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Amantadine and rimantadine for influenza A in children and the elderly

  1. Márcia G Alves Galvão2,
  2. Marilene Augusta Rocha Crispino Santos2,
  3. Antonio JL Alves da Cunha1,*

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 18 JAN 2012

Assessed as up-to-date: 27 JUN 2011

DOI: 10.1002/14651858.CD002745.pub3


How to Cite

Alves Galvão MG, Rocha Crispino Santos MA, Alves da Cunha AJL. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD002745. DOI: 10.1002/14651858.CD002745.pub3.

Author Information

  1. 1

    School of Medicine, Federal University of Rio de Janeiro, Department of Pediatrics, Rio de Janeiro, Rio de Janeiro, Brazil

  2. 2

    Municipal Secretariat of Health, Rio de Janeiro, RJ, Brazil

*Antonio JL Alves da Cunha, Department of Pediatrics, School of Medicine, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, 373, Edificio do CCS - Bloco K - 2o. andar, Sala K49, Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil. acunha@hucff.ufrj.br. antonioledo@yahoo.com.br.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 18 JAN 2012

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison.

Amantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza a (treatment)

Settings: all

Intervention: amantadine

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAmantadine

Cases of influenza A during prophylaxis

(follow up:14 to 18 weeks)
Medium risk populationRR 0.11 (0.04 to 0.3)773
(2])
⊕⊕⊝⊝
low1,2

10 per 1001 per 100
(0 to 3)

Fever after initiation of treatment

(follow-up: 3 days)
Medium risk populationRR 0.37 (0.08 to 1.75)104
(2)
⊕⊕⊝⊝
low3,4

23 per 1009 per 100
(2 to 40)

Cough after initiation of treatmentSee commentSee commentNot estimable0

(0)
See commentNo selected trial

Dizziness

(follow-up: 7 days)
Medium risk populationRR 6.63 (0.32 to 137.33)599
(2)
⊕⊝⊝⊝
very low3,4

0 per 1000 per 100
(0 to 0)

Nausea/ vomiting

(follow-up: 7 days)
Medium risk populationRR 0.54 (0.15 to 2)599
(2)
⊕⊝⊝⊝
very low3,4,5

13 per 1007 per 100
(2 to 27)

Stimulation/ insomnia

(follow-up: 7 days)
Medium risk populationRR 0.46 (0.12 to 1.74)599
(2)
⊕⊕⊝⊝
low3,4

3 per 1007 per 100
(2 to 27)

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

 *The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
1Allocation concealment not used or unclear.
2Sparse data.
3Allocation concealment unclear.
4Sparse data, confidence intervals do not rule out potential for null effect or harm.
5High heterogeneity unexplained.

 Summary of findings 2

 Summary of findings 3

 Summary of findings 4

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Influenza is an acute, usually self-limiting respiratory illness caused by infection with influenza viruses A or B, members of the Orthomyxoviridae family (Nicholson 1992). It is seasonal and occurs most frequently during autumn and winter in temperate regions, although in some tropical countries, it may occur throughout the year with one or two peaks during rainy seasons (Monto 2008; Yang 2010). The illness is characterised by an abrupt onset of symptoms. These symptoms include headache, fever, general aches, weakness and myalgia, accompanied by respiratory tract signs, particularly cough and sore throat. However, a wide spectrum of clinical presentations may occur, ranging from a mild, febrile upper respiratory illness, to severe prostration and respiratory and systemic signs and symptoms. The most common complication that occurs during outbreaks of influenza is pneumonia (both viral and bacterial). A number of extra-pulmonary complications may also occur. These include Reye's syndrome in children (most commonly between two and 16 years of age), myocarditis, pericarditis and central nervous system (CNS) diseases. Again these include encephalitis, transverse myelitis and Guillain-Barrè syndrome (Wiselka 1994).

 

Description of the intervention

Nowadays there are two main measures for the treatment and prophylaxis of influenza viruses: immunisation using influenza vaccines directly isolated from influenza A and B viruses, and antiviral agents (Demicheli 2000). Although vaccination is the primary strategy for the prevention of influenza, there are a number of likely scenarios for which effective antiviral agents would be of utmost importance. Immune systems of the elderly are less responsive to vaccination (Thomas 2010). Influenza vaccines are efficacious in children older than two, but little evidence is available for children under two (Jefferson 2010). During any influenza season, antigenic drift in the virus may occur after formulation of the year's vaccine. So, the vaccine can be less protective and outbreaks can more easily occur in high-risk populations. In the course of a pandemic, vaccine supplies would be inadequate. Vaccine production by current methods cannot be carried out with the speed required to halt the progress of a new strain of influenza virus; therefore, it is likely that vaccines would not be available for those infected by the first wave of the virus (Hayden 2004). Antiviral agents therefore form an important part of a rational approach to influenza management (Moscona 2005). Antiviral drugs for influenza currently include two classes, each with two drugs: M2 ion channel inhibitors: amantadine (AMT) and rimantadine (RMT) and neuraminidase inhibitors: zanamivir and oseltamivir. M2 ion channel inhibitors affect ion channel activity through the cell membrane. They are reported to be effective by interfering with the replication cycle of type A viruses (but not type B). The neuraminidase inhibitors interfere with the release of progeny influenza virus from infected host cells and are effective against influenza A and B (Moscona 2005). Both drug classes have shown partial effectiveness for prevention and treatment of influenza A viruses, although neuraminidase inhibitors are less likely to promote the development of drug-resistant influenza (Moscona 2005).

It is important that the patterns of sensitivity and resistance of influenza A viruses to antiviral drugs be permanently monitored, since these characteristics may change over time. Resistance to M2 inhibitors, remained low until 2003 (Bright 2005; Ziegler 1999). An epidemiological study into resistance to AMT carried out from 1991 to 1995 described a frequency of 1% (16/2017) of resistant variants among H1N1 and H3N2 viruses (Ziegler 1999). However, subsequently a dramatic increase occurred: strains of influenza A (H3N2) virus with a specific mutation (Ser31Asn) showed an increase in resistance to AMT in communities located in Asia and North America (Bright 2005; Bright 2006). This resistance in 70% to 90% of strains occurred despite the absence of sustained selective drug pressure (Bright 2005; Bright 2006).

During the 2005–2006 season, 16% of H1N1 and 91% of H3N2 viruses were resistant around the world. Although the estimate for the proportion of resistance of H1N1 viruses was very low, an analysis conducted in China showed that the frequency of resistant H1N1 viruses had greatly increased from 28% (8/29) in the 2004–2005 season to 72% (33/46) in the 2005–2006 season. Similar studies were conducted in other countries in the 2005–2006 season. The following frequencies of resistance were obtained: 45% (13/29) in Europe, 24% (4/17) in Taiwan and 33% (1/3) in Canada (Deyde 2007).

A global pandemic emerged in 2009, caused by a new influenza A strain (H1N1) (WHO 2010a). All influenza A (H1N1) viruses tested in WHO Collaborating Centres to date showed to be resistant to AMT and RMT (WHO 2011).

 

How the intervention might work

The use of AMT and RMT for treatment and prevention of influenza A in adults has already been the topic of a review (Jefferson 2009b). Results of that review confirmed that AMT and RMT had a comparable efficacy and effectiveness in the treatment of influenza A in healthy adults, although their effectiveness in interrupting transmission was probably low. As previous pandemics proved to be susceptible to this class of drugs, it seems reasonable to review the evidence of AMT and RMT for treating and preventing influenza A in children and the elderly (Hayden 2006b).

 

Why it is important to do this review

Although the disease occurs in all age groups (Pineda Solas 2006),, the risks of complications, hospitalisations and deaths from influenza are higher among three groups of people: 1) persons older than 65 years; 2) young children; and 3) persons of any age who have medical conditions that place them at increased risk. Rates of infection are highest amongst children, and children are also one of the most important links for transmission (Dolin 2005).

Pandemics occur when influenza spreads globally, infecting 20% to 40% of the world's population in one year. This results in as many as 10 million deaths (WHO 2003). They usually arise in China where pigs, ducks and humans live in close proximity to each other and spread westward to the rest of Asia, Europe and the Americas (Bonn 1997). In the past 110 years there have been five pandemics caused by different influenza A viral subtypes. The Spanish influenza pandemic (1918 to 1919) is considered to have caused an estimated 40 million deaths worldwide. Most years, typical influenza epidemics infect 5% to 20% of the population and result in anywhere between 250,000 and 500,000 deaths, according to the World Health Organization (WHO), although other estimates accounting for deaths due to complications of influenza are as high as 1 million to 1.5 million.

In 2009, a new influenza A strain (H1N1), caused a global pandemic. According to the WHO, as of 24 January 2010, more than 214 countries and overseas territories had reported laboratory-confirmed cases of pandemic influenza H1N1, resulting in at least 18,449 deaths (WHO 2010a).

In an earlier version of a Cochrane review in adults, the review authors stated that neuraminidase inhibitors were effective in reducing symptoms and complications, but criticisms led to doubts about their effectiveness against complications (Jefferson 2011). Doubts still remain about their effectiveness and safety because their evaluations were limited to manufacturer-sponsored trials. This fact led the authors to the development of a new Cochrane protocol (Jefferson 2011).

In a Cochrane review published in 2007, the review authors concluded that oseltamivir may be considered for the treatment of children aged one to 12 years with influenza infection (Matheson 2007). This antiviral is likely to shorten the duration of symptoms, hasten the return to normal activities and reduce the incidence of secondary complications. Nevertheless, the review authors also concluded that more data were needed to clarify the benefits of neuraminidase inhibitors for the treatment of influenza in asthmatic children (including addressing the potential confounder of prior vaccination).

Nowadays, neuraminidase inhibitors are used as a prescription drug for patients suffering from influenza on the recommendation of the WHO (WHO 2010b). Governments have spent billions of dollars stockpiling neuraminidase inhibitors as a public health measure (WHO 2010b). In previous pandemias, the influenza A virus was susceptible to AMT and RMT. Therefore, these antivirals could be a less expensive alternative in the management of influenza if the circulating strain proves to be susceptible to AMT and RMT (Hayden 2006b). However, we should emphasize the resistance patterns of the pandemic viruses in 2009. All influenza A (H1N1) viruses tested in WHO Collaborating Centres to date were sensitive to zanamivir and all were resistant to AMT and RMT (WHO 2011).

These facts reinforce the importance of conducting and maintaining reviews of a variety of treatments, especially less expensive ones, for the treatment and prevention of influenza.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

  1. To identify, retrieve and assess RCTs evaluating the effects of AMT or RMT on influenza A in children and the elderly.
  2. To assess the efficacy of AMT and RMT in preventing cases of influenza A in children and the elderly.
  3. To assess the efficacy of AMT and RMT in shortening the duration of influenza A manifestations in children and the elderly.
  4. To compare the frequency of adverse effects of AMT and RMT to control groups in children and the elderly.

In comparisons between groups intended for AMT or RMT prophylaxis or treatment compared with control groups we tested the following hypotheses:

  • there is no difference in the number of cases of influenza A or in the duration of influenza symptoms; and
  • there is no difference in the number of adverse effects.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs comparing AMT and/or RMT with placebo, control drugs, different doses or schedules of AMT or RMT, or both, or no intervention, in children and the elderly.

 

Types of participants

We included studies where at least 75% of the population was up to 19 years of age, or 65 years of age or older. We also included trials with a wider age range where data by age subgroups were available.

 

Types of interventions

Comparisons of AMT and/or RMT to placebo, control drugs, other antivirals, no interventions or different doses of AMT and/or RMT as prophylaxis and/or treatment for influenza A.

 

Types of outcome measures

 

Primary outcomes

  1. Response to treatment (measured as cases on the specified day of treatment): fever on day three of treatment, cough on day seven of treatment, malaise on day six of treatment and conjunctivitis and eye symptoms on day five of treatment.
  2. Cases of influenza, studied in all prophylaxis comparisons, including those in which two antivirals (RMT and zanamivir) (Gravenstein 2005; Schilling 1998) and two different doses of RMT were compared (Monto 1995).
  3. Cases of side effects in children: diarrhoea, exanthema, malaise, muscular limb pain, headache, dyspnoea, dizziness, stimulation/insomnia, nausea, vomiting, arrhythmia, gastrointestinal (GI) symptoms, CNS symptoms, change in behaviour, hyperactivity and tinnitus.
  4. Cases of side effects in the elderly: headache, dizziness, stimulation/insomnia, nausea, vomiting, anxiety, confusion, fatigue, depression, impaired concentration, loss of appetite, rash or allergic reaction, seizures or clonic twitching, dry mouth, insomnia or sleeplessness, body weakness and debility.

We used dichotomous outcomes for all the comparisons.

 

Secondary outcomes

The following outcomes appeared in the protocol but were not considered at the end in the analysis, as they were not reported in the included trials: patients' well-being, admission to hospital, general practitioner's (GP) visits and other drugs used. We could not analyse deaths. Although cited by Monto 1995, they were included among other causes of withdrawal.

 

Search methods for identification of studies

 

Electronic searches

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (July 2007 to June week 3, 2011) and EMBASE.com (July 2007 to June 2011). Details of the previous search are in Appendix 1.

The search strategy for MEDLINE and CENTRAL is in Appendix 2. We combined the MEDLINE search strategy with the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). See Appendix 3 for the EMBASE search strategy.

 

Searching other resources

We imposed no language or publication restrictions. We screened bibliographies of retrieved articles and reviews in order to identify further trials. We contacted pharmaceutical companies and researchers active in the field for unpublished trials.

