽  
Skin Prick Tests ◽  
The Individual

Оральный аллергический синдром представляет собой IgEопосредованную аллергическую реакцию на продукты питания растительного происхождения у лиц с сенсибилизацией к различным пыльцевым аллергенам. Впервые описан клинический случай орального аллергического синдрома при употреблении в пищу лимона у женщины 25 лет. Кроме того, в анамнезе у больной зарегистрированы сезонный аллергический риноконъюнктивит, бронхиальная астма, контактный аллергический дерматит, проявления лекарственной аллергии в виде крапивницы, диареи и др. Установлена сенсибилизация ко многим группам аллергенов и наличие явлений аллергического среднего отита и вызванного аллергенами лабиринтита. Установлена целесообразность аллергенспецифической диагностики с использованием различных методов (лабораторных и прик, прикприктестов) для назначения индивидуальной диеты и гипоаллергенного режима.Oral allergic syndrome is an IgEmediated allergic reaction to foods of plant origin in persons with sensitization to various pollen allergens. A clinical case of oral allergy syndrome caused by consumption of lemon in a 25yearold woman with sensitization to many groups of allergens and presence of allergic otitis media and allergyinduced labyrinthitis is presented. The patient had a history of seasonal allergic rhinoconjunctivitis, bronchial asthma, contact allergic dermatitis, urticaria as a manifestation of drug allergy. In vivo (skin prick tests, prickprick tests) and in vitro allergen specific diagnostics allowed to work out the individual diet and a hypoallergenic regime in this case.

Fluorine-Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier (BBB) Penetration Property of Novel Central Nervous System (CNS)-targeting HIV-1 Protease Inhibitors In Vitro .

2022 ◽  
Author(s):  
Masayuki Amano ◽  
Ravikiran S. Yedidi ◽  
Pedro Miguel Salcedo-Gómez ◽  
Hironori Hayashi ◽  
Kazuya Hasegawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Blood Brain Barrier ◽  
Drug Resistant ◽  
Wild Type ◽  
Hiv 1 ◽  
Cns Targeting

To date, there are no specific treatment regimens for the HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). In the present study, we report that two newly generated CNS-targeting HIV-1 protease inhibitors (PIs), GRL-08513 and GRL-08613, which have P1-3,5- bis -fluorophenyl- or P1- para -monofluorophenyl-ring, and P2-tetrahydropyrano-tetrahydrofuran ( Tp -THF) with a sulfonamide isostere, are potent against wild-type HIV-1s and multiple clinically isolated HIV-1s (EC 50 : 0.0001∼0.0032 μM). As assessed with HIV-1 variants that had been selected in vitro to propagate at 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly-PI-resistant variants (EC 50 : 0.003∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activity against HIV-2 ROD as well as severe multi-drug-resistant clinical HIV-1 variants. Additionally, when we assessed with the in vitro blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS-penetration among the evaluated compounds including the majority of FDA-approved cART drugs. In the crystallographic analysis of compound-protease (PR) complexes, it was demonstrated that the Tp -THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen-bond interactions with the active-site of HIV-1 PR. Furthermore, both the P1-3,5- bis -fluorophenyl- and P1- para -monofluorophenyl-rings sustain greater contact surfaces and form stronger van der Waals interactions with PR compared to the case of darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for the patients infected with wild-type/multi-drug-resistant HIV-1s, and might serve as candidates of preventive and/or therapeutic for HAND and other CNS complications.

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