http://groups.yahoo.com/group/aspartameNM/message/1098
Hoffman-La Roche Pharmaceuticals malarial mefloquine (Lariam) toxicity
since 1990, full text: Veterans Health Admin. 2004.06.23: formaldehyde from
11% methanol part of aspartame as cofactor? Murray 2004.06.27 rmforall

Rich Murray, MA Room For All rmforall@...
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-501-2298

2004 June 25 Chronic long-term, low-level formaldehyde exposure can
trigger similar symptoms, as well as a generalized hypersensitivity to
chemical challenges. For both drugs, females are more commonly vulnerable.
So, it is reasonable to explore if formaldehyde and its sources
are cofactors in mefloquine (Lariam) toxicty.

Informed experts explaine that ethanol hangovers, the classic "morning
after", are actually from formaldehyde produced hours after ingestion from
the methanol contamination common in dark wines and liquors.
The following case therefore may indicate that formaldehyde is indeed a
cofactor.

"Adverse reaction to mefloquine associated with ethanol ingestion,"
Wittes RC, Saginur R;
Canadian Medical Association Journal, 1995 Feb 15; 152(4): 515-7.
1995 Case report - one subject
A 40 year old man no history of neuropsychiatric illness took one 250-mg
tablet mefloquine weekly for malaria prophylaxis while in Tanzania;
No adverse reaction following first two doses, but with his third and his
fourth dose he consumed about half a litre whisky;
On those two occasions he experienced hallucinations, paranoid delusions and
suicidal ideation;
Subsequently continued taking mefloquine, but abstained from alcohol ethanol
and had no recurrence of psychiatric symptoms.

http://groups.yahoo.com/group/aspartameNM/message/1047
Avoiding Hangover Hell 2003.12.31 Mark Sherman, AP writer:
Robert Swift, MD [ formaldehyde from methanol in aspartame ]:
Murray 2004.01.16 rmforall

http://groups.yahoo.com/group/aspartameNM/message/1048
hangovers from formaldehyde from methanol (aspartame?):
Schwarcz: Linsley: Murray 2004.01.18

Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 2002.12.09 rmforall

Environ Health Perspect. 2003 Sep; 111(12): 1461-4.
Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity:
central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.
Pall ML.
School of Molecular Biosciences, 301 Abelson Hall, Washington State
University, Pullman, WA 99164, USA. martin_pall@...

The elevated nitric oxide/peroxynitrite and the neural sensitization
theories of multiple chemical sensitivity (MCS) are extended here to propose
a central mechanism for the exquisite sensitivity to organic solvents
apparently induced by previous chemical exposure in MCS.
This mechanism is centered on the activation of N-methyl-D-aspartate (NMDA)
receptors by organic solvents producing elevated nitric oxide and
peroxynitrite, leading in turn to increased stimulating of and
hypersensitivity of NMDA receptors.
In this way, organic solvent exposure may produce progressive sensitivity to
organic solvents.
Pesticides such as organophosphates and carbamates may act via muscarinic
stimulation to produce a similar biochemical and sensitivity response.
Accessory mechanisms of sensitivity may involve both increased blood-brain
barrier permeability, induced by peroxynitrite, and cytochrome P450
inhibition by nitric oxide.
The NMDA hyperactivity/hypersensitivity and excessive nitric
oxide/peroxynitrite view of MCS provides answers to many of the most
puzzling aspects of MCS while building on previous studies and views of this
condition. PMID: 12948884

Prof. Pall describes processes by which an initial trigger exposure, such as
carbon monoxide or formaldehyde, can generate hypersensitivity to many
substances. He himself had recovered from a sudden, debilitating attack of
multiple chemical sensitity in June/July 1997.

The 11% methanol component of aspartame
[ NutraSweet, Equal, Canderel, Benevia, E951 ] is widely admitted by
informed experts to be readily released in the human GI tract
(unlike the similar levels of methanol locked up in complex pepsin molecules
in many fruits and vegetables), to be inevitably and largely converted into
formaldehyde and then formic acid, which are both potent, cumulative toxins.

http://groups.yahoo.com/group/aspartameNM/message/1088
Murray, full plain text & critique:
chronic aspartame in rats affects memory, brain cholinergic receptors, and
brain chemistry, Christian B, McConnaughey M et al, 2004 May:
2004.06.05 rmforall