 

Data collection and analysis

 

Selection of studies

Two review authors (MG and MS) independently applied the selection criteria to all retrieved articles and extracted data using a data extraction form, specifically designed for this review. We resolved disagreements by consensus. We appointed one review author (AC) as arbitrator when necessary.

We entered extracted data into RevMan 2011. Combination of data was dependent on population characteristics and outcomes studied.

 

Data extraction and management

Two review authors (MG, MS) independently read the retrieved trials and applied the selection criteria. We independently extracted and reviewed data using the data collection form previously developed for this review. Two review authors (MG, MS) resolved disagreements on the quality of the trials by consensus. We appointed a third author (AC) as arbitrator if necessary.

We emailed primary studies' authors when the complete information sought was not available in study reports. We obtained authors' contact details from the study reports, other recent publications, university directories or by searching the world wide web. We recorded the following data.

  1. Setting: hospital, emergency, offices or clinics, primary health care, nursing homes, communities, prisons, military personnel, nursery or day care.
  2. Participants: criteria for patients to join the trial, age, gender, diagnostic criteria and co-morbid conditions.
  3. Interventions: placebo, other than AMT and RMT antiviral controls, comparing different doses or schedules of AMT and/or RMT or no intervention.
  4. Outcome measures: global symptom improvements, relief, death, cases of influenza, malaise, fever, nausea, arthralgia, rash, headache, systemic and serious side effects, well-being, admission to hospital, GP's visits, other drugs used, cough, coryza, sore throat, hoarseness, vomiting, abdominal pain, insomnia, irritability, behaviour changes and anorexia.
  5. Adverse effects: dry mouth, drowsiness/fatigue, constipation, urinary retention, sweating, headache, diarrhoea, palpitations, irritability, blurred vision, dizziness/light headedness, and nausea/vomiting and any other systemic and serious side effects.

 

Assessment of risk of bias in included studies

Two review authors (MG, MS) independently screened trial quality. We resolved disagreements by discussion. We appointed a third author (AC) to act as arbitrator when necessary. We used the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess the risk of bias. We developed a form and populated it to assess the risk of bias, based on a former Cochrane review (Ahovuo-Saloranta 2011). When applicable, we answered the questions, with 'Yes' indicating a low risk of bias, 'No' indicating a high risk of bias, and 'Unclear' indicating either a lack of information or uncertainty over the potential for bias.

1. Sequence generation was the method used to generate the allocation sequence appropriate to produce comparable groups. We answered 'Yes' if the authors described a random component in the sequence generation process (for example, a random number table, a computerised random number table, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots). If there was no or insufficient information about the sequence generation process, we marked this domain 'Unclear'. We marked “No” (high risk of bias) if the sequence was generated by: 1) odds and evens or date of birth; 2) some rule based on date (or day) of admission; 3) some rule based on hospital or clinic record number.

2. Allocation sequence concealment was the method used to conceal the allocation sequence appropriate to prevent the allocation being known in advance of, or during, enrolment. We marked this domain 'Yes' if the trial authors described adequate concealment (for example by means of either central allocation, sequentially numbered drug containers of identical appearance, or sequentially numbered opaque sealed envelopes), and 'No' if: 1) inadequate concealment was documented; 2) allocation concealment was not used (for example, using either an open random allocation schedule, assignment envelopes without appropriate safeguards, alternation or rotation, date of birth, or case record number). We marked ‘Unclear’ if: 1) insufficient information about allocation concealment was provided; 2) the information was unclearly reported.

3. Blinding of participants and personnel were adequate measures used to blind study participants and personnel from knowing which intervention a participant received. This domain was marked ’Yes’ if the RCT authors stated: 1) that there was no blinding; 2) incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by said incomplete blinding; 3) blinding of participants and key study personnel was ensured, and it is unlikely that the blinding could have been broken. The domain was marked ‘No’, representing high risk of bias, if the RCT authors described: 1) no blinding; 2) incomplete blinding, and the outcome was likely to be influenced by said incomplete blinding; 3) blinding of key study participants and personnel, but it was likely that the blinding could have been broken. This domain was marked 'Unclear' if there was insufficient information or if the study did not address this outcome.

4. Blinding of outcome assessment were adequate measures used to blind outcome assessors from knowing which intervention a participant received. This domain was marked ’Yes’ if there was: 1) no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding; 2) blinding of outcome assessors is ensured, and it is unlikely that the blinding could have been broken. This domain was marked ‘No’, representing a high risk of bias, if: 1) no blinding of outcome assessment was stated, and the outcome measurement was likely to be influenced by lack of blinding; 2) there was blinding of outcome assessors, but it was likely that the blinding could have been broken. This domain was marked ‘Unclear” if there was insufficient information or if the study did not address this outcome.

5. Incomplete outcome data describes how complete were the data for the clinical outcomes. Were drop-out rates and reasons for withdrawals reported? Were missing data imputed appropriately? This domain was marked 'Yes' (low risk of bias) if the RCT authors stated: 1) that there were no missing outcome data; 2) the reasons for missing outcome data were unlikely to be related to true outcome: 3) missing outcome data balanced out  across intervention groups, with similar reasons for missing data across said groups; 4) the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; 5) missing data were imputed using appropriate methods. This domain was marked 'No', representing a high risk of attrition bias, if: 1) the reason for missing outcome data was likely to be related to true outcome, with either an imbalance in numbers or reasons for missing data across intervention groups; 2) the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in the intervention effect estimate; 3) ‘as-treated’ analysis was done with substantial departure of the intervention received from that assigned at randomisation; 4) was potentially inappropriate application of simple imputation. 'Unclear' risk of bias there was the expected classification of studies in which there was insufficient reporting of attrition/exclusions to permit the classification as ‘Low risk’ or ‘High risk’ (e.g. number of randomised patients not stated, no reasons for missing data provided), or if the study did not address this outcome.

We completed a 'Risk of bias' table for each included study (see 'Risk of bias' tables in the Characteristics of included studies table).  

 

Measures of treatment effect

We calculated risk ratios (RRs) and 95% confidence intervals (CI) for each study as all the outcomes studied were dichotomous. We tested for heterogeneity for each outcome.

 

Unit of analysis issues

In the Gravenstein 2005 trial, the author stated that the study was conducted over three winter seasons and that some participants were randomised more than once. Taking into account that influenza was the outcome of interest, and that in each season different influenza viruses emerge, participants that had acquired the infection in one of the seasons could not be considered to be immunologically resistant to influenza in the next season. Consequently, we decided to include all participants described by the trial authors, as this does not seem to produce bias.

In the Crawford 1988 and Clover 1991 studies, eligible family members were randomly assigned as a block to study RMT in the prevention of influenza. For the purpose of this review, we selected the children as the subgroup of interest. It could be expected that children from families in the intervention group could be more protected from influenza than children in the control group. Nevertheless, no effect was shown in either of the three trials selected for this comparison (Clover 1986b; Clover 1991; Crawford 1988).

 

Dealing with missing data

We contacted the trial authors to request missing data when data were not clearly stated. We analysed the available data, taking into account the relatively small number and randomness of missing data.

 

Assessment of heterogeneity

We stored the data extracted from primary studies in the Review Manager software (RevMan 2011). All the outcomes we studied were dichotomous.
We determined if there were sufficiently homogeneous data to combine when there were two or more selected studies for a given comparison. We grouped the previously selected articles according to the characteristics of interventions, outcomes and populations studied. We had to take into account that pooled studies may still differ from each other even though the initial application of this filter was supposed to reduce the possibility of heterogeneity.

We initially inspected forest plots generated by RevMan 2011 to evaluate the possibility of heterogeneity between studies. We applied the Cochrane test for homogeneity. With this aim we set a P value of 0.1 as the limit for considering the existence of heterogeneity (CCI 2006). We also applied the I2 statistic to quantify heterogeneity among the trials and to verify the impact on the meta-analysis, considering that some clinical and methodological diversity always occurs in a meta-analysis. We considered values above 50% to be representative of significant heterogeneity (Higgins 2011) and explored the causes. We used the subgroup analysis of participants or a subgroup analysis of the studies selected for each comparison when the heterogeneity was relevant to the outcome of the meta-analysis.

 

Assessment of reporting biases

We considered assessment of reporting biases to be at risk because of the small number of studies selected for each comparison. Nevertheless, we relied on extensive research and carefully examined the references of the studies found in the search results to avoid reporting biases. We analysed all trials that met the inclusion criteria, independently of the journal's impact factor, the year of publication, the language in which the article was written and the origin of both author and publication. The use of these criteria can be confirmed by checking the lists of included and excluded studies.

 

Data synthesis

We used the risk ratio (RR) and respective 95% confidence interval (CI) as a summary measure to combine data. We calculated the necessary number of patients to be treated for an individual to benefit from treatment with respect to an outcome (number needed to treat to benefit (NNTB)) and its 95% CI, when a statistical difference was found. We estimated the occurrence of an event in the population, or absolute risk (baseline risk) based on the rate of event occurrence in controls (control group rate (CGR)) for this calculation.

We used the random-effects model to calculate the summary measure, with the assumption that although the articles could have addressed somewhat different issues, they could be viewed as a family of studies on similar questions. We considered that the articles were a random sample of all studies that addressed the questions we were interested in. Therefore, even considering the possibility of failure of the statistical tests of homogeneity, the combination of similar studies would still be a reasonable procedure. Although it is impossible to state if the articles were really a random sample of all research on an issue, this model contributes to a more realistic and less prone to overestimate accuracy (Fletcher 2006).

 

Subgroup analysis and investigation of heterogeneity

We pre-specified some subgroup analyses to investigate heterogeneity. We planned to take into account the drugs used for control and treatment, their doses and the previous use of anti-influenza vaccine(s). However, we stress that the subgroup analysis does not take into account the randomisation processes, so these results must be considered with caution.

 

Sensitivity analysis

We carried out sensitivity analyses to explore heterogeneity. We conducted subgroup analyses for subsets of participants. We had planned to analyse RMT and AMT separately and together. However, when we identified the use of different antivirals being used as a control, we performed a subgroup analysis. We separated the trials in which the comparison was made using different antiviral medications from those in which the control was made with placebo or other drugs. We also carried out subgroup analyses for subsets of immunised and non-immunised participants as well as according to the dosages of antivirals tested in the trials.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

We retrieved a total of 31 records in this updated search. Out of a total of 205 abstracts, titles and studies that we retrieved through the searches, 195 were written in English, three in Russian, two in Czech, three in German, one in French and one in Japanese. We discarded 129 studies. We assessed the remaining 78 articles in detail. It was necessary to contact 46 trial authors to verify that their studies met our selection criteria. We included 12 trials in this review. All of them are published trials and are described in the Characteristics of included studies table. We added another 38 trials in 2011 when we updated this review; we excluded all of them and our conclusions remain unchanged.

 

Included studies

The 12 included studies (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984; Payler 1984; Schilling 1998) were all randomised trials; 11 were blinded and one was unblinded (Schilling 1998). The methods of randomisation and the follow-up period were poorly described in all studies, although we could estimate that follow-up ranged from eight to 120 days. We classified the included trials into two major groups: those conducted in children and those in the elderly.

 

Trials in children

Eight selected studies looked at the following.

  1. Treatment with AMT (Kitamoto 1968; Kitamoto 1971) and RMT (Hall 1987).
  2. Prophylaxis with AMT (Finklea 1967; Payler 1984) and RMT (Clover 1986b; Clover 1991; Crawford 1988).
  3. Adverse effects due to AMT (Kitamoto 1968; Kitamoto 1971) and RMT (Clover 1986b; Crawford 1988; Hall 1987).

For treatment trials and the outcome fever on day three of treatment, the AMT arm size was 51 and the control arm size was 53 children (Kitamoto 1968; Kitamoto 1971). The RMT arm size was 37 and the control arm size was 32 children (Hall 1987). For the other outcomes, cough on day seven, malaise on day six and eye symptoms on day five, we selected just one trial (Hall 1987). The RMT arm size was 37 and control arm size was 32 children for each of these outcomes.

In the five prophylaxis trials, we applied wider age ranges for children than the definition stated in the protocol (participants up to 16 years of age). These trials included older participants who were adolescents by WHO definition (WHO 2007). Data regarding the proportion of the subgroup which strictly fulfilled the age criterion were not available in these studies or by contacting the trial authors. The respective age ranges were one to 17 years (Clover 1991), 13 to 19 years (Payler 1984), one to 18 years (Clover 1986b; Crawford 1988) and eight to 19 years of age (Finklea 1967). The AMT arm size was 368 (Finklea 1967 (104); Payler 1984 (264)) and the control arm size was 373 children (Finklea 1967 (133); Payler 1984 (240)). The RMT arm size was 84 (Clover 1986b (35); Clover 1991 (22); Crawford 1988 (27)) and the control arm size was 94 participants (Clover 1986b (41); Clover 1991 (24); Crawford 1988 (29)).

Reported adverse effects of AMT included exanthema, malaise, muscular limb pain, headache, arrhythmia and stimulation/insomnia. The antiviral arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1968 (84); Kitamoto 1971 (251)).

A reported adverse effect of AMT was dyspnoea. The antiviral arm size was 75 and control arm size was 84 children (Kitamoto 1968). For the adverse effects of hyperreactivity and tinnitus the RMT arm size was 27 and the control arm size was 29 children (Crawford 1988).

