JAGS SEPTEMBER 2010–VOL. 58, NO.
9 LETTERS TO THE EDITOR
Drugs with relatively short elimination half-lives typ-
ically require more-frequent daily dosing to avoid large
peak-to-trough concentration variation. Conversely, drugs
with long elimination half-lives generally require less-
frequent dosing because plasma concentration variations
between doses are smaller.
The pharmacokinetic comparison of memantine 20 mg
one daily and 10 mg twice daily demonstrates that peak-to-
trough fluctuations with once-daily dosing regimens is sim-
ilar to twice-daily dosing. Therefore, it is expected that the
efficacy and adverse effect profile would be comparable
between these dosing schemes. Recent clinical studies in
which the safety and tolerability of once-daily dosing has
been shown to be comparable with that of twice daily dos-
ing support the results of the analysis.4–7 Recent clinical
trials also suggest that an extended-release once-daily for-
mulation is well tolerated and effective for the treatment of
moderate to severe Alzheimer’s disease.8–10 Based on the
current pharmacokinetic analysis, a single conventional-
release 20-mg dose (two 10-mg tablets) may offer the same
daily convenience as a single extended-release formulation
and with similar tolerability as 10 mg taken twice daily.
Irving H. Gomolin, MDCM, AGSF
Division of Geriatric Medicine and Clinical Pharmacology
Winthrop University Hospital
Mineola, NY
Department of Medicine
Stony Brook University
Stony Brook, NY
Candace Smith, PharmD
Department of Clinical Pharmacy Practice
St. John’s University College of Pharmacy & Allied
Health Professions
Queens, NY
Thomas M. Jeitner, PhD
Applied Bench Core
Winthrop University Hospital
Mineola, NY
Department of Medicine
Stony Brook University
Stony Brook, NY
ACKNOWLEDGMENTS
Conflict of Interest: Dr. Jeitner is supported by the T. Sant-
mann Award. There are no or related paper presentations.
Author Contributions: Gomolin: conception, interpre-
tation of data, preparation of manuscript. Smith: pharma-
cokinetic analysis, interpretation of data, preparation of
manuscript. Jeitner: critical review of data and analysis,
preparation of manuscript
Sponsor’s Role: No sponsors were involved in the
conduct of this study.
REFERENCES
1. Namenda (memantine hydrochloride) current U.S. prescribing information.
Forest Pharmaceuticals; 2007.
2. Periclou A, Ventura D, Rao N et al. Pharmacokinetic study of memantine in
healthy and renally impaired subjects. Clin Pharmacol Ther 2006;79:134–143.
1813
3. Liu MY, Sheng-Nan M, Hui-Zhe W et al. Pharmacokinetics of single-dose and
multiple-dose memantine in healthy Chinese volunteers using an analytic
method of liquid chromatography-tandem mass spectrometry. Clin Therapeut
2008;30:641–653.
4. Forest laboratories Clinical Trial Registry. A long –term extension study eval-
uating the safety and tolerability of four memantine dosing regimens in pa-
tients with moderate to severe dementia of the Alzheimer’s type-Phases A and B
[on-line]. Available at http://www.forestclinicaltrials.com/CTR/CTRController/
CTRViewPdf?_file_id=scsr/SCSR_MEM-MD-03AB_final.pdf Accessed May
11, 2010.
5. Forest laboratories Clinical Trial Registry. A long-term extension study eval-
uating the safety and tolerability of BID and QD administration of memantine
in patients with mild to moderate dementia of the Alzheimer’s type-Phases A
and B [on-line]. Available at http://www.forestclinicaltrials.com/CTR/CTR
Controller/CTRViewPdf?_file_id=scsr/SCSR_MEM-MD-11AB_final.pdf Ac-
cessed May 11, 2010.
6. Jones RW, Bayer A, Inglis F et al. Safety and tolerability of once-daily versus
twice-daily memantine: A randomized, double-blind study in moderate to se-
vere Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22:258–262.
7. Ott BR, Blake LM, Kagan E et al. Open label, multicenter, 28-week extension
study of the safety and tolerability of memantine in patients with mild to
moderate Alzheimer’s disease. J Neurol 2007;254:351–358.
8. Forest laboratories Clinical Trial Registry. A randomized, double-blind, pla-
cebo-controlled evaluation of the safety and efficacy of memantine in patients
with moderate-to-severe dementia of the Alzheimer’s type [on-line]. Available
at http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_
file_id=scsr/SCSR_MEM-MD-50_final.pdf Accessed May 11, 2010.
