Inhibitors Oseltamivir Research Articles

Efficacy and safety of zanamivir in patients with influenza--impact of age, severity of infections and specific risk factors.

Influenza infections occur primarily in the winter season and may lead to serious morbidity and mortality, predominantly in patients with increased risk of complications; these include those with advanced age or with chronic clinical conditions. In this group, the rate of influenza-related hospitalization or death is considerably increased. New treatment options have been introduced for treatment of influenza infection, with the neuraminidase inhibitors zanamivir and oseltamivir being the most promising substances for treatment and prevention of influenza. Numerous double-blind, randomized, placebo-controlled trials in otherwise healthy individuals have demonstrated that zanamivir, when administered orally inhaled for 5 days, produced a statistically significant reduction (by 1.5 days) in the time to alleviation of influenza-related symptoms by compared to inhaled placebo (lactose). The time to alleviation was reduced by 2.5 days in high-risk patients and by 3.25 days in these patients with fever at enrollment. Likewise, the time to alleviation could be reduced by 2 days in patients with severe influenza-related symptoms aged under 50 years and by 7 days in the patient population aged over 50 years compared to placebo. In patients with asthma or chronic pulmonary disease, zanamivir demonstrated a comparable efficacy, reduced the rate of pulmonary complications and did not adversely affect pulmonary function. Zanamivir was well tolerated. In conclusion, zanamivir has proven to be efficacious in treating influenza infection: this was true especially in high-risk patient groups, e.g., patients with advanced age, underlying chronic medical conditions or presenting with severe influenza-related symptoms.

The management of influenza in people of working age.

Influenza is common, causing considerable morbidity and sickness absence from work in most winters. Influenza vaccines have been available for >40 years, but are not extensively used in the workforce (in the UK). Amantadine has been available for 25 years as a treatment and prophylactic against influenza A infection, but has scarcely been used. In the last 3 years, two neuraminidase inhibitor antivirals, zanamivir and oseltamivir, have been introduced to the market for the treatment and prophylaxis of influenza A and B infections. This review focuses on aspects of prevention and treatment of influenza appropriate to people of working age. Decisions based on the cost-effectiveness of prevention and treatment options differ when viewed from the perspective of the healthcare provider, the employer or the employee. Options currently available need to be directed to a wider range of people than those conventionally regarded as the target risk group.

Management of viral infections in immunocompromised cancer patients.

Immunocompromised cancer patients are at elevated risk for serious viral disease. The introduction into clinical use of potent antiviral agents and of rapid diagnostic tests resulted in the development of efficient management strategies for infections due to herpes simplex virus, varicellazoster virus, and cytomegalovirus. The emergence of herpesvirus resistance to acyclovir, ganciclovir, cidofovir, or foscarnet represents an important challenge. The new neuraminidase inhibitors zanamivir and oseltamivir are efficacious in the treatment of influenza in otherwise healthy adults, and need to be investigated among immunodeficient patients with malignancy. Preliminary data on pleconaril, a first broad-spectrum anti-picornaviral compound, are promising.

Management of viral infections in immunocompromised cancer patients.

Immunocompromised cancer patients are at elevated risk for serious viral disease. The introduction into clinical use of potent antiviral agents and of rapid diagnostic tests resulted in the development of efficient management strategies for infections due to herpes simplex virus, varicellazoster virus, and cytomegalovirus. The emergence of herpesvirus resistance to acyclovir, ganciclovir, cidofovir, or foscarnet represents an important challenge. The new neuraminidase inhibitors zanamivir and oseltamivir are efficacious in the treatment of influenza in otherwise healthy adults, and need to be investigated among immunodeficient patients with malignancy. Preliminary data on pleconaril, a first broad-spectrum anti-picornaviral compound, are promising.

Advances in the Diagnosis and Management of Influenza.

Vaccines are the mainstay of influenza prevention. In the treatment of a likely or certain case of influenza, ion channel inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) can be effective in reducing the duration of illness in adults. In the absence of a likely or certain influenza diagnosis, ion channel inhibitors or neuramindase inhibitors have lower effectiveness, and symptom relief becomes the rationale for treatment of influenza-like illness. Because both influenza and influenzalike illness are self-limiting, safety of interventions is paramount, especially in children. Echinacea extracts, steam, chicken soup, ipatropium bromide, and oxymetazoline in adults are the interventions that appear to have the best empirical evidence.