Nausea/vomiting, diarrhoea and dizziness were described as possible adverse effects for both antivirals. For nausea/vomiting, the AMT arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1971 (251); Kitamoto 1968 (84)). The RMT arm size was 38 (Crawford 1988 (1); Hall 1987 (37)) and the control arm size was 61 (Crawford 1988 (29); Hall 1987 (32)).

For diarrhoea and dizziness the AMT arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1968 (84), Kitamoto 1971 (251). The RMT arm size was 27 and the control arm size was 29 children for these adverse effects (Crawford 1988).

 

Trials in the elderly

We selected three trials in this age group that reported on prophylaxis with RMT; we did not select any treatment trials. We studied the following outcomes.

  1. Prophylaxis of laboratory and clinical infection (Monto 1995; Patriarca 1984).
  2. Adverse reactions (Monto 1995; Patriarca 1984).
  3. Different doses of RMT as a prophylactic antiviral (Monto 1995).
  4. Comparison to other antivirals in the prophylaxis of influenza (Gravenstein 2005; Schilling 1998).

For prophylaxis of laboratory and clinical infection, the RMT (200 mg/day) arm size was 44 (Monto 1995 (26); Patriarca 1984 (18)) and the placebo arm size was 31 participants (Monto 1995 (14); Patriarca 1984 (17)). The trial authors stated they limited this analysis to vaccinated participants in nursing homes with confirmed influenza, as it provided an estimate of the additional protective efficacy of RMT. The sample studied by Patriarca 1984 was made up of previously vaccinated participants, so all the participants were analysed (Monto 1995; Patriarca 1984).

In the adverse reaction studies focusing on stimulation/insomnia, confusion, fatigue, nausea, depression, loss of appetite and vomiting, the RMT (200 mg/day) arm size was 150 (Monto 1995 (132); Patriarca 1984 (18)) and the placebo arm size was 83 participants (Monto 1995 (66); Patriarca 1984 (17)). All randomly assigned participants were analysed.

In the adverse reaction study focusing on headache, impaired concentration, rash or allergic reaction, seizures or clonic twitching, the RMT (200 mg/day) arm size was 132 and the placebo arm size was 66 participants (Monto 1995).

In another adverse reaction study focusing on dizziness and anxiety, the RMT (200 mg/day) arm size was 18 and the placebo arm size was 17 participants (Patriarca 1984).

In the unique study evaluating different doses of RMT as a prophylactic drug to clinical and confirmed influenza A, the RMT (100 mg/day) arm size was 28 and the RMT (200 mg/day) arm size was 26 participants (Monto 1995).

Only one selected study focused on adverse effects related to different doses of RMT. The studied effects were confusion, depression, impaired concentration, insomnia or sleeplessness, loss of appetite, rash or allergic reaction, seizure or clonic twitching, dry mouth, fatigue or drowsiness, headache, body weakness and debility. The 100 mg/day arm size was 130 and the 200 mg/day arm size was 132 participants (Monto 1995).

We selected two trials for the comparison of RMT to another antiviral and the participants were also the elderly (Gravenstein 2005; Schilling 1998). The RMT arm size was 254 and the zanamivir arm size was 291 participants. No study used AMT for this kind of comparison.

 

Excluded studies

We excluded 91 studies for the following reasons.

  1. They were carried out in different age groups.
  2. They were not controlled trials.
  3. They assessed other drugs.
  4. They were non-human or laboratory studies.

 

Risk of bias in included studies

The overall risk of bias is presented graphically in Figure 1 and summarised in Figure 2.

 FigureFigure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

The trial authors of the 12 included studies stated that participants had been randomly allocated into treatment or control groups. In two of the studies (Hall 1987; Payler 1984) we obtained the following information by contacting the trial authors. Hall reported that a computer system was used to randomise participants. The university pharmacy was chosen to allocate and store the study drugs (Hall 1987). In Payler's study, randomisation had been carried out by the statistical department of a pharmaceutical company, which kept the key to the randomisation, and only when the study was analysed was the code broken (Payler 1984). There was no mention of any particular randomisation method in the other studies.

 

Blinding

Ten studies were described as double-blinded (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984). However, only in one trial were blinded people listed (Monto 1995). Although there was no blinding stated in Payler 1984, we judged that the outcome was not likely to be influenced by a lack of blinding. Schilling 1998 was described as an unblinded study; we also judge that the outcomes were unlikely to be influenced by a lack of blinding.

 

Incomplete outcome data

There were no missing participants in either Kitamoto 1971, Kitamoto 1968 or Payler 1984. The review authors considered that the reasons for missing outcome data were unlikely to be related to true outcome in the following studies: Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005. In the Hall 1987 trial, we considered that the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate. On the other hand, we considered the reasons for missing outcome data likely to be related to the true outcome data in two studies (Monto 1995; Patriarca 1984). In Schilling 1998 there was insufficient report of exclusion.

 

Selective reporting

The review authors did not identify any possible sources of reporting biases.

 

Other potential sources of bias

The review authors did not identify any other possible sources of bias.

 

Effects of interventions

See:  Summary of findings for the main comparison;  Summary of findings 2;  Summary of findings 3;  Summary of findings 4

We intended to carry out 12 comparisons, although we could only conduct eight comparisons.

 

Comparisons in children

  1. AMT and RMT compared to control (placebo and acetaminophen) in the treatment of influenza A in children.
  2. AMT and RMT compared to control (placebo and a specific treatment) in the prophylaxis of influenza A in children.
  3. Adverse effects of AMT and RMT compared to control (placebo and acetaminophen) in children.
  4. Use of different doses of AMT and RMT for prophylaxis or treatment of influenza A in children.
  5. Adverse effects related to different doses of AMT and RMT in children.
  6. AMT and RMT compared to other antivirals in children.

 

Comparisons in the elderly

  1. AMT and RMT compared to control in the treatment of influenza A in the elderly.
  2. AMT and RMT compared to control (placebo and zanamivir) in the prophylaxis of influenza A in the elderly.
  3. Adverse effects of AMT and RMT compared to control (placebo) in the elderly.
  4. Use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly.
  5. Adverse effects related to different doses of AMT and RMT in the elderly.
  6. AMT and RMT compared to other antivirals in the elderly.

 

Additional comparison (children plus the elderly)

We made a thirteenth comparison: the effect of RMT to control (placebo) in the prophylaxis of influenza A in children and the elderly.

 

Comparisons in children

 
Comparison 1: AMT and RMT compared to control (placebo and acetaminophen) in the treatment of influenza A in children

In the protocol, we originally planned to study the drug effect on reduction of fever and cough as they are considered the best predictors on influenza diagnosis. After collecting data, we verified that specific timelines for reduction of signs and symptoms were not reported in the included trials. We searched for another way to present an estimation of the response to AMT and RMT in patients with influenza. For this unplanned analysis, we considered the available data and arbitrarily chose a day of antiviral use to evaluate the response to the treatment. This choice was based on the Eccle 2005 study in which clinical manifestations were classified in early and later symptoms. Typically fever may last four to eight days, so we chose day three of treatment as the cut-off point to which it could be considered that the response to the drug would be useful. Cough is considered a later manifestation that develops slowly and can still be present a week later (Eccle 2005). In the same way, we chose day seven of treatment as the cut-off point by when the response to the drug could be considered useful.

Finally, we also decided to include other treatment outcomes as they were available in Hall's electronic correspondence to us. In the same way, we arbitrarily chose a day of antiviral use to evaluate the response to the treatment to make this unplanned analysis: 'malaise on day six', as it begins early but could still be present for one or two weeks (Eccle 2005; Smith 2006) and 'eye manifestations on day five', as it can occur early on in the course of the illness (Treanor 2005; Wright 2004)

AMT was compared to placebo (Kitamoto 1968; Kitamoto 1971) and RMT to acetaminophen (Hall 1987).

There was a protective effect of AMT and RMT in the occurrence of fever on day three of antiviral treatment, when trials using both antivirals were combined (Hall 1987; Kitamoto 1968; Kitamoto 1971) RR 0.39; 95% CI 0.20 to 0.79 ( Analysis 1.1).

The baseline risk of fever on day three of treatment was 0.28, calculated on the basis of the control group risk (CGR). The number of children needed to treat to benefit (NNTB) to prevent one case of fever on day three of treatment was six (95% CI 4 to 17) ( Analysis 1.1)

We also verified a protective effect of RMT for this outcome: RR 0.36; 95% CI 0.14 to 0.91 ( Analysis 1.1.2). The baseline risk of fever on day three of treatment was 0.38, calculated on the basis of the CGR. The NNTB was five (95% CI 3 to 25) ( Analysis 1.1). Just one trial reported this outcome (Hall 1987).

We observed no protective effect of AMT in the occurrence of fever on day three of treatment: RR 0.37; 95% CI 0.08 to 1.75 ( Analysis 1.1.1) (Kitamoto 1968; Kitamoto 1971).

We saw no protective effect of RMT regarding the occurrence of any of the following outcomes assessed: cases of pain on movement and visual distortion on day five (RR 0.58; 95% CI 0.10 to 3.24) ( Analysis 1.5), conjunctivitis on day five (RR 0.17; 95% CI 0.01 to 3.49) ( Analysis 1.4), malaise on day six (RR 1.04; 95% CI 0.63 to 1.70) ( Analysis 1.3) and cough on day seven (RR 0.83; 95% CI 0.63 to 1.10) ( Analysis 1.2). Just one study reported this outcome (Hall 1987).

No selected studies reported the use of AMT for these latter outcomes.

 
Comparison 2: AMT and RMT compared to control (placebo and to specific treatment) in the prophylaxis of influenza A in children

AMT was compared to placebo and specific treatment (Finklea 1967; Payler 1984) and RMT to placebo (Clover 1986b; Clover 1991; Crawford 1988).

The AMT (Finklea 1967; Payler 1984) and RMT trials (Clover 1986b; Clover 1991; Crawford 1988) were heterogeneous (Chi2 test 9.27, P = 0.05, I2 statistic 56.8%) and could not be combined.

A protective effect of AMT was observed with a RR 0.11; 95% CI 0.04 to 0.30 ( Analysis 2.1.1). The baseline risk of influenza was 0.10, calculated on the basis of the CGR. The NNTB was 12 (95% CI 9 to 17) for a period ranging from 14 (Payler 1984) to 18 weeks (Finklea 1967).

On the other hand, no protective effect of RMT was seen in the prophylaxis of cases of influenza (RR 0.49; 95% CI 0.21 to 1.15) ( Analysis 2.1.2) (Clover 1986b; Clover 1991; Crawford 1988).

 
Comparison 3: adverse effects of AMT and RMT compared to control (placebo and acetaminophen) in children

AMT was compared to placebo (Kitamoto 1968; Kitamoto 1971). RMT was compared to placebo (Clover 1986b; Crawford 1988) and to acetaminophen (Hall 1987).

AMT was not related to a higher risk of the following adverse effects: diarrhoea (RR 0.79; 95% CI: 0.42 to 1.47) ( Analysis 3.1), exanthema (RR 0.69; 95% CI 0.21 to 2.34) ( Analysis 3.2), muscular limb pain (RR 0.85, 95% CI 0.46 to 1.59) ( Analysis 3.4), headache (RR 0.73; 95% CI 0.52 to 1.03) ( Analysis 3.5), and stimulation and insomnia (RR 0.46; 95% CI: 0.12 to 1.74) ( Analysis 3.11) (Kitamoto 1968; Kitamoto 1971).

In the same way, AMT was not related to the outcomes dizziness and dyspnoea. For dizziness the RR was 6.63 (95% CI 0.32 to 137.33) ( Analysis 3.8.1) (Kitamoto 1968; Kitamoto 1971) and for dyspnoea the RR was 0.37 (95% CI 0.02 to 9.02) ( Analysis 3.6) (Kitamoto 1968).

The studies were heterogeneous for the outcomes malaise (Chi2 test 3.75, P = 0.05, I2 statistic 73.3%) and nausea/vomiting (Chi2 test 4.26, P = 0.04, I2 statistic 76.5%), although it seems that the author had used the same protocol. Nevertheless the heterogeneity for the outcome nausea/vomiting does not seem to be relevant, as AMT could be related either to an increase or to a reduction in the occurrence of this adverse effect (Kitamoto 1968; Kitamoto 1971).

No cases of arrhythmia were reported in those two trials.

RMT was not related to a higher risk of any of the following adverse effects assessed: CNS symptoms (RR 0.23; 95% CI 0.01 to 4.70) ( Analysis 3.9); change in behaviour (RR 0.23; 95% CI 0.01 to 4.70) ( Analysis 3.10); diarrhoea (RR 0.36; 95% CI 0.02 to 8.41) ( Analysis 3.1.2); dizziness (RR 3.21; 95% CI 0.14 to 75.68) ( Analysis 3.8.2); GI manifestations (RR 1.17; 95% CI 0.08 to 18.05) ( Analysis 3.7); hyperactivity (RR 0.36; 95% CI 0.02 to 8.41) ( Analysis 3.13); tinnitus (RR 3.21; 95% CI 0.14 to 75.68) ( Analysis 3.14); and cerebellar ataxia (RR 2.61; 95% CI 0.11 to 61.80) ( Analysis 3.12) (Clover 1986b; Crawford 1988; Hall 1987).

Each one of the adverse effects described above was studied in just one included study, except for nausea and vomiting (Crawford 1988; Hall 1987). In the same way, RMT was not related to a higher risk of nausea and vomiting: RR 0.96; 95% CI 0.10 to 9.01 ( Analysis 3.15.2).

