- •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
188 Drug Profiles
Chapter 10: Drug Profiles
Bernd Sebastian Kamps and Christian Hoffmann
Amantadine
Amantadine inhibits the replication of influenza A viruses by interfering with the uncoating of the virus inside the cell. Like rimantadine, it is an M2 inhibitor which blocks the ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991). The influenza virus enters its host cell by receptormediated endocytosis. Thereafter, acidification of the endocytotic vesicles is required for the dissociation of the M1 protein from the ribonucleoprotein complexes. Only then are the ribonucleoprotein particles imported into the nucleus via the nuclear pores. The hydrogen ions needed for acidification pass through the M2 channel. Amantadine blocks the channel (Bui 1996).
Amantadine is effective against all influenza A subtypes that have previously caused disease in humans (H1N1, H2N2 and H3N2), but not against influenza B virus, because the protein M2 is unique to influenza A viruses. For both the prevention and treatment of influenza A, amantadine has a similar efficacy to rimantadine (Stephenson 2001, Jefferson 2004). Comparative studies indicate that adverse effects were significantly more common with amantadine than rimantadine (Jefferson 2004). Amantadine is not active against the avian influenza subtype H5N1 strains which have recently caused disease in humans (Li 2004). Besides influenza, amantadine may also be indicated in the treatment of Parkinson’s disease and druginduced extrapyramidal reactions. Moreover, it may be effective as an adjunct to interferon-based combination therapy in patients with chronic hepatitis C who have failed prior hepatitis C therapy (Lim 2005).
With daily costs of 0.50 € per day in some European countries, amantadine is by far the cheapest treatment for influenza A, compared to daily costs of 5 € for rimantadine and 7 € for oseltamivir.
The use of amantadine is associated with the rapid emergence of drug-resistant variants. Resistant isolates of influenza A are genetically stable and fully transmissible, and the pathogenic potential is comparable to that of wild-type virus isolates. In immunocompromised patients, resistant virus can be shed for prolonged periods (Boivin 2002). According to a study which assessed more than 7,000 influenza A virus samples obtained from 1994 to 2005, drug resistance against amantadine and rimantadine has increased worldwide from 0.4 % to 12.3 % (Bright 2005). Virus samples collected in 2004 from South Korea, Taiwan, Hong Kong, and China showed drug-resistance frequencies of 15 %, 23 %, 70 %, and 74 %, respectively. Some authors have suggested that the use of amantadine and rimantadine should be frankly discouraged (Jefferson 2006). Recently, 109 out of 120 (91 %) influenza A H3N2 viruses isolated from patients in the US contained an amino acid change at position 31 of the M2 protein, which confers resistance to amantadine and rimantadine. On the basis of these results, the Centre for Disease Control recommended that neither amantadine nor rimantadine be used for the treatment or prophylaxis of
Amantadine 189
influenza A in the United States for the remainder of the 2005–06 influenza season (CDC 2006).
Pharmacokinetics
Amantadine is well absorbed orally and maximum drug concentrations (Cmax) are directly dose-related for doses of up to 200 mg/day. Doses above 200 mg/day may result in disproportional increases in Cmax. In healthy volunteers, peak concentration were reached after 3 hours and the half-life was 17 hours (range: 10 to 25 hours). Amantadine is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion.
In individuals older than 60 years, the plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased. The clearance is also reduced in patients with renal insufficiency: the elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 ml/min and averages eight days in patients on chronic haemodialysis. Amantadine is not removed by haemodialysis.
As the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body.
Toxicity
Gastrointestinal symptoms – mainly nausea but also vomiting, diarrhoea, constipation, and loss of appetite – are the major side effects. In addition, amantadine has a wide range of toxicities which may be in part attributable to the anticholinergic effects of the drug, and some reversible CNS side effects may occur during a 5-day- treatment in a substantial number of patients (van Voris 1981). As the occurrence of adverse effects is dose-related, adverse events are particularly common in the elderly and those with impaired renal function. Side effects begin within two days of the start of the drug, and usually disappear rapidly after cessation of treatment.
CNS toxicity may manifest as dizziness, nervousness, and insomnia. In a four-week prophylaxis trial, these symptoms occurred in up to 33 % of young individuals (Bryson 1980). Decreased performance on sustained attention tasks was also observed. Other CNS adverse effects include agitation, difficulty concentrating, insomnia, and lowered seizure threshold. In a direct comparison of the prophylactic use of amantadine and rimantadine, more patients receiving amantadine (13 % vs. 6% on rimantidine) withdrew from the study because of CNS side effects (Dolin 1982).
Less frequently (1-5 %) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral oedema, orthostatic hypotension, headache, somnolence, dream abnormality, agitation, dry nose, diarrhoea and fatigue (Symmetrel 2003).
Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. In the past, some patients attempted suicide by overdosing with amantadine. As a result, it is recommended that the minimum quantity of drug is prescribed (Symmetrel 2003).
Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has therefore resulted in cardiac, respiratory, renal or central nerv-