Implications of the Conformationally Flexible, Macrocyclic Structure of the First-Generation, Direct-Acting Anti-Viral Paritaprevir on Its Solid Form Complexity and Chameleonic Behavior

2021 ◽  
Author(s):  
Ahmad Y. Sheikh ◽  
Alessandra Mattei ◽  
Rajni Miglani Bhardwaj ◽  
Richard S. Hong ◽  
Nathan S. Abraham ◽  
...  
Keyword(s):  
First Generation ◽  
Direct Acting ◽  
Solid Form ◽  
Macrocyclic Structure

When Coadministration Cannot Be Avoided: Real World Experience of Direct Acting Antivirals for the Treatment of Hepatitis C Virus Infection in Patients on First Generation Anticonvulsants

2020 ◽  
pp. 089719002097776
Author(s):  
Kayla M. Natali ◽  
Humberto R. Jimenez ◽  
Jihad Slim
Keyword(s):  
Drug Interaction ◽  
Hepatitis C ◽  
Clinical Cure ◽  
First Generation ◽  
Virologic Response ◽  
Hcv Infection ◽  
Direct Acting Antivirals ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Direct Acting

Background Coadministration of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection and first generation anticonvulsants is currently not recommended due to a drug-drug interaction that could potentially lead to subtherapeutic DAA levels and subsequent treatment failure. Currently, there is limited data evaluating this interaction and timely treatment of HCV infection with DAAs is imperative to prevent liver-related morbidity and mortality. Methods A retrospective case series evaluating clinical cure of chronic HCV infection, defined as sustained virologic response (SVR) 12 weeks after completion of DAA therapy, in patients from three inner-city clinics who remained on first generation anticonvulsants during the treatment course. Results A total of five patients received standard dose DAAs for treatment of chronic HCV infection while being maintained on first generation anticonvulsants. The most common HCV genotype was 1a (80%), followed by 1b (20%). The majority of patients were treated with glecaprevir/pibrentasvir (80%) for eight weeks and one patient was treated with ledipasvir/sofosbuvir for 12 weeks. Anticonvulsant regimens consisted of carbamazepine, phenytoin, phenytoin plus phenobarbital, phenytoin plus levetiracetam, and phenobarbital plus lacosamide. All five patients achieved sustained virologic response (SVR) despite this drug-drug interaction. Conclusion Although every effort to prevent concomitant use of DAAs and potent inducers should be made, clinical cure may still be achieved in patients whom cannot avoid this coadministration.

Triple-therapy with first generation direct-acting antivirals: The cure of hepatitis C in HIV-positive patients?

2013 ◽  
Vol 51 (05) ◽  
Author(s):  
A Niedrecker ◽  
M Mandorfer ◽  
T Reiberger ◽  
BA Payer ◽  
M Peck-Radosavljevic
Keyword(s):  
Hepatitis C ◽  
Triple Therapy ◽  
First Generation ◽  
Hiv Positive ◽  
Direct Acting Antivirals ◽  
Direct Acting

scholarly journals Primary Care-Based Hepatitis C Treatment Outcomes With First-Generation Direct-Acting Agents

2015 ◽  
Vol 9 (5) ◽  
pp. 405-410 ◽  
Author(s):  
Christopher Woodrell ◽  
Jeffrey Weiss ◽  
Andrea Branch ◽  
Donald Gardenier ◽  
Katherine Krauskopf ◽  
...  
Keyword(s):  
Primary Care ◽  
Hepatitis C ◽  
Treatment Outcomes ◽  
First Generation ◽  
Hepatitis C Treatment ◽  
Direct Acting

scholarly journals Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

2021 ◽  
Vol 12 ◽  
Author(s):  
Adam B. Shapiro ◽  
Samir H. Moussa ◽  
Sarah M. McLeod ◽  
Thomas Durand-Réville ◽  
Alita A. Miller
Keyword(s):  
First Generation ◽  
Multidrug Resistant ◽  
Class A ◽  
Carbapenem Resistant ◽  
Medical Need ◽  
Spectrum Activity ◽  
Resistant Strains ◽  
Direct Acting ◽  
Lactamase Inhibitor ◽  
Broad Spectrum Activity

Durlobactam is a new member of the diazabicyclooctane class of β-lactamase inhibitors with broad spectrum activity against Ambler class A, C, and D serine β-lactamases. Sulbactam is a first generation β-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam’s ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. This sulbactam-durlobactam combination is currently in late-stage development for the treatment of Acinectobacter infections, including those caused by carbapenem-resistant isolates, for which there is a high unmet medical need. The following mini-review summarizes the molecular drivers of efficacy of this combination against this troublesome pathogen, with an emphasis on the biochemical features of each partner.

From first-generation hepatitis C virus protease inhibitors to direct-acting antivirals

2016 ◽  
Vol 28 (6) ◽  
pp. 733-734 ◽  
Author(s):  
Fabienne Marcellin ◽  
Isabelle Fournier ◽  
Maria P. Carrieri ◽  
Isabelle Poizot-Martin ◽  
Laurent Cotte
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
First Generation ◽  
Direct Acting Antivirals ◽  
Direct Acting

A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben

2015 ◽  
Vol 156 (21) ◽  
pp. 849-854 ◽  
Author(s):  
István Tornai
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
First Generation ◽  
Pegylated Interferon ◽  
Direct Acting Antivirals ◽  
Direct Acting Antiviral ◽  
Genotype 1A ◽  
Direct Acting ◽  
Ns5b Polymerase

The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40–50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy. Orv. Hetil., 2015, 156(21), 849–854.

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