 
Comparison 4: use of different doses of AMT and RMT for prophylaxis and treatment of influenza in children

There was no selected study conducted in children for this comparison.

 
Comparison 5: adverse effects related to different doses of AMT and RMT in children

There were no selected studies conducted in children for this comparison.

 
Comparison 6: AMT and RMT compared to other antivirals in children

There was no selected study conducted in children for this comparison.

 

Comparisons in the elderly

 
Comparison 7: AMT and RMT compared to control in the treatment influenza A in the elderly

There was no study selected for this comparison.

 
Comparison 8: AMT and RMT compared to control (placebo and zanamivir) in the prophylaxis of influenza A in the elderly

RMT to placebo (Monto 1995; Patriarca 1984) and to zanamivir (Schilling 1998). No protective effect of RMT was seen regarding the prophylaxis of influenza in the elderly: RR 0.74; 95% CI 0.13 to 4.07 ( Analysis 4.1).

Although care must be taken in the interpretation of the Chi2 test due to its low power in detecting heterogeneity in meta-analyses, we should emphasise the high P value observed in this comparison, considered alongside the I2 statistic value under 50%: Chi2 test 3.28; P = 0.19, I2 statistic 39%. We decided to explore the reasons of these findings as if the studies were heterogeneous, even though it would result in smaller samples impairing reaching to any definitive conclusion (Monto 1995; Patriarca 1984; Schilling 1998) .

Monto and Patriarca analysed previously vaccinated participants in blinded trials and used a placebo as control (Monto 1995; Patriarca 1984). Schilling did not state if the participants were vaccinated, although it was stated that the majority of the studied population had been previously immunised (Schilling 1998). This was an unblinded trial in which another antiviral (zanamivir) was used as a control drug.

When we excluded this study (Schilling 1998), the remaining trials (Monto 1995; Patriarca 1984) were shown to be homogeneous, but no protective effect of RMT prophylaxis in the occurrence of cases of influenza persisted (RR 0.45; 95% CI 0.14 to 1.41) ( Analysis 4.4).

Monto 1995 used two different doses of RMT in his trial (100 mg/day and 200 mg/day) and Patriarca 1984 used the conventional dose of 200 mg/day. Schilling 1998 used a single dose of 100 mg/day. We also combined Monto's 200 mg/day subgroup with Patriarca's study in which the same dose was administered, but again no protective effect of RMT was observed in the prophylaxis of influenza: RR 0.44; 95% CI 0.12 to 1.63) ( Analysis 4.2) (Monto 1995; Patriarca 1984; Schilling 1998).

Schilling's sample and Monto's 100 mg/day subgroup were heterogeneous and could not be combined (Chi2 test 2.55, P = 0.11, I2 statistic 60.8%) (Monto 1995; Schilling 1998).

There was no AMT study selected for comparison.

 
Comparison 9: adverse effects of AMT and RMT compared to control (placebo) in the elderly

There were two selected studies for these outcomes, both using RMT and placebo (Monto 1995; Patriarca 1984).

No effect of RMT was seen regarding any of the adverse outcomes assessed in the combined studies: stimulation and insomnia (RR 1.61; 95% CI 0.43 to 6.02) ( Analysis 5.2), confusion (RR 0.79; 95% CI 95% 0.40 to 1.56) ( Analysis 5.5), fatigue (RR 0.81; 95% CI 0.41 to 1.60) ( Analysis 5.6) and vomiting (RR 0.99, 95% CI 0.38 to 2.60) ( Analysis 5.14) (Monto 1995; Patriarca 1984).

In the same way, RMT was not related to the outcomes studied by Monto: headache (RR 0.83; 95% CI 0.21 to 3.38) ( Analysis 5.1); impaired concentration (RR 0.50; 95% CI 0.10 to 2.41); rash or allergic reaction (RR 3.53; 95% CI 0.18 to 67.28); seizures or clonic twitching (RR 2.00; 95% CI 0.23 to 17.54) and dry mouth (RR 0.70; 95% CI 0.23 to 2.12), as well as in those studied by Patriarca: dizziness (RR 0.94; 95% CI 0.15 to 5.97) ( Analysis 5.3) and anxiety (RR 2.83; 95% CI 0.92 to 8.74) ( Analysis 5.4) (Monto 1995; Patriarca 1984).

The articles were heterogeneous just for the occurrence of nausea (test for heterogeneity: Chi2 test 2.02; P = 0.16; I2 statistic 50.5%). Nevertheless, this heterogeneity does not seem to be relevant as RMT could be related either to an increase or to a reduction in the occurrence of nausea in each one of the studies: Patriarca 1984: RR 5.67; 95% CI 0.76 to 42.32 and Monto 1995: RR 1.17; 95% CI 0.47 to 2.90) ( Analysis 5.7).

It is important to stress the small samples studied in both trials. There was no AMT trial selected for comparison.

 
Comparison 10: use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly

A reduced RMT dose of 100 mg/day was comparable to the full dose of 200 mg daily for prophylaxis of influenza in the elderly, although a wide CI was verified (RR 0.93; 95% CI 0.21 to 4.20) ( Analysis 6.1). It should be emphasised the were few data available for these comparisons (Monto 1995).

There was no selected study using different doses of RMT in the elderly, nor any selected trial comparing different doses of AMT for prophylaxis and treatment of influenza in the elderly.

 
Comparison 11: adverse effects related to different doses of AMT and RMT in the elderly

There was no protective effect of a reduced dose of RMT in the occurrence of the following adverse reactions in the elderly: confusion (RR 0.82; 95% CI 0.41 to 1.65) ( Analysis 7.1), depression (RR 0.44; 95% CI 0.12 to 1.65) ( Analysis 7.2), impaired concentration (RR 0.68; 95% CI 0.11 to 3.98) ( Analysis 7.3), insomnia or sleeplessness (RR 1.02; 95% CI 0.26 to 3.97) ( Analysis 7.4), loss of appetite (RR 0.62; 95% CI 0.27 to 1.46) ( Analysis 7.5), rash or allergic reaction (RR 0.34; 95% CI 0.04 to 3.21) ( Analysis 7.6), seizures or clonic twitching (RR 0.11; 95% CI 0.01 to 2.07) ( Analysis 7.7), dry mouth (RR 1.16; 95% CI 0.43 to 3.11) ( Analysis 7.8), fatigue or drowsiness (RR 1.14; 95% CI 0.45 to 2.87) ( Analysis 7.9), headache (RR 1.02; 95% CI 0.30 to 3.42) ( Analysis 7.10) and body weakness or debility (RR 0.91; 95% CI: 0.38 to 2.18) ( Analysis 7.11) (Monto 1995).

There was no AMT trial selected for this comparison in the elderly.

 
Comparison 12: AMT and RMT compared to other antivirals in the elderly

In Gravenstein's, but not in Schilling's study identical placebo was used (Gravenstein 2005; Schilling 1998). When RMT was compared to zanamivir it was shown that zanamivir prevented influenza A more effectively than RMT in the elderly (Gravenstein 2005; Schilling 1998).

There was no AMT trial selected for this comparison in the elderly.

 

Additional comparison (children plus the elderly)

 
Comparison 13: RMT compared to control (placebo) in the prophylaxis of influenza A in children and the elderly

Originally in the protocol we planned only to make the above 12 comparisons. However, whilst analysing data we considered doing an additional comparison and put the two age groups together. As the small samples studied in RMT trials for prophylaxis might have influenced the observed results, we tried to overcome this limitation by combining the trials with RMT in children and in the elderly. RMT had no proven effect in preventing influenza in either age group, but could be effective when we combined the results from both groups. However, it must be stressed that extraneous characteristics between those groups, other than age or previous immunisations, may have occurred, impairing generalisation of these results. There were five studies selected for this comparison (Clover 1986b; Clover 1991; Crawford 1988; Monto 1995; Patriarca 1984) with 156 patients in the treatment group and 125 in the placebo control group. The combination of the trials showed a protective effect of RMT in preventing influenza A (RR 0.49; 95% CI 0.27 to 0.92).

The baseline risk of influenza A was 0.22, calculated on the basis of the CGR. The NNTB was 9.09 (95% CI 6.25 to 50). We should emphasise that the follow-up period ranged from 3 to 11 weeks.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

We used a comprehensive search strategy, and made every effort to identify relevant studies. In the majority of our comparisons, drawing definitive conclusions was impaired by the small number of selected articles and the small sample numbers. The studies demonstrated a decreased incidence of influenza A in children using AMT during a period ranging from 14 to 18 weeks. The NNTB indicates that for every nine to 17 children receiving AMT, one case of influenza A can be prevented.

RMT had no proven effect in preventing influenza in either age group, but could be effective when we combined the results of both groups. Nevertheless, any inferences from combining these groups must be treated with considerable caution, as they are different clinical groups combined with a small number of studies. Extraneous characteristics between those groups, other than age or previous immunisations, may also have occurred impairing generalisation of these results. Multiple comparisons should also be taken into account in the interpretation of these results.

When AMT and RMT were combined, they appeared to prevent the occurrence of fever on day three in children. However, when analysed separately, this effect was confirmed only for RMT. It must be emphasised that there was just one RMT trial selected for this outcome (Hall 1987) in which the baseline risk for the occurrence of fever on day three was 38%. For every five children (ranging from three to 25) treated with RMT in this unique small sample, it would be possible to prevent one case of fever on day three of treatment.

 

Overall completeness and applicability of evidence

It could be suggested that AMT is well tolerated by children, as its use was not related to an increase in the occurrence of the analysed adverse effects. Nevertheless, it may be difficult to distinguish between an adverse effect to the drug and a clinical manifestation of influenza itself. The outcomes muscular pain, headache, malaise, diarrhoea and nausea/vomiting may be adverse effects of AMT as well as clinical manifestations of influenza in children (MS 2006). In the same way, the outcome dyspnoea (Kitamoto 1968) may also occur due to other respiratory diseases, such as asthma, since an asthmatic episode may be triggered by respiratory viruses. So we must emphasise that adverse effects of the drug and clinical manifestations of influenza may had been confounded, since the selected trials were carried out in ill children.

RMT, administered exclusively on a prophylactic basis, was not related to an increase in the occurrence of the analysed adverse effects. In contrast to AMT studies, just nausea/vomiting could be confounded with influenza manifestations. The other adverse effects could not be confounded, as two of the three selected studies were about prophylaxis and were conducted in children without influenza (Clover 1986b; Crawford 1988). The third study (Hall 1987) was the only one carried out in children with influenza. Cerebellar ataxia and nausea/vomiting were the studied adverse effects in this trial. Cerebellar ataxia could not be confounded as it had not been described as an influenza manifestation. Cases of nausea/vomiting, which were also cited by Crawford, could have been confounded with influenza manifestations in Hall's article. The side effects nausea/vomiting were described in two studies (Crawford 1988; Hall 1987), while all the other adverse effects were mentioned in just one: diarrhoea, dizziness, hyperreactivity, tinnitus (Crawford 1988), GI symptoms, CNS symptoms, changes in behaviour (Clover 1986b) and cerebellar ataxia (Hall 1987). RMT also was considered to be well tolerated by the elderly, since it was not related to an increase in the incidence of adverse effects in this age group. But the studied samples were even smaller in the elderly than in the children's age group, and this fact may have influenced our results (Monto 1995; Patriarca 1984).

When analysing the antivirals adverse reactions, we could not even try to overcome the limitation of the small number of articles and the small samples studied by combining the results of both age groups, as the trial authors had described different outcomes (Clover 1986b; Crawford 1988; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984).

Comparison of different doses of antiviral drugs was available only for RMT and was tested in only one study related to the elderly group. There was no selected trial regarding the treatment either in children or in participants using AMT in both age groups. Both doses showed to be comparable in the prophylaxis of influenza as well as in the occurrence of adverse effects with no proven efficacy (Monto 1995).

Data on comparison to other antivirals was available just for RMT and zanamivir for prophylaxis of influenza A in the elderly group. This fact allowed a comparison of drugs of the two different classes of antivirals: M2 ion channel inhibitors and neuraminidase inhibitors. Zanamivir more effectively prevented influenza A in the elderly group (Gravenstein 2005; Schilling 1998).

Although the M2 ion channel inhibitors are increasingly subject to viral resistance (Goodman 2006), it does not mean that we should abandon AMT and RMT. These antivirals proved to be effective prophylactics against influenza in the 1968 Hong Kong pandemic and in the 1977 pandemic-like event 'Russian influenza'. Although the same resistance marker (Ser31Asn) was present in two isolates of influenza A (H5N1) obtained from patients in China in 2003 and in one lineage of avian and human H5N1 viruses in Thailand, Vietnam and Cambodia, most tested isolates from a second lineage that had been circulating in Indonesia, China, Mongolia, Russia and Turkey appear to be sensitive to AMT (Hayden 2005). Furthermore, the next pandemic virus may be one that, like H2N2, is susceptible to this class of drug. If the circulating strain were known to be susceptible to M2 inhibitors, these drugs would offer a less costly alternative to other antivirals (neuraminidase inhibitors) for prophylaxis against influenza.

 

Quality of the evidence

We selected a total of 12 RCTs (2494 participants: 1586 children and adolescents and 908 elderly participants).

The main factors that affect the strength of evidence are the sparsity of data and the unclear risk of selection bias (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984; Schilling 1998). Two of these studies, both on the elderly, were classified as high risk of bias because of incomplete outcome data (Monto 1995; Patriarca 1984) and high probability of detection bias (Monto 1995). Two trials, both in children and adolescents, were considered to have a low risk of bias (Hall 1987; Payler 1984).