Challenges and options in the management of viral infections after stem cell transplantation.

During the period of profound combined immunodeficiency after bone marrow or peripheral blood stem cell transplantation (SCT), patients are at increased risk for serious viral disease. Recent advances in rapid diagnostic methods and the introduction of potent antiviral compounds have made it possible to establish efficient management strategies for several herpesviruses. Acyclovir, valaciclovir, and famciclovir are widely used for the treatment of herpes simplex virus or varicella zoster virus disease. Intravenous ganciclovir, foscarnet, and cidofovir are available for prevention or therapy of cytomegalovirus disease, and oral valganciclovir could become a valuable alternative to intravenous treatment if shown to be effective and safe after SCT. Preliminary data on pleconaril for therapy of picornaviral disease are promising. Future investigations may help to clarify the role of the neuraminidase inhibitors zanamivir and oseltamivir in the management of influenza in SCT recipients. The emergence of viruses resistant to antiviral drugs is of concern, and alternative treatment strategies need to be defined.

Neuraminidase inhibitors in patients with underlying airways disease.

Influenza virus infection accounts for significant morbidity, mortality, and healthcare expenditures among persons worldwide. Approximately 20,000 to 40,000 people in the US die each year as a result of influenza. Individuals most susceptible to adverse outcomes include the elderly and those with asthma, chronic obstructive pulmonary disease (COPD), heart disease, renal failure, malignancy, or immunosuppression. Prior to the AIDS epidemic, underlying respiratory disease was the greatest risk factor for influenza-related hospitalization ranking third to heart disease and malignancy for risk of mortality. Although the influenza vaccine can help prevent pneumonia and hospitalization, it is limited by less than ideal immunization rates and the possibility of viral antigenic shifts that render the vaccine ineffective. Pharmacologic interventions play an important role in the management of influenza virus infection by shortening the duration of symptoms. The advent of the neuraminidase inhibitors (NAIs) zanamivir and oseltamivir has significantly affected the treatment of influenza. Unlike NAIs, the older therapeutic options amantadine and rimantadine may cause significant central nervous system adverse effects. In addition, amantadine and rimantadine are not active against influenza B viruses, whereas NAIs are active against both influenza A and B. Post-marketing surveillance of the NAIs has revealed that bronchospasm may occur in patients with underlying respiratory disease treated with the NAI zanamivir. Recent data suggest zanamivir is effective in patients with underlying respiratory disease, but the data are insufficient to elucidate the true risk of bronchospasm. Based on post-marketing reports, zanamivir should be used with caution in patients with asthma or COPD. Although oseltamivir has not been associated with any significant respiratory adverse effects, no data exist on the safety and efficacy of this NAI in patients with underlying respiratory disease.

Cost-effectiveness of vaccination versus treatment of influenza in healthy adolescents and adults.

At present time, there is uncertainty regarding whether influenza-like illness in healthy adults is best managed by preventive efforts that use the trivalent influenza vaccine, administration of neuraminidase inhibitors at the onset of illness, or recommendation of supportive care alone at the onset of illness. We conducted a cost-effectiveness analysis that examined these 3 strategies for managing influenza-like illness. Vaccination with inactivated trivalent vaccine would save approximately 25 dollars per person while resulting in a net gain of approximately 3.2 quality-adjusted hours relative to providing treatment with the neuraminidase inhibitor oseltamivir. A quality-adjusted hour is a fraction of a quality-adjusted life-year, which is the equivalent of 1 year lived in perfect health. Treatment with oseltamivir was associated with an incremental cost-effectiveness of approximately 27,619 dollars per quality-adjusted life-year gained relative to providing supportive care. Vaccination is cost-saving relative to providing either treatment with oseltamivir or providing supportive care alone.