9. Forest laboratories Clinical Trial Registry. An open-label evaluation of the
safety of memantine in patients with moderate-to-severe dementia of the Alz-
heimer’s type [on-line]. Available at http://www.forestclinicaltrials.com/CTR/
CTRController/CTRViewPdf?_file_id=scsr/SCSR_MEM-MD-51_final.pdf
Accessed May 11, 2010.
10. Forest laboratories Clinical Trial Registry. An open-label extension study
evaluating the safety and tolerability of memantine in patients with moderate
to severe dementia of the Alzheimer’s type [on-line]. Available at http://www.
forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_
MEM-MD-54_final.pdf Accessed May 11, 2010.
LOWER MORTALITY FROM H1N1 INFLUENZA IN
OLDER ARGENTINEANS: MEN MORE AFFECTED
To the Editor: Argentina was the first nation in 2009 to
declare an H1N1 epidemic in the southern hemisphere.1,2
Up to the end of 2009 southern hemisphere winter, Argen-
tina was second only to the United States in the number of
reported deaths from H1N1.2 Only one pediatric study has
reported H1N1 influenza mortality in Argentina.3
Conversely, several studies in North America and
Europe have reported that the age distribution of the
2009 pandemic H1N1 virus differs from the populations
traditionally at risk for seasonal influenza.4–6 During peak
periods of seasonal influenza, most hospitalizations occur in
toddlers and frail elderly people, but reports from the
northern hemisphere showed that older people were at
lower risk of current H1N1 infection, although they were at
greater risk of hospitalization and death once infected
by this virus.4–7 Consequently, H1N1 population attribut-
able mortality risk did not differ significantly between
older and younger adults during 2009 in the northern
hemisphere.4–6
This letter reports H1N1 mortality risk in Argentina in
2009, stratified according to age group (Figure 1A). Cases
were confirmed using reverse transcription polymerase
chain reaction (RT-PCR). Mortality per 100,000 inhabit-
ants was 0.6 for people aged 10 to 19, 2.5 for people aged
50 to 59, and 0.9 in people aged 60 and older. Except for
1814 LETTERS TO THE EDITOR
Figure 1. (A) H1N1 incident mortality according to age group in
Argentina, 2009. (B) 2009 H1N1 mortality in Argentina ac-
cording to age group. The broken line shows expected mortality
for the older age group. Expected mortality of people aged 60
and older was estimated using mathematical modeling based on
previous H1N1 epidemics,8 the rhythm of increasing mortality
from the age of 20 to 59 in current H1N1 pandemic and on
previous seasonal influenza epidemics in Argentina (2007/08).
children younger than 10, the mortality rate increased with
age but started to decrease in adults aged 60 and older. The
mortality of people aged 60 and older was 64% lower than
in those aged 50 to 59. Possible explanations include min-
imal contact by older age groups with young travelers and
school-aged children who amplify transmission during the
early stage of the epidemic.1 Alternatively, young adults are
more likely to be exposed, to exhibit fever, and to be tested
for H1N1 once infected.
Nevertheless, there is compelling evidence to suggest
that a main reason why older Argentineans had much lower
mortality is due to immune cross-protection from prior ex-
posure to H1N1 strains circulating worldwide from 1918
(Spanish influenza) to 1957, when they were replaced by
H2N2 viruses.8,9 Many of the older immigrants to Argen-
tine are survivors of the Spanish influenza, and the highest
titers of cross-reactive antibodies to H1N1 are elicited in
the European population born before 1950, whereas indi-
viduals born after 1950 generally have lower titers and lack
this cross-protection.10
These findings are in agreement with previous obser-
vations demonstrating that the smaller number of infections
in older Americans was not simply a reflection of less testing
SEPTEMBER 2010–VOL. 58, NO. 9 JAGS
in this group.7 In Finland, there was an age-related differ-
ence in the prevalence of neutralizing antibody titers against
the 2009 H1N1 virusF96% in those born before 1919 and
less than 5% in those born after 1950.10 This fact is con-
sistent with the low frequency of the 2009 H1N1 influenza
in nursing homes and the high frequency of outbreaks in
schools in Argentina.2,3
Traditionally, in immunologically naive populations,
mortality follows a U-shaped curve because younger adults
have stronger immune responses.8 Therefore, the finding
that older Argentineans have a lower mortality than mid-
dle-aged adults is unusual but explainable in terms of im-
munological memory acquired from 1918 to 1957, when
H1N1 circulated world wide.8–10
Using mathematical modeling based on previous H1N1
epidemics,8 the tread of increasing mortality from the age of
20 to 59 in current H1N1 pandemic, and on previous sea-
sonal influenza epidemics in Argentina (2007–2008), it can
be estimated that expected mortality in people aged 60 and
older would be 4.9 per 100,000 when the immune memory
factor was removed from the model (Figure 1B). The actual
mortality rate of 0.9 per 100.000 supports the hypothesis of
cross-protection acquired in prior exposure to H1N1
strains circulating worldwide from 1918 to 1957.