 

Potential biases in the review process

The use of unpublished data, obtained in electronic correspondence with two of the 12 contact trial authors (Hall 1987; Payler 1984), was the identified potential of bias in this review process.

 

Agreements and disagreements with other studies or reviews

Although a systematic review carried out in adults (Jefferson 2009a) showing that both AMT and RMT are efficacious and safe in the prophylaxis and treatment of influenza A symptoms, we could not reach the same conclusion in children and the elderly, except for prophylaxis with AMT in children. This antiviral was effective in preventing influenza A in children. As in the adults review, RMT shortens the duration of fever in children.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

According to available data, AMT was effective in the prophylaxis against influenza A in children. The safety of the drug was not well established, but it should be tried if one takes into account the important role of children in transmitting infections. Currently, RMT cannot be recommended as a prophylactic drug for either age group. Nevertheless, if we consider: 1) it is a safe drug; 2) the results of the combined age groups, and 3) the possibility that the next pandemic virus is susceptible to this class of drug, as indicated in former pandemics, we can still consider this 'old' drug as a less costly alternative to neuraminidase inhibitors.

Our conclusions regarding the effectiveness of both antivirals for the treatment of influenza A in children was limited to a proven benefit of RMT in the abatement of fever by day three of treatment with RMT. This benefit does not seem to justify a recommendation for using RMT to treat all children with influenza A infection, but only for selected cases in which fever may cause undesirable consequences. We could not reach a conclusion regarding AMT in the elderly, or antiviral treatment in this age group, as no trials fulfilled our selection criteria.

Caution must be taken when considering the results, as multiple comparisons were developed using the same sample. Therefore, it is possible that statistically significant results could have occurred by chance.

 
Implications for research

Definitive conclusions may have been impaired by the small number of selected studies and the small sample numbers used. Further research is necessary for:

Treatment

AMT for the treatment of influenza A in children to increase the sample numbers and the power of the studies.
RMT for the treatment of influenza A in children in order to confirm the observed result from the only selected study and to see if the drug could be useful in treating other clinical manifestations of influenza.
AMT and RMT for the treatment of influenza A in the elderly, as no identified studies fulfilled our inclusion criteria.

Prophylaxis

RMT in children to increase the sample numbers and the power of the studies, in order to achieve more definitive conclusions.
AMT in the elderly as there was no identified studies fulfilling our inclusion criteria for this age group.
RMT in the elderly to increase the sample numbers and the power of the studies, in order to achieve more definitive conclusions.

Adverse effects

AMT in children without influenza to avoid confounding adverse reactions of the antiviral with clinical manifestations of influenza.
RMT in the elderly to increase the sample numbers and the power of the studies.

Different doses of AMT and RMT

Further information is necessary on both drugs in both age groups.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

The authors would like to thank Amanda Burls, Rebecca Mears, David Moore, Lisa Gold and Karen Elley for the use of their protocol. We also would like to thank Tom Jefferson and Richard Stubbs for comments provided on the draft protocol. We acknowledge Elizabeth Dooley from the Cochrane Acute Respiratory Infections Group for helping us in all phases of the review process; Ruth Foxlee and Sarah Thorning, for their essential help with the search strategy, the Iberoamerican Cochrane Centre and especially the kindness of Marta Roque, who helped us in the statistical and methodological aspects of the review. We also acknowledge Raimundo Santos, Vladmír Plesnik, Oleg Borisenko and Stuko Nakano with the assessment and translation of the essential topics for this review of the clinical trials published in German, French, Czech, Russian and Japanese. We also thank Jonathan Haliburton for reviewing the English version of this manuscript.The review authors wish to thank Caroline Hall, David Payler and Vladmír Plesnik, who generously provided us with unpublished trial data. Finally, we wish to thank the following referees who gave their permission to be acknowledged for commenting on this review: Maryann Napoli, Nelcy Rodriguez, and Tom Jefferson.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. AMT and RMT compared to control in the treatment of influenza A in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fever day 33173Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.79]

    1.1 AMT
2104Risk Ratio (M-H, Random, 95% CI)0.37 [0.08, 1.75]

    1.2 RMT
169Risk Ratio (M-H, Random, 95% CI)0.36 [0.14, 0.91]

 2 Cough day 7169Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.10]

    2.1 RMT
169Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.10]

 3 Malaise day 6169Risk Ratio (M-H, Random, 95% CI)1.04 [0.63, 1.70]

    3.1 RMT
169Risk Ratio (M-H, Random, 95% CI)1.04 [0.63, 1.70]

 4 Conjunctivitis day 5169Risk Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.49]

    4.1 RMT
169Risk Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.49]

 5 Eye symptoms day 5 (pain on movement and visual distortion)169Risk Ratio (M-H, Random, 95% CI)0.58 [0.10, 3.24]

    5.1 RMT
169Risk Ratio (M-H, Random, 95% CI)0.58 [0.10, 3.24]

 
Comparison 2. AMT and RMT compared to control in the prophylaxis of influenza A in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Infection5951Risk Ratio (M-H, Random, 95% CI)0.25 [0.09, 0.66]

    1.1 AMT
2773Risk Ratio (M-H, Random, 95% CI)0.11 [0.04, 0.30]

    1.2 RMT
3178Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.15]

 
Comparison 3. Adverse effects of AMT and RMT compared to control in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea3655Risk Ratio (M-H, Random, 95% CI)0.79 [0.42, 1.47]

    1.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.81 [0.43, 1.53]

    1.2 RMT
156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]

 2 Exanthema2599Risk Ratio (M-H, Random, 95% CI)0.69 [0.21, 2.34]

    2.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.69 [0.21, 2.34]

 3 Malaise2599Risk Ratio (M-H, Random, 95% CI)0.89 [0.41, 1.96]

    3.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.89 [0.41, 1.96]

 4 Muscular, limb pain2599Risk Ratio (M-H, Random, 95% CI)0.85 [0.46, 1.59]

    4.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.85 [0.46, 1.59]

 5 Headache2599Risk Ratio (M-H, Random, 95% CI)0.73 [0.52, 1.03]

    5.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.73 [0.52, 1.03]

 6 Dyspnoea1159Risk Ratio (M-H, Random, 95% CI)0.37 [0.02, 9.02]

    6.1 AMT
1159Risk Ratio (M-H, Random, 95% CI)0.37 [0.02, 9.02]

 7 Gastrointestinal symptoms176Risk Ratio (M-H, Random, 95% CI)1.17 [0.08, 18.05]

    7.1 RMT
176Risk Ratio (M-H, Random, 95% CI)1.17 [0.08, 18.05]

 8 Dizziness3655Risk Ratio (M-H, Random, 95% CI)4.69 [0.53, 41.75]

    8.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)6.63 [0.32, 137.33]

    8.2 RMT
156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]

 9 Central nervous system symptoms176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]

    9.1 RMT
176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]

 10 Change in behaviour176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]

    10.1 RMT
176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]

 11 Stimulation/insomnia2599Risk Ratio (M-H, Random, 95% CI)0.46 [0.12, 1.74]

    11.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.46 [0.12, 1.74]

 12 Cerebelar ataxia169Risk Ratio (M-H, Random, 95% CI)2.61 [0.11, 61.80]

    12.1 RMT
169Risk Ratio (M-H, Random, 95% CI)2.61 [0.11, 61.80]

 13 Hyperreactivity156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]

    13.1 RMT
156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]

 14 Tinnitus156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]

    14.1 RMT
156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]

 15 Nausea/vomiting4724Risk Ratio (M-H, Random, 95% CI)0.61 [0.24, 1.58]

    15.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.54 [0.15, 2.00]

    15.2 RMT
2125Risk Ratio (M-H, Random, 95% CI)0.96 [0.10, 9.01]

 16 Arrythmia2599Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.1 AMT
2599Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. AMT and RMT compared to control in the prophylaxis of influenza A in the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 RMT (proved and clinical infection)3191Risk Ratio (M-H, Random, 95% CI)0.74 [0.13, 4.07]

 2 RMT 200275Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.63]

 3 RMT 1002130Risk Ratio (M-H, Random, 95% CI)1.42 [0.10, 21.10]

 4 RMT Monto (100 + 200) and Patriarca2103Risk Ratio (M-H, Random, 95% CI)0.45 [0.14, 1.41]

 
Comparison 5. Adverse effects of AMT and RMT compared to control in the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache1198Risk Ratio (M-H, Random, 95% CI)0.83 [0.21, 3.38]

    1.1 RMT
1198Risk Ratio (M-H, Random, 95% CI)0.83 [0.21, 3.38]

 2 Stimulation/insomnia2233Risk Ratio (M-H, Random, 95% CI)1.61 [0.43, 6.02]

    2.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)1.61 [0.43, 6.02]

 3 Dizziness135Risk Ratio (M-H, Random, 95% CI)0.94 [0.15, 5.97]

    3.1 RMT
135Risk Ratio (M-H, Random, 95% CI)0.94 [0.15, 5.97]

 4 Anxiety135Risk Ratio (M-H, Random, 95% CI)2.83 [0.92, 8.74]

    4.1 RMT
135Risk Ratio (M-H, Random, 95% CI)2.83 [0.92, 8.74]

 5 Confusion2233Risk Ratio (M-H, Random, 95% CI)0.79 [0.40, 1.56]

    5.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)0.79 [0.40, 1.56]

 6 Fatigue2233Risk Ratio (M-H, Random, 95% CI)0.81 [0.41, 1.60]

    6.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)0.81 [0.41, 1.60]

 7 Nausea2233Risk Ratio (M-H, Random, 95% CI)1.99 [0.45, 8.75]

    7.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)1.99 [0.45, 8.75]

 8 Depression2233Risk Ratio (M-H, Random, 95% CI)1.63 [0.53, 4.98]

    8.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)1.63 [0.53, 4.98]

 9 Impaired concentration1198Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.41]

    9.1 RMT
1198Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.41]

 10 Loss of appetite2233Risk Ratio (M-H, Random, 95% CI)1.11 [0.56, 2.17]

    10.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)1.11 [0.56, 2.17]

 11 Rash or allergic reaction1198Risk Ratio (M-H, Random, 95% CI)3.53 [0.18, 67.28]

    11.1 RMT
1198Risk Ratio (M-H, Random, 95% CI)3.53 [0.18, 67.28]

 12 Seizures or clonic twitching1198Risk Ratio (M-H, Random, 95% CI)2.0 [0.23, 17.54]

    12.1 RMT
1198Risk Ratio (M-H, Random, 95% CI)2.0 [0.23, 17.54]

 13 Dry mouth1198Risk Ratio (M-H, Random, 95% CI)0.7 [0.23, 2.12]

    13.1 RMT
1198Risk Ratio (M-H, Random, 95% CI)0.7 [0.23, 2.12]

 14 Vomiting2233Risk Ratio (M-H, Random, 95% CI)0.99 [0.38, 2.60]

    14.1 RMT
2233Risk Ratio (M-H, Random, 95% CI)0.99 [0.38, 2.60]

 
Comparison 6. Use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical and laboratorial infection154Risk Ratio (M-H, Random, 95% CI)0.93 [0.21, 4.20]

    1.1 RMT
154Risk Ratio (M-H, Random, 95% CI)0.93 [0.21, 4.20]

 
Comparison 7. Adverse effects related to different doses of AMT and RMT in the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Confusion1262Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.65]

    1.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.65]

 2 Depression1262Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.65]

    2.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.65]

 3 Impaired concentration1262Risk Ratio (M-H, Random, 95% CI)0.68 [0.11, 3.98]

    3.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.68 [0.11, 3.98]

 4 Insomnia or sleeplessness1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.26, 3.97]

    4.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.26, 3.97]

 5 Loss of appetite1262Risk Ratio (M-H, Random, 95% CI)0.62 [0.27, 1.46]

    5.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.62 [0.27, 1.46]

 6 Rash or allergic reaction1262Risk Ratio (M-H, Random, 95% CI)0.34 [0.04, 3.21]

    6.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.34 [0.04, 3.21]

 7 Seizure or clonic twitching1262Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 2.07]

    7.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 2.07]

 8 Dry mouth1262Risk Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.11]

    8.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.11]

 9 Fatigue and drowsiness1262Risk Ratio (M-H, Random, 95% CI)1.14 [0.45, 2.87]

    9.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)1.14 [0.45, 2.87]

 10 Headache1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.30, 3.42]

    10.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.30, 3.42]

 11 Body weakness or debility1262Risk Ratio (M-H, Random, 95% CI)0.91 [0.38, 2.18]

    11.1 RMT
1262Risk Ratio (M-H, Random, 95% CI)0.91 [0.38, 2.18]

 
Comparison 8. AMT and RMT compared to other antivirals in the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 RMT and zanamivir2545Risk Ratio (M-H, Random, 95% CI)4.63 [1.46, 14.72]

 
Comparison 9. Additional comparison: RMT compared to control in the prophylaxis of influenza A in children and the elderly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Infection5281Risk Ratio (M-H, Random, 95% CI)0.49 [0.27, 0.92]

    1.1 RMT
5281Risk Ratio (M-H, Random, 95% CI)0.49 [0.27, 0.92]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); MEDLINE (1966 to July 2007); and EMBASE (1980 to July 2007).

The MEDLINE and CENTRAL search strategy are shown below. We combined the MEDLINE search string with the Cochrane highly sensitive search strategy phases one and two as published in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). We adapted the search strategy to search EMBASE.

