Is oseltamivir effective in the treatment of influenza A (H1N1)?
Results: Among 3230 RT-PCR-positive patients, 2316 had influenza A of whom 1216 received oseltamivir monotherapy within 2 days of symptom onset (9 seasonal H1N1; 662 H3N2; 545 H1N1pdm2009). Except for 9 patients with naturally resistant seasonal H1N1 (2008/9), no resistance was detected in Day 1 samples.
Is H1N1 resistant to amantadine?
H1N1 virus is considered to be resistant to M2 inhibitors (amantadine and rimantadine) while it is sensitive to neuraminidase inhibitors (oseltamivir and zanamivir).[8–10] During H5N1 (2005) and H1N1 (2009) outbreaks neither amantadine nor rimantadine could be used due to resistance.
What are the references for human influenza A H5N1?
References 1. Lewis DB. Avian flu to human influenza. Annu Rev Med. 2006;57:139–54. [PubMed] [Google Scholar] 2. Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 1998;351:472–7. [PubMed] [Google Scholar] 3.
Does oseltamivir cause respiratory distress?
However, in patients within the study group, psychiatric problems were observed in 7.5% of those who received oseltamivir and 5% of those who received zanamivir. While respiratory distress was not observed in those who used oseltamivir, it was seen in 12.5% of the zanamivir group (P< 0.05).
Where did H5N1 virus spread?
The spread of A (H5N1) virus infection was most extensive in the lungs of control animals ( Fig. 3A ), which were characterized by extensive inflammation and necrosis of the bronchiolar epithelium, perivascular and peribronchiolar inflammation and edema and the destruction and loss of type II pneumocytes in the alveoli. In the control lungs, a broad zone of strongly positive type II pneumocytes along the leading edge of lesions represented recently and actively infected alveoli. In animals that received oseltamivir, the extent and severity of the lesions and active infection were moderately reduced when treatment was initiated at 48 hpi ( Fig. 3B ). Viral antigen–positive type II pneumocytes were abundant at the periphery of lesions when treatment was initiated at 48 or 72 hpi but were spread throughout lesions when treatment was delayed until 96 or 120 hpi. In mice that received T-705 at 48 or 72 hpi ( Fig. 3F,G ), the pulmonary lesions were mild to moderate, with virus–positive cells scattered throughout the affected areas. The zone of strongly positive type II pneumocytes along the leading edge of lesions was narrow in lungs when T-705 treatment was initiated at 48 or 72 hpi, but it was characterized by broad leading edges containing abundant antigen-positive cells when treatment was delayed until 96 or 120 hpi. In contrast, combination therapy with oseltamivir and T-705 markedly reduced the extent and severity of pulmonary damage resulting from A (H5N1) virus infection when treatment was initiated at 48 hpi and caused only mild to moderate lesions when treatment was initiated at 72, 96, or 120 hpi ( Fig. 3K–M ). The lungs of mice receiving combination therapy did not have a zone of strongly positive type II pneumocytes adjacent to the leading edge of lesions, indicating the absence of recently infected cells.
Is oseltamivir effective against HPAI?
This study is the first to investigate the efficacy of combination therapy with oseltamivir and T-705 against HPAI A (H5N1) virus infection, and, more importantly, the potential of combination therapy to extend the treatment window when treatment is delayed by up to 120 hpi. Although various antiviral agents have been used in combination with NAIs (e.g., amantadine, rimantadine, ribavirin, human IFN-α, plant extracts and others) for different subtypes of influenza viruses 42, including the HPAI A (H5N1) viruses 17, 43, the major drawback of these studies has been the use of non–FDA-approved drugs (ribavirin, human IFN-α, plant extracts) and the high frequency of resistance to other compounds (amantadine, rimantadine) among circulating human viruses 17, 43. The development of T-705 presented an opportunity to use it in a combination therapy regimen. In murine lethal-infection models, T-705 showed strong efficacy against a variety of influenza viruses, including A (H5N1) viruses 21, 23, 44, 45, 46, with treatment being delayed by up to 72 hpi 21 and the efficacy of combined oseltamivir and T-705 against several strains of seasonal influenza viruses as well as mouse-adapted low pathogenic A (H5N1) influenza virus was also investigated in mice 23, 47. Extending the treatment window is important if patients admitted to hospital more than 48 h after the onset of symptoms are to be successfully treated and administering suboptimal doses of drug combinations, as opposed to the optimal dose of a single drug, may not only inhibit virus replication but also reduce the possibility of drug side effects, e.g., by decreasing the mitochondrial toxicity associated with nucleoside analogs 48, 49.
Abstract
Oseltamivir and zanamivir are currently licensed worldwide for influenza treatment and chemoprophylaxis. Both drugs require twice-daily administration for 5 days for treatment.
Introduction
Influenza is a serious respiratory illness, which can be debilitating, and could cause complications that lead to hospitalization and death, especially in elderly individuals. This respiratory disease is caused by influenza A and B viruses, which are pathogens that are highly contagious among humans.
Compound
Laninamivir (R-125489) is a potent NA inhibitor of various influenza viruses. Its chemical structure is ( 2R,3R,4S )-3-acetamido-2- [ ( 1R,2R )-2,3-dihydroxy-1-methoxypropyl]-4-guanidino-3,4-dihydro-2 H -pyran-6-carboxylic acid, as shown in Figure 2 [ 29 ]. It demonstrated a prolonged survival effect in a mouse infection model with influenza virus.
In vitro activities
A summary of NA inhibitory activities is shown in Table 1. Laninamivir had potent inhibitory activity to NAs of various influenza viruses, such as the seasonal H1N1 [ 29 ], pandemic (2009) H1N1 [ 4 ], H3N2 [ 29 ], HPAI H5N1 viruses [ 33] and influenza B viruses [ 29 ].
In vivo efficacy
In vitro inhibitory activities of laninamivir were not largely different from those of two other NA inhibitors. However, octanoyl laninamivir, CS-8958, showed good efficacy by a single intranasal administration in an animal infection model.
Two unique characteristics of CS-8958 and laninamivir as a long-acting drug
The therapeutic and prophylactic efficacies achieved after the single intranasal administration of CS-8958 could be a result of the unique characteristics of the compounds described below.
Clinical studies
The next important point is to confirm whether the long-lasting characteristic of laninamivir after a single intranasal administration of CS-8958 observed in animals is applicable to humans or not.