Pharmacol Biochem Behav. 2004 May; 78(1): 121-7.
Chronic aspartame affects T-maze performance, brain cholinergic receptors
and Na(+),K(+)-ATPase in rats.
Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A, Hammond L,
Harrell S, Metcalf K, Muehlenbein D, Spruill W, Brinson L, McConnaughey M.
Department of Pharmacology, Brody School of Medicine, East Carolina
University, Greenville, NC 27858, USA;
North Carolina School of Science and Mathematics, Durham, NC 27811.
http://www.ecu.edu/pharmacology/faculty/mcconnaughey.html
Mona M. McConnaughey, Ph.D. Research Assistant Professor
Department: PHARMACOLOGY & TOXICOLOGY
Office: Brody Medical Science 6E-120A 252-744-2756
MCCONNAUGHEYM@...

http://groups.yahoo.com/group/aspartameNM/message/1067
eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
Belsito, Nov 2003: Murray 2004.03.30 rmforall [ 150 KB ]

It is certain that high levels of aspartame use, above 2 liters daily for
months and years, must lead to chronic formaldehyde-formic acid toxicity.

Fully 11% of aspartame is methanol-- 1,120 mg aspartame in 2 L diet soda,
almost six 12-oz cans, gives 123 mg methanol (wood alcohol).
The methanol is immediately released into the body after drinking--
unlike the large levels of methanol locked up in complex pepsin molecules
inside many fruits and vegetables.
Within hours, the liver turns much of the methanol into formaldehyde, and
then much of that into formic acid, both of which in time are partially
eliminated as carbon dioxide and water.

However, about 30% of the methanol remains in the body as cumulative
durable toxic metabolites of formaldehyde and formic acid-- 37 mg daily,
a gram every month, accumulating in and affecting every tissue.

If only 10% of the methanol is retained daily as formaldehyde, that would
give 12 mg daily formaldehyde accumulation-- about 60 times more than the
0.2 mg from 10% retention of the 2 mg EPA daily limit for formaldehyde in
drinking water.

Bear in mind that the EPA limit for formaldehyde in drinking water is
1 ppm, or 2 mg daily for a typical daily consumption of 2 L of water.

http://groups.yahoo.com/group/aspartameNM/message/835
ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999:
Murray 2002.05.30 rmforall

This long-term low-level chronic toxic exposure leads to typical patterns of
increasingly severe complex symptoms, starting with headache, fatigue, joint
pain, irritability, memory loss, rashes, and leading to vision and eye
problems, and even seizures. In many cases there is addiction. Probably
there are immune system disorders, with a hypersensitivity to these toxins
and other chemicals.

J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70% of the radioactive methanol in aspartame put into
the stomachs of 3 to 7 kg monkeys was eliminated within 8 hours, with little
additional elimination, as carbon dioxide in exhaled air and as water in
the urine.
They did not mention that this meant that about 30% of the methanol must
transform into formaldehyde and then into formic acid, both of which must
remain as toxic products in all parts of the body.
They did not report any studies on the distribution of radioactivity in body
tissues, except that blood plasma proteins after 4 days held 4% of the
initial methanol.
This study did not monitor long-term use of aspartame.

The low oral dose of aspartame and for methanol was 0.068 mmol/kg, about 1
part per million [ppm] of the acute toxicity level of 2,000 mg/kg, 67,000
mmol/kg, used by McMartin (1979).
Two L daily use of diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg
person, a dose of 67 mmole/kg, a thousand times more than the dose in this
study.
By eight hours excretion of the dose in air and urine had leveled off at
67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine, so 68.7
% was excreted, and 31.3% was retained.
This data is the average of 4 monkeys.
"...the 14C in the feces was negligible."

"That fraction not so excreted (about 31%) was converted to body
constituents through the one-carbon metabolic pool."
"All radioactivity measurements were counted to +-1% accuracy..."
This indicates that the results could not be claimed to have a precision of
a tenth of a percent. OK, so this is a nit-pick-- but I believe espousing
spurious accuracy is a sign of scientific insecurity.