MEDLINE (OVID)
1 exp INFLUENZA/
2 influenza.mp.
3 or/1-2
4 exp AMANTADINE/
5 amantadine.mp.
6 exp RIMANTADINE/
7 rimantadine.mp.
8 or/4-7
9 3 and 8

EMBASE (Embase.com)
1 exp INFLUENZA/
2 influenza.ti. or influenza.ab.
3 or/1-2
4 exp AMANTADINE/
5 amantadine.ti. or amantadine.ab.
6 exp RIMANTADINE/
7 rimantadine.ti. or rimantadine.ab.
8 or/4-7
9 3 and 8
10 Randomized Controlled Trial/
11 Controlled Study/
12 exp RANDOMIZATION/
13 Single Blind Procedure/
14 Double Blind Procedure/
15 Crossover Procedure/
16 Phase 3 Clinical Trial/
17 Phase 4 Clinical Trial/
18 or/10-17
19 9 and 18

 

Appendix 2. MEDLINE search strategy

MEDLINE (OVID)
1 exp Influenza, Human/
2 influenza*.tw.
3 flu.tw.
4 exp Influenzavirus A/
5 or/1-4
6 exp Amantadine/
7 amantadine.tw,nm.
8 symmetrel.tw,nm.
9 Rimantadine/
10 rimantadine.tw,nm.
11 flumadine.tw,nm.
12 or/6-11
13 5 and 12

 

Appendix 3. EMBASE.com search strategy

#13. #9 AND #12
#12. #10 OR #11
#11. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR allocat*:ab,ti OR assign*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#10. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#9. #3 AND #8
#8. #4 OR #5 OR #6 OR #7
#7. rimantadine:ab,ti OR flumadine:ab,ti
#6. 'rimantadine'/de
#5. amantadine:ab,ti OR symmetrel:ab,ti
#4. 'amantadine'/de
#3. #1 OR #2
#2. influenza*:ab,ti OR flu:ab,ti
#1. 'influenza'/de OR 'influenza virus a'/exp

 

Feedback

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms
 

Amantadine and rimantadine for influenza A in children and the elderly, 24 January 2008

 

Summary

A year ago CDC provided a recommendation not to use these drugs for 'flu supporting this recommendation by newly acquired resistance of the virus. I believe that this recommendation ought to be at least discussed in the review and better, addressed e.g. by analysis of RCTs data for time periods e.g. before 2000 and after etc.
Also it would be nice to have the abstract rich with data, not just a statement.

Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

 

Reply

We do agree that the issue of viral resistance is of utmost importance. We have stressed this concern in the Background and in the Discussion sections. We expect, from what is written in the text, that readers would be aware of the problem.

Background: ...Both drug classes have shown partial effectiveness for prevention and treatment of influenza A viruses, although neuraminidase inhibitors are less likely to promote the development of drug-resistant influenza (Moscona 2005)

Discusion : Data on comparison to other antivirals was available just for RMT and zanamivir for prophylaxis of influenza A in the elderly group. This fact allowed a comparison of drugs of the two different classes of antivirals: M2 ion channel inhibitors and neuraminidase inhibitors. Zanamivir more effectively prevented influenza A in the elderly group (Gravenstein 2005; Schilling 1998). Although the M2 ion channel inhibitors are increasingly subject to viral resistance (Goodman 2006) it does not mean that we should abandon AMT and RMT. These antivirals proved effective for prophylaxis against influenza illness in the 1968 pandemic of “Hong Kong Influenza” and in 1977 pandemic-like event involving “Russian influenza”. Although the same resistance marker (Ser31Asn) was present in two isolates of influenza A (H5N1) obtained from patients in China in 2003 and in one lineage of avian and human H5N1 viruses in Thailand, Vietnam, and Cambodia, most tested isolates from a second lineage that has been circulating in Indonesia, China, Mongolia, Russia, and Turkey appear to be sensitive to amantadine (Hayden 2005). Futhermore, the next pandemic virus may be one that, like H2N2, is susceptible to this class of drugs. If the circulating strain were known to be susceptible to M2 inhibitors, these drugs would offer a less costly alternative to other antivirals (neuraminidase inhibitors) for prophylaxis against illness.

 

Contributors

Vasiliy Vlassov
Feedback comment added 12 June 2008

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 27 June 2011.


DateEventDescription

27 June 2011New search has been performedSearches updated. No new trials fulfilled our inclusion criteria. We excluded 38 new trials (Bantia 2010; Boltz 2010; Brammer 2009; Burch 2009; Cady 2011; Carter 2008; Cayley 2010; Chawla 2009; Chen 2007; Cheng 2009; Choi 2009; Chou 2008; Cowling 2008; Curran 2010; De la Camara 2007; DeLaney 2010; Falagas 2010; Farlow 2008; Fiore 2008; Guo 2007; Hota 2007; Kalia 2008; Kim 2011; Kirkby 2010; Korenke 2008; Langlet 2009; Matheson 2007; Miyachi 2011; Moffat 2008; Morrison 2007; Nuesch 2007; Sato 2008; Simeonova 2009; Tappenden 2009; Thomas 2008; Wailoo 2008; Welton 2008; Whitley 2007).

27 June 2011New citation required but conclusions have not changedThe conclusions remain unchanged.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 4, 2000
Review first published: Issue 1, 2008


DateEventDescription

13 May 2009AmendedNo changes - republished to fix technical problem.

12 June 2008Feedback has been incorporatedFeedback comment added.

25 May 2008AmendedConverted to new review format.

26 July 2007New search has been performedSearches conducted.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

Márcia G Alves Galvão (MG) selected the trials, extracted data and was responsible of the methodological aspects of the review.
Marilene Augusta Rocha Crispino Santos (MS) selected the trials, extracted data, was responsible of the methodological aspects of the review and supervised the day-to-day work of the review.
Antonio Ledo Alves da Cunha (AC) was appointed as an arbitrator to solve disagreements between MG and MS on the selection of the trials. He supervised the work in all phases and provided his experience on the development of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

None known.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Differences between protocol and review
  18. Index terms

Originally in the protocol we planned to study the drug effect on reduction of fever and cough, as they are considered the best predictors on influenza diagnosis. After collecting data, we verified that specific timelines for reduction of signs and symptoms were not reported in the included trials. So, we considered the available data and arbitrarily chose a day of antiviral use to evaluate the response to the treatment. This choice was based on Eccle's study in which clinical manifestations were classified in early and later symptoms (Eccle 2005).

We applied wider age ranges for children than the definition stated in the protocol (participants up to 16 years of age). Trials in older participants who were adolescents by WHO definition (WHO 2007) were also included. Data regarding the proportion of the subgroup which strictly fulfilled the age criterion in protocol were not available in five studies or by contacting the trial authors. The respective age ranges were one to 17 years (Clover 1991), 13 to 19 years (Payler 1984), one to 18 years (Clover 1986b; Crawford 1988), and eight to 19 years of age (Finklea 1967).

