- •Global Impact
- •Epidemics and Pandemics
- •Current Situation
- •Individual Impact
- •The Virus
- •Requirements for Success
- •Virology
- •Natural Reservoir + Survival
- •Transmission
- •H5N1: Making Progress
- •Individual Management
- •Epidemic Prophylaxis
- •Exposure Prophylaxis
- •Vaccination
- •Antiviral Drugs
- •Epidemic Treatment
- •Pandemic Prophylaxis
- •Pandemic Treatment
- •Global Management
- •Epidemic Management
- •Pandemic Management
- •Containment
- •Drugs
- •Vaccines
- •Distribution
- •Conclusion
- •Golden Links
- •Interviews
- •References
- •Avian Influenza
- •The Viruses
- •Natural hosts
- •Clinical Presentation
- •Pathology
- •LPAI
- •HPAI
- •Differential Diagnosis
- •Laboratory Diagnosis
- •Collection of Specimens
- •Transport of Specimens
- •Diagnostic Cascades
- •Direct Detection of AIV Infections
- •Indirect Detection of AIV Infections
- •Transmission
- •Transmission between Birds
- •Poultry
- •Humans
- •Economic Consequences
- •Control Measures against HPAI
- •Vaccination
- •Pandemic Risk
- •Conclusion
- •References
- •Structure
- •Haemagglutinin
- •Neuraminidase
- •M2 protein
- •Possible function of NS1
- •Possible function of NS2
- •Replication cycle
- •Adsorption of the virus
- •Entry of the virus
- •Uncoating of the virus
- •Synthesis of viral RNA and viral proteins
- •Shedding of the virus and infectivity
- •References
- •Pathogenesis and Immunology
- •Introduction
- •Pathogenesis
- •Viral entry: How does the virion enter the host?
- •Binding to the host cells
- •Where does the primary replication occur?
- •How does the infection spread in the host?
- •What is the initial host response?
- •Cytokines and fever
- •Respiratory symptoms
- •Cytopathic effects
- •Symptoms of H5N1 infections
- •How is influenza transmitted to others?
- •Immunology
- •The humoral immune response
- •The cellular immune response
- •Conclusion
- •References
- •Pandemic Preparedness
- •Introduction
- •Previous Influenza Pandemics
- •H5N1 Pandemic Threat
- •Influenza Pandemic Preparedness
- •Pandemic Phases
- •Inter-Pandemic Period and Pandemic Alert Period
- •Surveillance
- •Implementation of Laboratory Diagnostic Services
- •Vaccines
- •Antiviral Drugs
- •Drug Stockpiling
- •General Measures
- •Seasonal Influenza Vaccination
- •Political Commitment
- •Legal and Ethical Issues
- •Funding
- •Global Strategy for the Progressive Control of Highly Pathogenic Avian Influenza
- •Pandemic Period
- •Surveillance
- •Treatment and Hospitalisation
- •Human Resources: Healthcare Personnel
- •Geographically Targeted Prophylaxis and Social Distancing Measures
- •Tracing of Symptomatic Cases
- •Border Control
- •Hygiene and Disinfection
- •Risk Communication
- •Conclusions
- •References
- •Introduction
- •Vaccine Development
- •History
- •Yearly Vaccine Production
- •Selection of the yearly vaccine strain
- •Processes involved in vaccine manufacture
- •Production capacity
- •Types of Influenza Vaccine
- •Killed vaccines
- •Live vaccines
- •Vaccines and technology in development
- •Efficacy and Effectiveness
- •Side Effects
- •Recommendation for Use
- •Indications
- •Groups to target
- •Guidelines
- •Contraindications
- •Dosage / use
- •Inactivated vaccine
- •Live attenuated vaccine
- •Companies and Products
- •Strategies for Use of a Limited Influenza Vaccine Supply
- •Antigen sparing methods
- •Rationing methods and controversies
- •Pandemic Vaccine
- •Development
- •Mock vaccines
- •Production capacity
- •Transition
- •Solutions
- •Strategies for expediting the development of a pandemic vaccine
- •Enhance vaccine efficacy
- •Controversies
- •Organising
- •The Ideal World – 2025
- •References
- •Useful reading and listening material
- •Audio
- •Online reading sources
- •Sources
- •Laboratory Findings
- •Introduction
- •Laboratory Diagnosis of Human Influenza
- •Appropriate specimen collection
- •Respiratory specimens
- •Blood specimens
- •Clinical role and value of laboratory diagnosis
- •Patient management
- •Surveillance
- •Laboratory Tests
- •Direct methods
- •Immunofluorescence
- •Enzyme immuno assays or Immunochromatography assays
- •Reverse transcription polymerase chain reaction (RT-PCR)
- •Isolation methods
- •Embryonated egg culture
- •Cell culture
- •Laboratory animals
- •Serology
- •Haemagglutination inhibition (HI)
- •Complement fixation (CF)
- •Ezyme immuno assays (EIA)
- •Indirect immunofluorescence
- •Rapid tests
- •Differential diagnosis of flu-like illness