New modalities for preventing and treating influenza

Influenza continues to plague children and adults annually, causing moderate to severe disease and, in some cases, leading to death caused by primary or secondary infection. New epidemiologic studies confirm that the impact of influenza on children is great. Public health officials expect a pandemic that is likely to dramatically increase the morbidity and mortality from influenza. New modalities that have arisen for prevention and treatment include the cold-adapted nasal vaccine and new neuraminidase inhibitors (oseltamivir and zanamivir), which have been approved for use in children. Like older agents (amantadine and rimantadine), the neuraminidase receptor agents must be used within the first 2 days of illness to be effective for therapy. Correct and early diagnosis is, therefore, necessary. The greatest advantages of newer agents are the additional efficacy against influenza B virus and the low frequency of drug resistance. Shortened illness and a reduction in minor complications are the main observed benefits of therapy. Because new agents are much more expensive than are older ones, dynamic cost-benefit analysis specific for children is needed to determine the utility of these drugs. Vaccination remains the most cost-effective approach to influenza disease. Universal vaccination of children remains a consideration for the future. Copyright © 2001 by W.B. Saunders Company

Antiviral agents for influenza, hepatitis C and herpesvirus, enterovirus and rhinovirus infections.

Advances in antiviral therapy have involved both development of new, effective drugs and modification of pre-existing drugs or regimens to increase effectiveness. New agents against influenza virus are the neuraminidase inhibitors zanamivir and oseltamivir, which target specific viral processes and have minimal side effects. New agents for herpesviruses (famciclovir, valaciclovir, valganciclovir) have greater oral bioavailability, allowing less frequent dosing, but mechanisms of action are similar to older agents (aciclovir, ganciclovir). Pleconaril has some activity against enteroviruses and is available for compassionate use in meningitis; it also shows some efficacy against rhinoviruses in ongoing trials, but is not available for routine clinical use. Hepatitis C treatment efficacy has improved dramatically with the introduction of combination interferon-ribavirin therapy, with sustained-response rates up to 60%.

New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu).

A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr(2).OEt(2) as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.

Comparative study of nasopharyngeal aspirate and nasal swab specimens for detection of influenza

The neuraminidase inhibitors zanamivir and oseltamivir have been shown to be effective in the treatment of influenza A and B viral infections. Both of these drugs are ineffective against respiratory...

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60 The neuraminidase inhibitor oseltamivir is efficacious against A/Hong Kong/156/97 (H5N1) and H9N2 influenza viruses : I. A. Leneva 1,4, N. Roberts 2, R. G. Webster 1,3 1Department of Virology/Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, 2Roche Discovery Welwyn, Roche Products Ltd., Welwyn Garden City AL73AY, UK, 3Department of Pathology, University, of Tennessee, Memphis, Tennessee 38105, 4Department

60 The neuraminidase inhibitor oseltamivir is efficacious against A/Hong Kong/156/97 (H5N1) and H9N2 influenza viruses : I. A. Leneva 1,4, N. Roberts 2, R. G. Webster 1,3 1Department of Virology/Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, 2Roche Discovery Welwyn, Roche Products Ltd., Welwyn Garden City AL73AY, UK, 3Department of Pathology, University, of Tennessee, Memphis, Tennessee 38105, 4Department

Antiviral agents for treating influenza.

The new neuraminidase inhibitors zanamivir and oseltamivir are important additions to the treatment of influenza, being the first class of agents active against both influenza A and influenza B. The decision to use these agents rather than amantadine or rimantadine, which are effective only against influenza A, should be based on the age of the patient, antiviral activity, side effect profile, ease of administration, drug interactions, and cost. All of these agents are effective only when started within 24 to 48 hours of onset of symptoms. To avoid inappropriate use of these agents, treatment should be continued only in patients with a confirmed diagnosis of influenza. Although effective in decreasing symptoms, none of these agents prevent pneumonia or hospitalization secondary to influenza.

00/00577 Effect of component changes to system energy performance

Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs.As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season.Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis.

The Comparative Pharmacokinetics and Safety of the Oral Neuraminidase Inhibitor Oseltamivir when Given in Multiple Doses to Healthy Japanese and Caucasian Subjects.

The Comparative Pharmacokinetics and Safety of the Oral Neuraminidase Inhibitor Oseltamivir when Given in Multiple Doses to Healthy Japanese and Caucasian Subjects.