Disease relevance of GS-4104

• CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza [1].
• Secondary complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of combined oseltamivir recipients (P = .03) [2].
• These results indicate that oseltamivir has significant antiviral activity in experimental human influenza B virus infection when used for prophylaxis or early treatment [3].
• Three randomized, double-blind, placebo-controlled, parallel-group studies evaluated oral oseltamivir for early treatment (75 or 150 mg twice daily for 5 days) or prevention (75 mg once or twice daily for 7 days) of experimental influenza B virus infection in healthy susceptible adults [3].
• Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir [4].

Psychiatry related information on GS-4104

• For the treatment of ferrets inoculated with the less pathogenic A/Turkey/15/06 (H5N1) virus, 10 mg/kg/day of oseltamivir was sufficient to reduce the lethargy of the animals, significantly inhibit inflammation in the upper respiratory tract, and block virus spread to the internal organs [5].

High impact information on GS-4104

• Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza [6].
• Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy (95% CI, 57%-95%; P<.001) [7].
• Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo (7.2%) recipients [7].
• Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment [1].
• Zanamivir is delivered by inhalation because of its low oral bioavailability whereas oseltamivir is administered by mouth [8].

Chemical compound and disease context of GS-4104

• The influenza virus neuraminidase (NA) inhibitors zanamivir and oseltamivir were introduced into clinical practice in various parts of the world between 1999 and 2002 [9].
• These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans [10].
• The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses [11].
• An ethyl ester prodrug of GS4071, GS4104, has exhibited good oral bioavailability in rat, mouse, and dog models and is currently being developed for the treatment of influenza A and B virus infections [12].
• Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection [13].

Biological context of GS-4104

• In prevention study C (n=58), oseltamivir did not reduce infection rates (85 versus 84%) but significantly reduced median AUC virus titre (10.0 versus 66.9 log10 TCID50 x h/ml; P=0.03) and duration of viral shedding (36 versus 84 h; P=0.03) compared with placebo [3].
• Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802 [14].
• The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80% [14].
• Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice [15].
• In these preclinical toxicology studies, the dose of oseltamivir exceeded that which would be used in humans [16].

Anatomical context of GS-4104

• Since influenza virus replicates primarily in the surface epithelial cells of the respiratory tract, the ability of the prodrug to deliver GS4071 to the bronchoalveolar lining fluid (BALF) following an oral dose of GS4104 should be an important indicator of its potential efficacy [12].
• In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity [17].
• The sensitivity of viruses to oseltamivir correlated with the sensitivity of viral sialidase to the compound, demonstrating the potential utility of this modified cell line for detecting NA inhibitor-resistant viruses [18].
• Liver microsomes rapidly hydrolyzed oseltamivir, but no hydrolysis was detected with intestinal microsomes or plasma [19].
• However, omega-hydroxylated products of oseltamivir were produced by rat liver microsomes [20].

Associations of GS-4104 with other chemical compounds

• In the presence of antiplatelet agent clopidogrel, the hydrolysis of oseltamivir was inhibited by as much as 90% when the equal concentration was assayed [19].
• DATA SOURCES: Computer-assisted MEDLINE searches for article and manual searches of conference proceedings on influenza, influenza vaccination, rimantadine, amantadine, oseltamivir, zanamivir, asthma, and/or COPD [21].
• The emergence of resistance to adamantanes (amantadine and rimantadine) and recently oseltamivir while H5N1 vaccines are still at the developmental stage of phase I clinical trial are causes for grave concern [22].
• RESULTS: Bioequivalence was achieved for the primary pharmacokinetic parameters Cmax and AUC(0, infinity ) of Ro 64-0802 following administration of oseltamivir with either Maalox suspension or Titralac(R) tablets vs administration of oseltamivir alone [23].
• The influenza neuraminidase (NA) inhibitors peramivir, oseltamivir, and zanamivir are potent inhibitors of NAs from both influenza A and B strains [24].

Gene context of GS-4104

• The commercial NA inhibitor oseltamivir had a similar effect and also enhanced the neutralizing activity of SP-A and bronchoalveolar lavage fluid [25].
• RAW 264.7 macrophages were exposed to interferon-gamma (IFN-gamma), live influenza (A/PR/8/34) or a combination of both and were treated with NIs (oseltamivir or zanamivir) [26].
• Administration of the selective NA inhibitor oseltamivir improved survival, independent of viral replication and morbidity from influenza [27].
• Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104 [12].
• Quantification of the influenza virus load by real-time polymerase chain reaction in nasopharyngeal swabs of patients treated with oseltamivir [28].

Analytical, diagnostic and therapeutic context of GS-4104

• Cohort eligibility criteria included minimum baseline enrolment duration of 3 months, age of at least 1 year and no influenza vaccination on the date of influenza diagnosis or oseltamivir dispensing [29].
• Skin reactions in patients with influenza treated with oseltamivir: a retrospective cohort study [29].
• In contrast, among subjects with an influenzalike illness but without a confirmed influenza infection, the incidence of LRTCs (6.7% vs 5.3%), overall antibiotic use (19.7% vs 19.3%), or hospitalizations (1.7% vs 1.9%) was similar between placebo and oseltamivir recipients, respectively [30].
• Oseltamivir 75 mg twice daily for 5 days was well tolerated in clinical trials in healthy adults and high-risk patients, with nausea and vomiting being the most commonly reported events [31].
• Prophylactic oral administration of oseltamivir was effective in reducing the incidence of influenza illness according to pooled data from 2 large placebo-controlled, double-blind trials of healthy nonimmunised volunteers during periods of seasonal influenza activity [32].

References