- •Diagnosis of suspected human infection with an avian influenza virus
- •Introduction
- •Specimen collection
- •Virological diagnostic modalities
- •Other laboratory findings
- •New developments and the future of influenza diagnostics
- •Conclusion
- •Useful Internet sources relating to Influenza Diagnosis
- •References
- •Clinical Presentation
- •Uncomplicated Human Influenza
- •Complications of Human Influenza
- •Secondary Bacterial Pneumonia
- •Primary Viral Pneumonia
- •Mixed Viral and Bacterial Pneumonia
- •Exacerbation of Chronic Pulmonary Disease
- •Croup
- •Failure of Recovery
- •Myositis
- •Cardiac Complications
- •Toxic Shock Syndrome
- •Reye’s Syndrome
- •Complications in HIV-infected patients
- •Avian Influenza Virus Infections in Humans
- •Presentation
- •Clinical Course
- •References
- •Treatment and Prophylaxis
- •Introduction
- •Antiviral Drugs
- •Neuraminidase Inhibitors
- •Indications for the Use of Neuraminidase Inhibitors
- •M2 Ion Channel Inhibitors
- •Indications for the Use of M2 Inhibitors
- •Treatment of “Classic” Human Influenza
- •Antiviral Treatment
- •Antiviral Prophylaxis
- •Special Situations
- •Children
- •Impaired Renal Function
- •Impaired Liver Function
- •Seizure Disorders
- •Pregnancy
- •Treatment of Human H5N1 Influenza
- •Transmission Prophylaxis
- •General Infection Control Measures
- •Special Infection Control Measures
- •Contact Tracing
- •Discharge policy
- •Global Pandemic Prophylaxis
- •Conclusion
- •References
- •Drug Profiles
- •Amantadine
- •Pharmacokinetics
- •Toxicity
- •Efficacy
- •Resistance
- •Drug Interactions
- •Recommendations for Use
- •Warnings
- •Summary
- •References
- •Oseltamivir
- •Introduction
- •Structure
- •Pharmacokinetics
- •Toxicity
- •Efficacy
- •Treatment
- •Prophylaxis
- •Selected Patient Populations
- •Efficacy against Avian Influenza H5N1
- •Efficacy against the 1918 Influenza Strain
- •Resistance
- •Drug Interactions
- •Recommendations for Use
- •Summary
- •References
- •Rimantadine
- •Introduction
- •Structure
- •Pharmacokinetics
- •Toxicity
- •Efficacy
- •Treatment
- •Prophylaxis
- •Resistance
- •Drug Interactions
- •Recommendations for Use
- •Adults
- •Children
- •Warnings
- •Summary
- •References
- •Zanamivir
- •Introduction
- •Structure
- •Pharmacokinetics
- •Toxicity
- •Efficacy
- •Treatment
- •Prophylaxis
- •Children
- •Special Situations
- •Avian Influenza Strains
- •Resistance
- •Drug Interactions
- •Recommendations for Use
- •Dosage
- •Summary
- •References
194 Drug Profiles
18.Reuman PD, Bernstein DI, Keefer MC, Young EC, Sherwood JR, Schiff GM. Efficacy and safety of low dosage amantadine hydrochloride as prophylaxis for influenza A. Antiviral Res 1989; 11: 27-40. Abstract: http://amedeo.com/lit.php?id=2712549
19.Sears SD, Clements ML. Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus. Antimicrob Agents Chemother 1987; 31: 1470-3. Abstract: http://amedeo.com/lit.php?id=3435099
20.Stephenson I, Nicholson KG. Influenza: vaccination and treatment. Eur Respir J 2001; 17: 1282-93. Abstract: http://amedeo.com/lit.php?id=11491177 – Full text at http://erj.ersjournals.com/cgi/content/full/17/6/1282
21.Sugrue RJ, Hay AJ. Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel. Virology 1991; 180: 617-24. Abstract: http://amedeo.com/lit.php?id=1989386
22.Symmetrel (package insert). Endo Pharmaceuticals Inc., Chadds Ford, 2003. http://influenzareport.com/link.php?id=6
23.Van Voris LP, Betts RF, Hayden FG, Christmas WA, Douglas RG Jr. Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA 1981; 245: 1128-31. Abstract: http://amedeo.com/lit.php?id=7007668
Oseltamivir
Introduction
Oseltamivir is a potent and selective inhibitor of the neuraminidase enzyme of the influenza viruses A and B. The neuraminidase enzyme is responsible for cleaving sialic acid residues on newly formed virions and plays an essential role in the release and spread of progeny virions. When exposed to oseltamivir, the influenza virions aggregate on the surface of the host cell, thereby limiting the extent of infection within the mucosal secretions (McNicholl 2001) and reducing viral infectivity.
Oseltamivir is indicated in the prophylaxis of influenza and for the treatment of uncomplicated acute illness due to influenza in patients 1 year and older who have been symptomatic for no more than 2 days. H5N1 strains are generally sensitive against oseltamivir, but there are no data on its clinical efficacy.