Unexpectedly, mortality in older Argentinean men was
twice that in older women. The reasons for this difference
are unknown but may involve cultural factors such as older
Argentinean men leaving home to work or engaging in so-
cial activities more often than women. Another possible
explanation is the difference in life expectancies between
the sexes in older Argentineans (men, 72 vs women, 79).
Antibodies titles against H1N1 tend to be higher in older
age groups and this 7-year gap in life expectancy between
the sexes might lead to a survival effect (lower levels of
immunity in young-old groups).
In conclusion, lower mortality was found in older Ar-
gentineans in the current H1N1 pandemic, which may have
potential implications for future health policies, such as
lower priority for immunization of nonfrail older people
against H1N1. Only the final effect of the H1N1 epidemic
upon mortality was analyzed, and reliable data on general
incidence and hospitalization rates according to age group
are not available from official Argentinean sources. Even
though H1N1 geriatric mortality was low in Argentina, it is
possible that, once infected, older Argentineans have higher
risk of hospitalization and death than younger adults.4–6 In
this sense, elderly people would have a lower priority for
anti-H1N1 immunization campaigns but a greater need for
oseltamivir indication and hospitalization than nonpreg-
nant younger adults.
Matheus Roriz-Cruz, MD, PhD
Idiane Rosset, GNP, MPH, PhD
Collaborative Study Group on Aging
Department of Internal Medicine and Faculty of Nursing
Federal University of ‘‘Rio Grande do Sul’’
Rio Grande do Sul, Brazil
Manuel Montero-Odasso, MD, PhD
Division of Geriatric Medicine
University of Western Ontario
London, Ontario, Canada
JAGS SEPTEMBER 2010–VOL. 58, NO. 9
Manuel Montero-Odasso, MD, PhD
Geriatric Medicine Specialist Career
Faculty of Medicine
University of Buenos Aires
Buenos Aires, Argentina
ACKNOWLEDGMENTS
Conflict of Interest: The editor in chief has reviewed the
conflict of interest checklist provided by the authors and has
determined that the authors have no financial or any other
kind of personal conflicts with this paper.
Author Contributions: Roriz-Cruz: study concept.
Roriz-Cruz, Idiane Rosset, and Montero-Odasso: obtained
raw data from Argentinean Ministry of Health, interpreted
and analyzed data, and wrote the manuscript.
Sponsor’s Role: None.
REFERENCES
1. World Health Organization. Human Infection with Pandemic (H1N1) 2009
Virus: Updated Interim WHO Guidance on Global Surveillance (10 July
2009). Geneva: WHO, 2009.
2. Ministry of Health of Argentine. Influenza pandémica (H1N1) 2009.
República Argentina. Informe semana epidemiológica n1 52 (06/Jan/2010).
Buenos Aires: Ministry of Health, 2010.
3. Libster R, Bugna J, Coviello S et al. Pediatric hospitalizations associated with
2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med 2010;362:
45–55.
4. Echevarrı́a-Zuno S, Mejı́a-Aranguré JM, Mar-Obeso A et al. Infection and
death from influenza A H1N1 virus in Mexico: A retrospective analysis. Lancet
2009;374:2072–2079.
5. Louie JK, Acosta MCalifornia Pandemic (H1N1) Working Group. et al. Fac-
tors associated with death or hospitalization due to pandemic 2009 influenza A
(H1N1) infection in California. JAMA 2009;302:1896–902.
6. Donaldson LJ, Rutter PD, Ellis BM et al. Mortality from pandemic A/H1N1
2009 influenza in England: Public health surveillance study. BMJ 2009;339:
b5213.
