oseltamivir carboxylate
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2021 ◽  
pp. 35-42
Author(s):  
В.С. ШНАУКШТА ◽  
М.У. ДУЙСЕНОВА ◽  
А.М. ЕЛЬЖАСОВА

Разработана и валидирована методика количественного определения осельтамивира карбоксилат (OSTC) в плазме крови человека. Пробоподготовку проводили осаждением белков метанолом. Количественное определение OSTC проводили методом ВЭЖХ с масс-селективным детектором Triple Quad QQQ LС/MS. В качестве подвижной фазы использовали раствор: муравьиная кислота 0,1%- метанол c градиентным элюированием. Разработанная методика была валидирована по следующим валидационным параметрам: селективность, линейность, правильность, прецизионность, предел количественного определения, эффект переноса и стабильность растворов. Путем валидации доказана пригодность разработанной биоаналитической методики для фармакокинетических исследований. Полученный аналитический диапазон 10-1000 нг/мл позволяет применять методику для исследований биоэквивалентности.


2021 ◽  
Author(s):  
Rachel J. Hagey ◽  
Menashe Elazar ◽  
Siqi Tian ◽  
Edward A. Pham ◽  
Wipapat Kladwang ◽  
...  

Currently approved anti-influenza drugs target viral proteins, are subtype limited, and are challenged by rising antiviral resistance. To overcome these limitations, we sought to identify a conserved essential RNA secondary structure within the genomic RNA predicted to have greater constraints on mutation in response to therapeutics targeting this structure. Here, we identified and genetically validated an RNA stemloop structure we termed PSL2, which serves as a packaging signal for genome segment PB2 and is highly conserved across influenza A virus (IAV) isolates. RNA structural modeling rationalized known packaging-defective mutations and allowed for predictive mutagenesis tests. Disrupting and compensating mutations of PSL2's structure give striking attenuation and restoration, respectively, of in vitro virus packaging and mortality in mice. Antisense Locked Nucleic Acid oligonucleotides (LNAs) designed against PSL2 dramatically inhibit IAV in vitro against viruses of different strains and subtypes, possess a high barrier to the development of antiviral resistance, and are equally effective against oseltamivir carboxylate-resistant virus. A single dose of LNA administered 3 days after, or 14 days before, a lethal IAV inoculum provides 100% survival. Moreover, such treatment led to the development of strong immunity to rechallenge with a ten-fold lethal inoculum. Together, these results have exciting implications for the development of a versatile novel class of antiviral therapeutics capable of prophylaxis, post-exposure treatment, and 'just-in-time' universal vaccination against all IAV strains, including drug-resistant pandemics.


2021 ◽  
Vol 14 (4) ◽  
pp. 371
Author(s):  
Jiqing Ye ◽  
Lin Lin ◽  
Jinyi Xu ◽  
Paul Kay-sheung Chan ◽  
Xiao Yang ◽  
...  

Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate (OC) in complex with NA. In this study, a series of C-5-NH2-acyl derivatives of OC containing the pyrazole moiety were synthesized. Several derivatives exhibited substantial inhibitory activity against NA. Moreover, in silico ADME evaluation indicated that the derivatives were drug-like with higher oral absorption rates and greater cell permeability than OC. Additionally, molecular docking studies revealed that the derivatives interacted with both the NA enzyme active site and 150-cavity as expected. The results provided useful information for further structural optimization of OC.


2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Lei Zhao ◽  
Yunzheng Yan ◽  
Qingsong Dai ◽  
Xingzhou Li ◽  
Ke Xu ◽  
...  

ABSTRACT Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum antiviral potentials.


2020 ◽  
Vol 112 ◽  
pp. 104569
Author(s):  
Lucie Loukotková ◽  
Mallikarjuna Basavarajappa ◽  
Annie Lumen ◽  
Rosemary Roberts ◽  
Donald Mattison ◽  
...  

2019 ◽  
Vol 6 (10) ◽  
Author(s):  
Francisco Bautista ◽  
Dan Engelhard ◽  
Carmelo Rizzari ◽  
Margarita Baka ◽  
Jesús Saavedra-Lozano ◽  
...  

Abstract This randomized phase 1b study evaluated the pharmacokinetics/pharmacodynamics of conventional-dose (30–75 mg twice daily [BID]) vs triple-dose (90–225 mg BID; weight-adjusted) oseltamivir for treatment of influenza in severely immunocompromised children <13 years. Oseltamivir carboxylate (OC) Cmax and AUC0-12h were ~2-fold higher with triple-dose vs conventional-dose oseltamivir. Increased dose/exposure of oseltamivir/OC did not improve virological outcomes or reduce viral resistance. Median time to cessation of viral shedding was similar with triple-dose and conventional-dose oseltamivir (150.7 vs 157.1 hours, respectively); median time to alleviation of baseline fever was longer with conventional-dose oseltamivir (28.4 vs 11.3 hours). No new safety signals were identified.


Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2176 ◽  
Author(s):  
Yaping Hu ◽  
Binfeng Chen ◽  
Zaiqiang Lei ◽  
Hongqian Zhao ◽  
Hongxi Zhu ◽  
...  

A series of NH2-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC50 value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH2, was 3.50 μM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors.


2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Romain Carrez ◽  
Julien Brillault ◽  
Nicolas Grégoire ◽  
Isabelle Lamarche ◽  
Julian Laroche ◽  
...  

ABSTRACT The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure of the active moiety at the infection site within lung.


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