Clinical studies have shown that neuraminidase inhibitors can decrease the duration of influenza-related symptoms if initiated within 48 hours of onset. Clinical efficacy is about 60-70 % and, for treatment started within 48 hours, symptoms such as myalgias, fever, and headache were reduced by approximately 0.7-1.5 days (McNicholl 2001). Treatment is more effective if initiated within 30 hours of symptom onset in febrile individuals. Treatment with oseltamivir does not seem to adversely affect the primary in vivo cellular immune responses to influenza virus infection (Burger 2000).
Oseltamivir is generally well-tolerated with the only clinically important side effect being mild gastrointestinal upset (Doucette 2001). Recently, the drug has been linked to a number of cases of psychological disorders and two teenage suicides in Japan. However, there is currently no evidence of a causal relationship between oseltamivir intake and suicide.
Oseltamivir 195
Structure
Oseltamivir is an ethyl ester prodrug which requires ester hydrolysis to be converted to the active form, oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5- amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. The discovery of oseltamivir was possible through rational drug design utilising available x-ray crystal structures of sialic acid analogues bound to the active site of the influenza virus neuraminidase (Lew 2000). Oseltamivir was developed through modifications to the sialic acid analogue framework (including the addition of a lipophilic side chain) that allow the drug to be used orally (Kim 1998). The structural formula is as follows:
During its early development, oseltamivir and its active metabolite were known as GS4104 and Ro 64-0796, and GS4071 and Ro 64-0802, respectively.
Pharmacokinetics
Following oral administration, oseltamivir is readily absorbed from the gastrointestinal tract. After conversion to the active metabolite oseltamivir carboxylate in the liver, it distributes throughout the body, including the upper and lower respiratory tract (Doucette 2001). The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80 %. The active metabolite is detectable in plasma within 30 minutes and reaches maximum concentrations after 3 to 4 hours. Once peak plasma concentrations have been attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours (He 1999).
The terminal plasma elimination half-life is 1.8 h in healthy adults. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance, and averages 23 h after oral administration in individuals with a creatinine clearance < 30 ml/min (Doucette 2001). A dosage reduction to 75 mg once daily is recommended for patients with a creatinine clearance < 30 ml/min (1.8 l/h) (He 1999).
Plasma protein binding is 3 %. The drug and the active metabolite are excreted by glomerular filtration and active tubular secretion without further metabolism (Hill 2001). Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases (He 1999). Thus, the potential is low for drug-drug interactions, which appear to be limited to those arising from competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter. Probenecid blocks the renal secretion of oseltamivir, more than doubling systemic exposure oseltamivir carboxylate (Hill 2002). This competition is unlikely to be clinically
196 Drug Profiles
relevant, but there has been speculation about using probenecid to “stretch” oseltamivir stocks in situations of pandemic shortage (Butler 2005).
The metabolism of oseltamivir is not compromised in hepatically impaired patients and no dose adjustment is required (Snell 2005).
In elderly individuals, exposure to the active metabolite at steady state is approximately 25 % higher compared with young individuals; however, no dosage adjustment is necessary (He 1999).
Young children 1 to 12 years of age clear the active metabolite oseltamivir carboxylate at a faster rate than older children and adults, resulting in lower exposure. Increasing the dose to 2 mg/kg twice daily resulted in drug exposures comparable to the standard 1 mg/kg twice daily dose used in adults (Oo 2001). Infants as young as 1 year old can metabolise and excrete oseltamivir efficiently (Oo, 2003). In younger children, use of oseltamivir is contraindicated (see Toxicity).
Toxicity
The most frequent side effects are nausea and vomiting which are generally of a mild to moderate degree and usually occur within the first 2 days of treatment.
The following adverse reactions have been identified during post-marketing use of oseltamivir. In many cases, it is not possible to reliably estimate their frequency or establish a cause relationship to oseltamivir exposure:
!Rash, swelling of the face or tongue, toxic epidermal necrolysis
!Hepatitis, abnormal liver function tests
!Arrhythmias
!Seizures, confusion
!Aggravation of diabetes
Oseltamivir use does not appear to be associated with an increased risk of skin reactions (Nordstrom 2004); however, anecdotal reports describe isolated skin reactions, i.e. the case of generalised rash after prophylactic use of oseltamivir and zanamivir in two patients with hepatoma associated with liver cirrhosis (Kaji 2005). After a comprehensive review of the available data, the FDA has recently required serious skin/hypersensitivity reactions be added to the oseltamivir product label. Patients should be cautioned to stop taking oseltamivir and contact their health care providers if they develop a severe rash or allergic symptoms (FDA 2005).
The use of oseltamivir in infants younger than 1 year is not recommended as studies on juvenile rats revealed potential toxicity of oseltamivir for this age group. Moreover, high drug levels were found in the brains of 7-day-old rats which were exposed to a single dose of 1,000 mg/kg oseltamivir phosphate (about 250 times the recommended dose in children). Further studies showed the levels of oseltamivir phosphate in the brain to be approximately 1,500 times those seen in adult animals. The clinical significance of these preclinical data for human infants is uncertain. However, given the uncertainty in predicting the exposure in infants with immature blood-brain barriers, it is recommended that oseltamivir not be administered to children younger than 1 year, the age at which the human blood-brain barrier is generally recognised to be fully developed (Dear Doctor-Letter, http://InfluenzaReport.com/link.php=id=2).