We planned only to make 12 comparisons. However, whilst analysing data we considered doing an additional comparison and put the two age groups together. As the small samples studied in RMT trials for prophylaxis might have influenced the observed results, we tried to overcome this limitation by combining the trials with RMT in children and in the elderly. It must be stressed that extraneous characteristics between those groups, other than age or previous immunisations, may have occurred, impairing generalisation of these results.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Clover 1986b {published data only}
  • Clover RD, Crawford SA, Abell TD, Ramsey CN Jr, Glezen WP, Couch RB. Effectiveness of rimantadine prophylaxis of children within families. American Journal of Diseases of Children 1986;140(7):706-9. [: CN-00043175]
Clover 1991 {published data only}
Crawford 1988 {published data only}
Finklea 1967 {published data only}
  • Finklea JF, Hennessy AV, Davenport FM. A field trial of amantadine prophylaxis in naturally-occurring acute respiratory illness. American Journal of Epidemiology 1967;85:403-12. [: 5337715]
Gravenstein 2005 {published data only}
  • Gravenstein S, Drinka P, Osterweil D, Schilling M, Krause P, Elliot M, et al. Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population. Journal of the American Medical Directors Association 2005;6:359-66.
Hall 1987 {published data only}
  • Hall CB, Dolin R, Gala CL, Markovitz DM, Zhang YQ, Madore PH, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics 1987;80:275-82. [: CN-00049308]
Kitamoto 1968 {published data only}
  • Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in influenza A2-double-blind studies. Japanese Journal of Tuberculosis and Chest Diseases 1968;15(1):17-26. [: CN-00004214]
Kitamoto 1971 {published data only}
  • Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in naturally occurring Hong Kong influenza - double-blind studies. Japanese Journal of Tuberculosis and Chest Diseases 1971;17(1):1-7. [: CN-0000725]
Monto 1995 {published data only}
  • Monto AS, Ohmit SE, Hornbuckle K, Pearce CL. Safety and efficacy of long-term use of rimantadine for prophylaxis of type A influenza in nursing homes. Antimicrobial Agents and Chemotherapy 1995;39:2224-8. [: CN-00121619]
Patriarca 1984 {published data only}
  • Patriarca PA, Kater NA, Kendal AP, Bregman DJ, Smith JD, Sikes RK. Safety of prolonged administration of rimantadine hydrochloride in prophylaxis of influenza A virus infections in nursing homes. Antimicrobial Agents and Chemotherapy 1984;26(1):101-3. [: CN-00035517]
Payler 1984 {published data only}
Schilling 1998 {published data only}
  • Schilling M, Polvinelli L, Krause P, Gravenstein M, Ambrozaitis A, Jones HH, et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine 1998;16:1771-4. [: 9778755]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
AAPCID 2007 {published data only}
Allen 2006 {published data only}
  • Allen UD, Aoki FY, Stiver HG. The use of antiviral drugs for influenza: recommended guidelines for practitioners. Canadian Journal of infectious Diseases and Medical Microbiology 2006;17(5):273-84.
Anonymous 2006 {published data only}
  • Anonymous. Antiviral drugs in influenza: an adjunct to vaccination in some situations. Prescrire International 2006;15(81):21-30.
Anonymous 2007 {published data only}
  • Anonymous. Oseltamivir: new indication. Prevention of influenza in at-risk children: vaccination is best. Prescrire International 2007;16(87):9-11.
Aoky 1985a {published data only}
Aoky 1985b {published data only}
  • Aoky FY, Silver HG, Sitar DS, Boudreault A, Ogilvie RI. Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults. Clinical Pharmacology and Therapeutics 1985;37(2):128-36. [: CN-00036657]
Aoky 1986 {published data only}
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Atmar 1990 {published data only}
  • Atmar RL, Greenberg SB, Quarles JM, Wilson SZ, Tyler B, Feldman S, et al. Safety and pharmacokinetics of rimantadine small-particle aerosol. Antimicrobial Agents and Chemotherapy 1990;34(11):2228-33. [: CN-00073727]
Baker 1969 {published data only}
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Bantia 2010 {published data only}
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Barr 2007b {published data only}
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Bauer 2007 {published data only}
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Belenky 1998 {published data only}
  • Belenky S, Gentile D, Doyle W, Patel A, Hayden F, Skoner D. Rimantadine effect on specific serum hemagglutination inhibition and nasal antibodies in experimental influenza virus exposure of adults. American Journal of Respiratory and Critical Care Medicine 1998;157(3):A173. [: CN-00428220]
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Boltz 2010 {published data only}
Brady 1990 {published data only}
  • Brady MT, Sears SD, Pacini DL, Samorodin R, DePamphilis J, Oakes M, et al. Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic. Antimicrobial Agents and Chemotherapy 1990;34(9):1633-6. [: CN-00073150]
Brammer 2009 {published data only}
Bricaire 1990 {published data only}
  • Bricaire F, Hannoun C, Boissel JP. Prevention of influenza A. Effectiveness and tolerance of rimantadine hydrochloride [Prevention de la grippe A. Efficacite et tolerance du chlor hydrate de rimantadine]. Nouvelle Presse Médicale 1990;19(2):69-72. [: CN-00065369]
Bryson 1990 {published data only}
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Burch 2009 {published data only}
  • Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al. Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation. Health Technology Assessment 2009;13(58):1-265.
Cady 2011 {published data only}
  • Cady SD, Wang J, Wu Y, Degrado WF, Hong M. Specific binding of adamantane drugs and direction of their polar amines in the pore of the influenza M2 transmembrane domain in lipid bilayers and dodecylphosphocholine micelles determined by NMR spectroscopy. Journal of the American Chemical Society 2011;133(12):4274-84.
Callmander 1968 {published data only}
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Carter 2008 {published data only}
  • Carter NJ, Plosker GL. Prepandemic influenza vaccine H5N1 (split virion, inactivated, adjuvanted) [Prepandrix(trademark)]: a review of its use as an active immunization against influenza A subtype H5N1 virus. BioDrugs 2008;22(5):279-92.
Cayley 2010 {published data only}
Chawla 2009 {published data only}
  • Chawla R, Sharma RK, Bhardwaj JR. Influenza A (H1N1) outbreak and challenges for pharmacotherapy. Indian Journal of Physiology and Pharmacology 2009;53(2):113-26.
Chemaly 2006 {published data only}
  • Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ el al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006;85(5):278-87.
Chen 2007 {published data only}
Cheng 2004 {published data only}
Cheng 2009 {published data only}
  • Cheng HY. Assessing the quality of evidence from randomized, controlled dug and nutritional supplement trials conducted among nursing home residents between 1968 and 2004: what can we learn?. Journal of the American Medical Directors Association 2009;10(1):28-35.
Choi 2009 {published data only}
Chou 2008 {published data only}
Cohen 1976 {published data only}
  • Cohen A, Togo Y, Khakoo R, Waldman R, Sigel M. Comparative clinical and laboratory evaluation of the prophylactic capacity of ribavirin, amantadine hydrochloride, and placebo in induced human influenza type A. The Journal of Infectious Diseases 1976;133(Suppl):A114-20. [: CN-0014092]
Cohen 2006 {published data only}
  • Cohen J, Cairns C, Paquette C, Faden L. Compairing patient access to pharmaceuticals in the UK and US. Applied Health Economics and Health Policy 2006;5(3):177-87.
Cowling 2008 {published data only}
  • Cowling BJ, Fung ROP, Cheng CKY, Fang VJ, Chan KH, Seto WH, et al. Preliminary findings of a randomized trial of non-pharmaceutical interventions to prevent influenza transmission in households. PLoS ONE 2008;3:5.
Curran 2010 {published data only}
  • Curran MP,  Leroux-Roels I. Inactivated split-virion seasonal influenza vaccine (Fluarix®): a review of its use in the prevention of seasonal influenza in adults and the elderly. Drugs 2010;70(12):1519-43.
Dawkins 1968 {published data only}
  • Dawkins AT Jr, Gallager LR, Togo Y, Hornick RB, Harris BA. Studies on induced influenza in man. II. Double-blind study designed to assess the prophylactic efficacy of an analogue of amantadine hydrochloride. Journal of the American Medical Association 1968;203:1095-9. [: CN-00001969]
De la Camara 2007 {published data only}
  • De La Camara R, Lopez-Jimenez J, Vallejo C, Vazquez L, Luis Perez J, Varo E, et al. Update on viral infections in immunocompromised patients. Enfermedades Infecciosas y Microbiologia Clinica 2007;25(Suppl 1):2-11.
DeLaney 2010 {published data only}
  • DeLaney E, Smith MJ, Harvey BT, Pelletier KJ, Aquino MP, Stone JM, et al. Extracorporeal life support for pandemic influenza: the role of extracorporeal membrane oxygenation in pandemic management. Journal of Extra-Corporeal Technology 2010;42(4):268-80.
Denys 1963 {published data only}
  • Denys A, Szram S, Tkaczewski W, Niedzielska H, Bochenska J, Kulawczyk M, et al. Antiviral activity of rimantadine, virological, pathomorphological, and clinical studies. Acta Microbiologica Polonica. Series A: Microbiologia Generalis 1973;5:217-20. [: CN-00009559]
Dolamore 2003 {published data only}
  • Dolamore MJ. Influenza prophylaxis in long-tern care facility: a case-control study of the risk factors for adverse drug reactions to amantadine. Current Therapeutic Research, Clinical and Experimental 2003;64(9):753. [MEDLINE: 2004048279]
Dolin 1982 {published data only}
  • Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. The New England Journal of Medicine 1982;307(10):580-4. [: CN-00201667]
Doyle 1998 {published data only}
  • Doyle WJ, Skoner DP, Patel A, Hayden FG. Effect of rimantadine on induced specific serum haemagglutination-inhibiting antibody and nasal IgA titres after experimental exposure of adults to influenza A virus. Antiviral Therapy 1998;3(1):19-23. [: CN-00201667]
Drinevskii 1998 {published data only}
  • Drinevskii VP, Osidak LV, Natsina VK, Afanas'eva OI, Mil'kint KK, Danini GV, et al. Chemotherapeutics for treatment of influenza and other viral respiratory tract infections in children [Khimiopreparaty v terapii grippa i drugikh respiratomykh infektsii u detei]. Antibiotiki i Khimioterapiia 1998;43(9):29-34. [: CN-00332458]
Drinka 1998 {published data only}
  • Drinka PJ, Gravenstein S, Schilling M, Krause P, Miller BA, Shult P. Duration of antiviral prophylaxis during nursing home outbreaks of influenza. A comparison of 2 protocols. Archives of Internal Medicicine 1998;158(19):2155-9. [: CN-00156407]
Enger 2004 {published data only}
Falagas 2010 {published data only}
  • Falagas ME, Vouloumanou EK, Baskouta E, Rafailidis PI, Polyzos K, Rello J. Treatment options for 2009 H1N1 influenza: evaluation of the published evidence. International Journal of Antimicrobial Agents 2010;35(5):421-30.
Farlow 2008 {published data only}
Fiore 2008 {published data only}
Furuta 2005 {published data only}
Galabov 2006 {published data only}
  • Galabov AS, Simeonova L, Gegova G. Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice. Antiviral Chemistry & Chemotherapy 2006;17(5):251-8.
Galbraith 1969a {published data only}
  • Galbraith AW, Oxford JS, Schild GC, Watson GI. Protective effect of 1-adamantanamine hydrochloride on influenza A2 infections in the family environment: a controlled double-blind study. Lancet 1969;2(7629):1026-8. [: CN-00003903]
Galbraith 1969b {published data only}
  • Galbraith AW, Oxford JS, Schild GC, Watson GI. Study of 1-adamantanamine hydrochloride used apophylactically during the Hong-Kong influenza epidemic in the family environment. Bulletin of the World Health Organization 1969;41(3):677-82. [: 00004308]
Galbraith 1971 {published data only}
  • Galbraith AW, Oxford JS, Schild GC, Potter CW, Watson GI. Therapeutic effect of 1-adamantanamine hydrochloride in naturally occurring influenza A 2-Hong Kong infection. A controlled double-blind study. Lancet 1971;2(7716):113-5. [: 00006011]
Galbraith 1973 {published data only}
  • Galbraith AW, Schild GC, Potter CW, Watson GI. The therapeutic effect of amantadine in influenza occurring during the winter of 1971-2 assessed by double-blind study. Journal of the Royal College of General Practitioners 1973;23(126):34-7. [: CN-00008567]
Garman 2004 {published data only}
Gerth 1966 {published data only}
  • Gerth HJ. Influenza prevention with 1-amino-adamantan-hydrochloride.II [Grippeprophylaxe mit 1-Amino-adamantan-hydrochlorid]. Die Medizinische Welt 1966;2:96-100. [: CN-00000687]
Griffin 2004 {published data only}
  • Griffin SDC, Harvey R, Clarke DS, Barclay WS, Harris M, Rowlands DJ. A conserved basic loop in hepatitis C virus p7 protein is required for amantadine-sensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. The Journal of General Virology 2004;85(2):451-61. [MEDLINE: 2004096848]
Guo 2007 {published data only}
Hay 1986 {published data only}
  • Hay AJ, Zambon MC, Wolstenholme AJ, Skehel JJ, Smith MH. Molecular basis of resistance of influenza A viruses to amantadine. The Journal of Antimicrobial Chemotherapy 1986;18:19-29. [: 00341317]
Hayden 1979 {published data only}
  • Hayden FG, Hall WJ, Douglas RGJ, Speers DM. Amantadine aerosols in normal volunteers; pharmacology and safety testing. Antimicrobial Agents and Chemotherapy 1979;16(5):644-50. [: CN-00341319]
Hayden 1980 {published data only}
  • Hayden FG, Hall WJ, Douglas FG Jr. Therapeutic effects of aerolized amantadine in naturally acquired infection due to influenza A virus. The Journal of Infectious Diseases 1980;141(5):535-42. [: CN-00022657]
Hayden 1981 {published data only}
  • Hayden FG, Gwaltney JM Jr, Van de Castle RL, Adams KF, Giordani F. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrobial Agents and Chemotherapy 1981;19(2):226-33. [: CN-00029040]
Hayden 1982 {published data only}
  • Hayden FG, Zylidnikov DM, Iljenko VI, Padolka YV. Comparative therapeutic effect of aerolized and oral rimantadine HCl in experimental human influenza A virus infection. Antiviral Research 1982;2(3):147-53. [: CN-00029306]
Hayden 1985 {published data only}
  • Hayden FG, Minocha A, Spyker DA, Hoffman HE. Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrobial Agents and Chemotherapy 1985;28(2):216-21. [: CN-00341320]
Hayden 1986 {published data only}
Hayden 1989 {published data only}
  • Hayden FG, Belshe RB, Clover RB, Hay AJ, Oakes MG, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. New England Journal of Medicine 1989;321(25):1696-702. [: CN-00064208]
Hayden 1991 {published data only}
  • Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine. Antimicrobial Agents and Chemotherapy 1991;35:1741-7. [: CN-00079594]
Hayden 2000 {published data only}
  • Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliott MJ, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. New England Journal of Medicine 2000;343(18):1282-9. [: CN-00399563]
Hayden 2006 {published data only}
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Hornick 1969 {published data only}
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Hota 2007 {published data only}
Hout 2006 {published data only}
  • Hout DR, Gomez LM, Pacyniak E, Miller JM, Hill MS, Stephens EB. A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian-human immunodeficiency virus (SHIV(KU-1bMC33)) susceptible to rimantadine. Virology 2006;348(2):449-61.
Hout 2006b {published data only}
  • Hout DR, Gomez ML, Pacyniak E, Gomez LM, Fegley B, Mulcahy ER el al. Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIVKU1bMC33) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques. Virology 2006;344(2):541-59.
Hurt 2007 {published data only}
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Ilyushina 2005 {published data only}
Ilyushina 2006 {published data only}
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Ilyushina 2007 {published data only}
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Ilyushina 2007b {published data only}
  • Ilyushina NA, Hoffmann E, Solomon R, Webster RG, Govorkova EA. Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice. Antiviral Therapy 2007;12(3):363-70.
Ison 2006 {published data only}
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Ito 2000 {published data only}
  • Ito S, Iijima N, Kanemaki K, Hayashi S, Hujii S, Watanabe T, et al. Therapeutic efficacy of amantadine hydrochloride in patients with epidemic influenza A virus infection. Nihon Kokyuki Gakkai Zasshi [Journal of the Japanese Respiratory Society] 2000;38(12):897-902. [: CN: 00327106]
Ito 2006 {published data only}
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Jefferson 2006a {published data only}
Jefferson 2009a {published data only}
  • Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti D. Amantadine and rimantadine for preventing and treating influenza A in adults. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD001169.pub3; PUBMED: PMID: 12137620]
Jones 2006 {published data only}
  • Jones JC, Turpin EA, Bultmann H, Brandt CR, Schultz-Cherry S. Inhibition of influenza virus infection by a novel antiviral peptide that targets viral attachment to cells. Journal of Virology 2006;80(24):11960-7.
Kalia 2008 {published data only}
Kantor 1980 {published data only}
  • Kantor RJ, Stevens D, Potts DW, Noble GR. Prevention of influenza A/USSR/77 (H1N1): an evaluation of the side effects and efficacy of amantadine in recruits at Fort Sam Houston. Military Medicine 1980;145(5):312-5. [: CN-00176323]
Kawai 2005 {published data only}
  • Kawai N, Ikematsu H, Iwaki N, Satoh I, Kawashima T, Maeda T, et al. Factors influencing the effects of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America 2005;40:1309-16.
Khakoo 1981 {published data only}
  • Khakoo RA, Watson GW, Waldman RH, Ganguly R. Effect of inosiplex (Isoprinosine (Reg. trademark)) on induced human influenza A infection. Journal of Antimicrobial Chemotherapy 1981;7(4):389-97. [: CN-00192285]
Kim 2011 {published data only}
  • Kim SH, Hong SB, Yun SC, Choi WI, Ahn JJ, Lee YJ, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. American Journal of Respiratory and Critical Care Medicine 2011;183(9):1207-14.
Kirkby 2010 {published data only}
  • Kirkby R, Calabrese C, Kaltman L, Monnier J, Herscu P. Methodological considerations for future controlled influenza treatment trials in complementary and alternative medicine. Journal of Alternative and Complementary Medicine 2010;16(3):275-83.
Kiso 2004 {published data only}
Kitamoto 1969 {published data only}
  • Kitamoto O. Early diagnosis and treatment of influenza. Naika. Internal medicine 1969;23(6):1271-6. [: CN-00003590]
Knight 1969 {published data only}
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Knight 1970a {published data only}
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Knight 1970b {published data only}
  • Knight V, Fedson D, Baldini J, Douglas R, Couch R. Amantadine therapy of epidemic influenza A (Hong Kong). Infection and Immunity 1970;1:200-4.
Knight 1981 {published data only}
Korenke 2008 {published data only}
Krylov 1978 {published data only}
  • Krylov VF, Ketilladze ES, Smagulova EG, Alekseeva AA, Nefelova MM. Use of rimantadine in familial foci during an epidemic of influenza caused by A1 virus [Primenenie rimantadina v semeinykh ochagakh v period epidemii grippa, vyzvannogo virusom A1]. Voprosy Virusologii 1978;3:277-82. [: CN-00018933]
Kulichenko 2003 {published data only}
  • Kulichenko LL, Kireyeva LV, Malyshikina EN, Wikman G. A randomized controlled study of Kan Jang versus amantadine in the treatment of influenza in Volgograd. Journal of Erbal Pharmacotherapy 2003;3(1):77-93. [: CN-00473824]
Langlet 2009 {published data only}
  • Langlet P,  D'Heygere F,  Henrion J,  Adler M,  Delwaide J,  Van Vlierberghe H et al. Clinical trial: a randomized trial of pegylated-interferon-alpha-2a plus ribavirin with or without amantadine in treatment-naive or relapsing chronic hepatitis C patients. Alimentary Pharmacology & Therapeutics 2009; Vol. 30, issue 4:352-63.
Le Tissier 2005 {published data only}
  • Le Tissier PR, Carmignac DF, Lilley S, Sesay AK, Phelps CJ, Houston P, et al. Hypothalamic growth hormone-releasing hormone (GHRH) deficiency: target ablation pf GHRH neurons in mice using a viral ion channel transgene. Molecular Endocrinology 2005;19(5):1251-62.
Leeming 1969 {published data only}
Leone 2005 {published data only}
Leung 1979 {published data only}
  • Leung P, McIntosh K, Chai H. Amantadine prophylaxis against influenza A/USSR in children with chronic asthma. Journal of Allergy and Clinical Immunology 1979;63(3):140. [: CN-00353210]
Lim 2007 {published data only}
Lin 2006 {published data only}
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Linder 2005 {published data only}
Lipatov 2007 {published data only}
  • Lipatov AS, Evseenko VA, Yen HL, Zaykovskaya AV, Durimanov AG, Zolotykh SI, et al. Influenza (H5N1) viruses in poultry, Russian Federation, 2005-2006. Emerging Infectious Diseases 2007;13(4):539-46.
Little 1976 {published data only}
  • Little JW, Hall WJ, Douglas RG Jr, Hyde RW, Speers DM. Amantadine effect on peripheral airways abnormalities in influenza A study in 15 students with natural influenza A infection. Annals of Internal Medicine 1976;85(2):177-82. [: CN-00014385]
Little 1978 {published data only}
  • Little JW, Hall WJ, Douglas RG Jr, Mudholkar GS, Speer DM, Patel K. Airway hyperreactivity and peripheral airway dysfunction in influenza A infection. American Review of Respiratory Disease 1978;118(2):295-303. [: CN-00018956]
Lutz 2005 {published data only}
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Lynd 2005 {published data only}
Machado 2004 {published data only}
Mallia 2007 {published data only}
  • Mallia P, Johnston SL. Influenza infection and COPD. International Journal of Chronic Obstructive Pulmonary Disease 2007;2(1):55-64.
Maricich 2004 {published data only}
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Mase 2007 {published data only}
  • Mase M, Eto M, Imai K, Tsukamoto K, Yamaguchi S. Characterization of H9N2 influenza A viruses isolated from chicken products imported into Japan from China. Epidemiology and Infection 2007;135(3):386-91.
Mate 1970 {published data only}
  • Mate J, Simon M, Juvancz I, Takatsy G, Hollos I, Farkas E. Prophylatic use of amantadine during Hong Kong influenza epidemic. Acta Microbiologica Academiae Scientiarum Hungaricae 1970;17(3):285-96.
Mate 1971 {published data only}
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Matheson 2007 {published data only}
Matsuya 2007 {published data only}
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Matthews 2004 {published data only}
McCullers 2004 {published data only}
McKay 2006 {published data only}
Mishin 2005 {published data only}
Miyachi 2011 {published data only}
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Moffat 2008 {published data only}
Monto 1979 {published data only}
Morrison 2007 {published data only}
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Muldoon 1976 {published data only}
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Nafta 1970 {published data only}
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Natsina 1994 {published data only}
  • Natsina VK, Drinevskii VP, Milkint KK. Remantadine in the treatment of influenza in children [Primenenie remantadina dlia lecheniia grippa u detei]. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk Vestnik 1994;9:51-5. [: CN-00110913]
Nuesch 2007 {published data only}
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O'Donoghute 1973 {published data only}
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Obrosova-Serova 1972 {published data only}
  • Obrosova-Serova NP, Fedorova GI, Glukhov PI, Shal'nov MI, Litvinov VG. Effectiveness of midantan and interferon inducers as means of non-specific prevention of influenza [Izuchenie effektivnosti midantana i stimuliatorav interferona kak sredstv nespetsificheskoi profilaktiki grippa]. Antibiotiki 1972;17:734-8. [: CN-00007887]
Oker-Blom 1970 {published data only}
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Ong 2007 {published data only}
Pachucki 2004 {published data only}
  • Pachucki CT, Kurshid MA, Nawrocki J. Utility of reverse transcriptase PCR for rapid diagnosis of influenza A virus infection and detection of amantadine-resistant influenza A virus isolates. Journal of Clinical Microbiology 2004;42(6):2796-8. [MEDLINE: 2004251487]
Peiris 2004 {published data only}
Pemberton 1986 {published data only}
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Petterson 1980 {published data only}
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Pritchard 1989 {published data only}
Quarles 1981 {published data only}
Quilligan 1966 {published data only}
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Rabinovich 1969 {published data only}
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Reis 2006 {published data only}
  • Reis J, John D, Heimeroth A, Mueller HH, Oertel WH, Arndt T, et al. Modulation of human motor cortex excitability by single doses of amantadine. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 2006;31(12):2758-66.
Reuman 1989a {published data only}
  • Reuman PD, Bernstein DI, Keely SP, Young EC, Sherwood, JR, Schiff GM. Differential effect of amantadine hydrochloride on systemic and local immune response to influenza A. Journal of Medical Virology 1989;27(2):137-41. [: CN-00058423]
Reuman 1989b {published data only}
  • 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 Research 1989;11(1):27-40. [: CN-00059636]
Risenbrough 2005 {published data only}
Rose 1980 {published data only}
  • Rose HJ. Therapeutic effects of aerosolized amantadine in naturally acquired infection due to influenza A virus. Journal of Infectious Diseases 1980;141(5):535-42. [: CN-00022657]
Rothberg 2005 {published data only}
Saito 2006 {published data only}
  • Saito R, Li D, Shimomura C, Masaki H, Le MR, Nquyen HL, et al. An off-seasonal amantadine-resistant H3N2 influenza outbreak in Japan. The Tohoku Journal of Experimental Medicine 2006;210(1):21-7.
Sato 2008 {published data only}
  • Sato M, Saito R, Sato I, Tanabe N, Shobugawa Y, Sasaki A, et al. Effectiveness of oseltamivir treatment among children with influenza A or B virus infections during four successive winters in Niigata City, Japan. Tohoku Journal of Experimental Medicine 2008;214(2):113-20.
Sauerbrei 2006 {published data only}
  • Sauerbrei A, Haertl A, Brandstaedt A, Schmidtke M, Wutzler P. Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors. Medical Microbiology and Immunology 2006;195(2):65-71.
Schapira 1971 {published data only}
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Schmidt 2004 {published data only}
Sears 1987 {published data only}
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Semlitsch 1992 {published data only}
  • Semlitsch HV, Anderer P, Saletu B. Topographic mapping of long latency "cognitive" event-related potentials (P 300): a double-blind, placebo-controlled study with amantadine in mild dementia. Journal of Neural Transmission. Parkinson's Disease and Dementia Section 1992;4:319-36. [: CN-00087210]
Serkedjieva 2007 {published data only}
  • Serkedjieva J, Toshkova R, Antonova-Nikolova S, Stefanova T, Teodosieva A, Ivanova I. Effect of a plant polyphenol-rich extract on the lung protease activities of influenza-virus-infected mice. Antiviral Chemistry & Chemotherapy 2007;18(2):75-82.
Shuler 2007 {published data only}
  • Schuler CM, Iwamoto M, Bridges CB, Marin M, Neeman R, Gargiullo P, et al. Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004. Pediatrics 2007;119(3):587-95.
Shvetsova 1974 {published data only}
  • Shvetsova EG, Malysheva AM, Karapats NM, Oleinikova EV, Vasil'eva RI. Comparative study of the epidemiological efficacy of specific and nonspecific influenza preventive agents [Sravnitel'noe izuchenie epidemiologicheskoi effektivnosti speisificheskikh i nespetsificheskikh sredstv profilaktiki grippa]. Zhurnal Mikrobiologii Epidemiologii i Immunobiologii [Journal of microbiology, epidemiology and immunobiology] 1974;51(4):47-51. [: CN-00010299]
Simeonova 2009 {published data only}
  • Simeonova L, Gegova G, Galabov AS. Rimantadine and oseltamivir combination effects in a therapeutic course of application against influenza a (H3N2) in mice. Antiviral Research 2009;82(2):A37.
Skoner 1999 {published data only}
  • Skoner DP, Gentile DA, Patel A, Doyle WJ. Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus. The Journal of Infectious Diseases 1999;180(1):10-4. [: CN-00163791]
Smorodintsev 1970a {published data only}
  • Smorodintsev AA, Zlydnikov DM, Kiselva AM, Romanov JA, Kanantsev AP, Rumovsky VI. Evaluation of amantadine in artificially induced A2 and B influenza. JAMA 1970;213(9):1448-54. [: CN-00004739]
Smorodintsev 1970b {published data only}
  • Smorodintsev AA, Karpuhin GI, Zlydnikov DM, Malyseva AM, Svecova EG, Burov SA, et al. The prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong Kong influenza in Leningrad in 1969. Bulletin of the World Health Organization 1970;42(6):865-72. [: CN-00005082]
Smorodintsev 1970c {published data only}
  • Smorodintsev AA, Karpuhin GI, Zlydnikov DM. The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad. Annals of the New York Academy of Sciences 1970;173:44-73.
Somani 1991 {published data only}
  • Somani SK, Degelau J, Cooper SL, Guay DRP, Ehresman D, Zaske D. Comparision of pharmacokinetic and safety profiles of amantadine 50 and 100 mg daily doses in elderly nursing home residents. Pharmacotherapy 1991;11(6):440-66. [: CN-00441230]
Tajima 2006 {published data only}
  • Tajima T, Kakayama E, Kondo Y, Hirai F, Ito H, Iitsuka T, et al. Etiology and clinical study of community-acquired pneumonia in 157 hospitalized children. Journal of infection and chemotherapy: official journal of the Japan Society of Chemotherapy 2006;12(6):372-9.
Takemura 2005 {published data only}
  • Takemura Y, Ishida H, Saitoh H, Kure H, Kakoi H, Ebisawa K, et al. Economic consequence of immediate testing for C-reactive protein and leukocyte count in new outpatients with acute infection. Clinica Chimica Acta: International Journal of Clinical Chemistry 2005;360(1-2):114-21.
Tappenden 2009 {published data only}
  • Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): A systematic review and economic evaluation. Health Technology Assessment 2009;13(11):iii-148.
Terabayashi 2006 {published data only}
  • Terabayashi T, Morita M, Ueno M, Nakamura T, Urashima T. Inhibition of influenza-virus-induced cytopathy by sialylglycoconjugates. Carbohydrate Research 341;13:2246-53.
Thomas 2008 {published data only}
Thompson 1987 {published data only}
  • Thompson J, Fleet W, Lawrence E, Pierce E, Morris L, Wright P. A comparison of acetaminophen and rimantadine in the treatment of influenza A infection in children. Journal of Medical Virology 1987;21(3):249-55. [: CN-00047234]
Togo 1968 {published data only}
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Togo 1970 {published data only}
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Togo 1972 {published data only}
Townsend 2006 {published data only}
Van der Wouden 2005 {published data only}
Van Voris 1981 {published data only}
Van Voris 1985 {published data only}
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Wailoo 2008 {published data only}
Webster 1986 {published data only}
  • Webster R, Kawaoka Y, Bean W. Vaccination as strategy to reduce the emergence of amantadine and rimantadine-resistant strains of A/Chick/Pennsylvania/83 (H5N2) influenza virus. Journal of Antimicrobial Chemotherapy 1986;18:157-64. [: CN-00341633]
Welton 2008 {published data only}
  • Welton NJ, Cooper NJ, Ades AE, Lu G, Sutton AJ. Mixed treatment comparison with multiple outcomes reported inconsistently across trials: evaluation of antivirals for treatment of influenza A and B. Statistics in Medicine 2008;27(27):5620-39.
Wendel 1966 {published data only}
Whitley 2007 {published data only}
Wingfield 1969 {published data only}
  • Wingfield WL, Pollack D, Grunert RR. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. New England Journal of Medicine 1969;281(11):579-84.
Wong 2006 {published data only}
Wright 1976 {published data only}
  • Wright PF, Khaw KT, Oxman MN, Shwachman H. Evaluation of the safety of amantadine-HCL and the role of respiratory viral infections in children with cystic fibrosis. Journal of Infectious Diseases 1976;134(2):144-9. [: CN-00208364]
Wultzler 2004 {published data only}
  • Wultzler P, Kossow KD, Lode H, Ruf BR, Scholz H, Vogel GE, et al. Antiviral treatment and prophylaxis of influenza in primary care: German recommendations. Journal of Clinical Virology: The Official Publication of the Pan American Society for Clinical Virology 2004;31(2):84-91. [: Unique identifier: 15364262]
Yamaura 2003 {published data only}
  • Yamaura K, Yoshihara M. Investigation of the reconsultation rate and pharmacoeconomic evaluation of period of influenza treatment by oseltamivir. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan 2003;123(10):887-91.
Younkin 1983 {published data only}
  • Younkin SW, Betts RF, Roth FK, Douglas RG Jr. Reduction in fever and symptoms in young adults with influenza A/Brazil/78 H1N1 infection after treatment with aspirin or amantadine. Antimicrobial Agents and Chemotherapy 1983;23(4):577-82. [: CN-00031339]
Yuen 2005 {published data only}
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Zeuzem 1999 {published data only}
  • Zeuzem S, Teuber G, Naumann U, Berg T, Raedle J, Hartmann S, et al. Randomised, double-blind, placebo-controlled trial of interferon-alfa with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 1999;30(4):200A. [: CN-00271208]

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
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