7. Fisman DN, Savage R, Gubbay J et al. Older age and a reduced likelihood of
2009 H1N1 virus infection. N Engl J Med 2009;361:2000–2001.
8. Palese P, Tumpey TM, Garcia-Sastre A. What can we learn from reconstructing
the extinct 1918 pandemic influenza virus? Immunity 2006;24:121–124.
9. Xu R, Ekiert DC, Krause JC et al. Structural basis of preexisting immunity to
the 2009 H1N1 pandemic influenza virus. Science 2010;328:357–360.
10. Ikonen N, Strengell M, Kinnunen L et al. High frequency of cross-reacting
antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly
in Finland. EuroSurveill 2010;15: pii: 19478.
COMFORT FEEDING ‘‘ALWAYS’’
To the Editor: Kudos to Palecek and colleagues for their
proposal to add ‘‘comfort feeding only’’ to our armament-
arium when eating difficulties arise in patients with ad-
vanced dementia.1 For most, providing food and water is a
deeply held core value defining what it means to care well
for another human being. Families, even those with clear
directives from their loved ones, struggle when the only
option to tube feeding is no feeding. From the trenches I
might suggest a slight change in the term to ‘‘comfort feed-
ing always.’’ The word ‘‘only’’ implies restriction, when the
goal of this proposed new order is to emphasize that ap-
propriate attention to nutritional needs will always be ren-
dered. With respect to Dr. Brauner’s excellent companion
editorial, ‘‘only’’ does not need to be promulgated to stand
up against a default practice of tube feeding.2 The order
defines a practice plan that offers food and liquids as tol-
LETTERS TO THE EDITOR 1815
erated and, when they can no longer be tolerated, the pres-
ence and attention of a caregiver to provide human contact.
It brings the best and most appropriate standard of care we
can offer these patients and their loved ones.
Margaret A. Noel, MD
MemoryCare
Asheville, NC
ACKNOWLEDGMENTS
Conflict of Interest: The editor in chief has reviewed the
conflict of interest checklist provided by the author and has
determined that the author has no financial or any other
kind of personal conflicts with this paper.
Author Contributions: Margaret Noel prepared and
wrote this letter.
Sponsor’s Role: There was no sponsor involved in this
letter.
REFERENCES
1. Palecek EJ, Teno JM, Casarett DJ et al. Comfort feeding only: A proposal to
bring clarity to decision-making regarding difficulty with eating for persons
with advanced dementia. J Am Geriatr Soc 2010;58:580–584.
2. Brauner DJ. Reconsidering default medicine. J Am Geriatr Soc 2010;58:
599–601.
AN UNUSUAL CASE OF EPISTAXIS AND
STAPHYLOCOCCUS AUREUS BACTEREMIA IN AN
OLDER CHINESE WOMAN
To the Editor: An 80-year-old Chinese woman with ad-
vanced Alzheimer’s disease, ischemic heart disease, hyper-
tension, and hyperlipidemia presented with a 1-week
history of recurrent epistaxis and bloody ear discharge.
She was a known nasal carrier of methicillin-resistant
Staphylococcus aureus (SA) and had been admitted to the
hospital three times in recent months for urinary tract in-
fections and lower limb cellulitis. Physical examination was
unremarkable. Nasal endoscopy and otoscopy revealed
crusting in the nasal cavity with a fleshy mass at the right
external auditory canal floor extending posteriorly to the
right postnasal space (PNS). In addition, she had a bilateral
subtotal perforation of the tympanic membrane and
chronic suppurative otitis media. A computed tomography
scan detailed the heterogeneous enhancing right PNS mass
extending toward the left nasopharynx. Histology revealed
extensive necrosis, fibrinopurulent exudates, mixed-type
inflammatory infiltrate, and clusters of gram-positive cocci.
No malignant cells, granulomas, giant cells, or acid-fast
bacilli were seen. Anti-Epstein-barr virus viral capsid
antigen titers were normal (immunoglobulin Ao5, early
antigeno5). Because the suspicion of nasopharyngeal car-
cinoma (NPC) was high, a repeat biopsy was performed
that was again negative for malignancy.
Six days after the biopsy, she presented with heavy
epistaxis, altered consciousness, and a high white blood cell
count (24.79  109/L). Physical examination was unre-
markable, and initial investigations with chest X-ray and
urinalysis did not reveal a likely source of infection. She was