The abstract ends, "It was concluded that aspartame was digested to its
three constituents that were then absorbed as natural constituents of the
diet."
Thus, the concept is very subtly insinuated that methanol, as a
constituent of aspartame, is absorbed as a natural constituent of the diet.
"Dietary methanol is derived in large part from fresh fruits and
vegetables."
This is a serious error, since the large amounts of methanol in fresh fruits
and vegetables are not readily released by human digestion. (W. C. Monte,
1984)
Nowhere in this report are mentioned the dread words, "formaldehyde" and
"formic acid".

http://groups.yahoo.com/group/aspartameNM/message/870
Aspartame: Methanol and the Public Interest 1984: Monte:
Murray 2002.09.23 rmforall

Dr. Woodrow C. Monte Aspartame: methanol, and the public health.
Journal of Applied Nutrition 1984; 36 (1): 42-54.
(62 references) Professsor of Food Science [retired 1992]
Arizona State University, Tempe, Arizona 85287 woodymonte@...
The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is
112 mg, 10% of the aspartame.
The EPA limit for water is 7.8 mg daily for methanol (wood alcohol), a
deadly cumulative poison.
Many users drink 1-2 L daily.
The reported symptoms are entirely consistent with chronic methanol
toxicity. (Fresh orange juice has 34 mg/L, but, like all juices, has 16
times more ethanol, which strongly protects against methanol.)

"Fruit and vegetables contain pectin with variable methyl ester content.
However, the human has no digestive enzymes for pectin (6, 25) particularly
the pectin esterase required for its hydrolysis to methanol (26).

http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold:
Wilson: CIIN: Murray 2002.12.12 rmforall

Thrasher (2001): "The major difference is that the Japanese demonstrated
the incorporation of FA and its metabolites into the placenta and fetus.
The quantity of radioactivity remaining in maternal and fetal tissues
at 48 hours was 26.9% of the administered dose." [ Ref. 14-16 ]

Arch Environ Health 2001 Jul-Aug; 56(4): 300-11.
Embryo toxicity and teratogenicity of formaldehyde. [100 references]
Thrasher JD, Kilburn KH. toxicology@...
Sam-1 Trust, Alto, New Mexico, USA.
http://www.drthrasher.org/formaldehyde_embryo_toxicity.html full text

http://www.drthrasher.org/formaldehyde_1990.html full text Jack Dwayne
Thrasher, Alan Broughton, Roberta Madison. Immune activation and
autoantibodies in humans with long-term inhalation exposure to formaldehyde.
Archives of Environmental Health. 1990; 45: 217-223. "Immune activation,
autoantibodies, and anti-HCHO-HSA antibodies are associated with long-term
formaldehyde inhalation." PMID: 2400243

http://ww.presidiotex.com/barcelona/index.html full text
Formaldehyde derived from dietary aspartame binds to tissue components in
vivo.
Life Sci June 26 1998; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular,
Facultat de Biologia, Universitat de Barcelona, Spain.
http://www.bq.ub.es/cindex.html Línies de Recerca: Toxicitat de
l'aspartame http://www.bq.ub.es/grupno/grup-no.html
Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas,
Sr. Jordi Virgili, Dr. Xavier Remesar, Dr. Jose Antonio
Fernandez-Lopez, Dr. Mariŕ Alemany [male]
Fac. Biologia Tel.: (93)4021521, FAX: (93)4021559
Sra. Carme Trocho "Trok-ho" Fac. Biologia Tel.: (93)4021544,
FAX: (93)4021559 alemany@...

http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 2002.01.17 rmforall
Jerry D Smith, Chris M Terpening, Siegfried OF Schmidt, and John G Gums
Relief of Fibromyalgia Symptoms Following
Discontinuation of Dietary Excitotoxins.
The Annals of Pharmacotherapy 2001; 35(6): 702-706.
Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL, USA.
BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is
often difficult to treat effectively.
CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome
for two to 17 years are described.
All had undergone multiple treatment
modalities with limited success. All had complete, or nearly complete,
resolution of their symptoms within months after eliminating monosodium
glutamate (MSG) or MSG plus aspartame from their diet.
All patients were women with multiple comorbidities
prior to elimination of MSG.
All have had recurrence of symptoms whenever MSG is ingested.

Siegfried O. Schmidt, MD Asst. Clinical Prof. siggy@...
Community Health and Family Medicine, U. Florida, Gainesville, FL
Shands Hospital West Oak Clinic Gainesville, FL 32608-3629
352-376-5071

http://groups.yahoo.com/group/aspartameNM/message/1016
President Bush & formaldehyde (aspartame) toxicity: Ramazzini Foundation
carcinogenicity results Dec 2002: Soffritti: Murray 2003.08.03 rmforall

p. 88 "The sweetening agent aspartame hydrolyzes in the gastrointestinal
tract to become free methyl alcohol, which is metabolized in the liver
to formaldehyde, formic acid, and CO2. (11)"
Medinsky MA & Dorman DC. 1994; Assessing risks of low-level
methanol exposure. CIIT Act. 14: 1-7.

Ann N Y Acad Sci. 2002 Dec; 982: 87-105.
Results of long-term experimental studies on the carcinogenicity of
formaldehyde and acetaldehyde in rats.
Soffritti M, Belpoggi F, Lambertin L, Lauriola M, Padovani M, Maltoni C.
Cancer Research Center, European Ramazzini Foundation for Oncology and
Environmental Sciences, Bologna, Italy. crcfr@...

http://groups.yahoo.com/group/aspartameNM/message/935
Comet assay finds DNA damage from sucralose, cyclamate, saccharin in
mice: Sasaki YF & Tsuda S Aug 2002: Murray 2003.01.01 rmforall
[ Also borderline evidence, in this pilot study of 39 food additives,
using test groups of 4 mice, for DNA damage from for stomach, colon,
liver, bladder, and lung 3 hr after oral dose of 2000 mg/kg aspartame--
a very high dose. Methanol is the only component of aspartame that can lead
to DNA damage. ]

http://groups.yahoo.com/group/aspartameNM/message/1077
eight depressed people react strongly to aspartame, Prof. Ralph G. Walton,
MD, 1993 double-blind study, full text: Murray 2004.04.26 rmforall

Walton, RG, "Adverse reactions to aspartame: double-blind challenge in
patients from a vulnerable population," 1993, with Robert Hudak and
Ruth J. Green-Waite, Biological Psychiatry, 34 (1), 13-17.
Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern Ohio
Universities, College of Medicine, Dept. of Psychiatry, Youngstown,
OH 44501, Chairman, The Center for Behavioral Medicine,
Northside Medical Center, 500 Gypsy Lane, P.O. Box 240 Youngstown,
OH 44501 330-740-3621 rwalton193@...
http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm

http://groups.yahoo.com/group/aspartameNM/message/1071
research on aspartame (methanol, formaldehyde, formic acid) toxicity:
Murray 2004.06.25 rmforall

http://groups.yahoo.com/group/aspartameNM/message/927
Donald Rumsfeld, 1977 head of Searle Corp., got aspartame FDA approval:
Turner: Murray 2002.12.23 rmforall

http://groups.yahoo.com/group/aspartameNM/message/1094
the 11% methanol component of aspartame becomes formaldehyde, now ruled a
carcinogen by WHO International Agency for Research on Cancer: Murray
2004.06.16 rmforall

Many scientific studies and case histories report: * headaches * many body
and joint pains (or burning, tingling, tremors, twitching, spasms, cramps,
stiffness, numbness, difficulty swallowing) * fever, fatigue, swollen
glands * "mind fog", "feel unreal", poor memory, confusion, anxiety,
irritability, depression, mania, insomnia, dizziness, slurred speech, sexual
problems, poor vision, hearing (deafness, tinnitus), or taste * red face,
itching, rashes, allergic dermatitis, hair loss, burning eyes or throat, dry
eyes or mouth, mouth sores, burning tongue * obesity, bloating, edema,
anorexia, poor appetite or excessive hunger or thirst * breathing
problems, shortness of breath * nausea, diarrhea or constipation * coldness
* sweating * racing heart, low or high blood pressure, erratic blood sugar
levels * hypothryroidism or hyperthyroidism * seizures * birth defects
* brain cancers * addiction * aggrivates diabetes, autism, allergies,
lupus, ADHD, fibromyalgia, chronic fatigue syndrome, multiple chemical
sensitivity, multiple sclerosis, pseudotumor cerebri and interstitial
cystitis (bladder pain).

In mutual service, Rich Murray
****************************************************************

From: "David Goldsmith" <eohdfg@...>
To: <Occ-Env-Med-L@...>
Subject: Latest story on Lariam from UPI--VA alerts doctors to malaria-drug
concerns
Date: Friday, June 25, 2004 8:14 AM
Sender: Occupational & Environmental Medicine for Clinicians & Public
Health Professionals <Occ-Env-Med-L@...>
Poster: David Goldsmith <eohdfg@...>
Subject: Latest story on Lariam from UPI--VA alerts doctors to
malaria-drug concerns

WASHINGTON, June 24 (UPI) -- The Department of Veterans Affairs is warning
doctors to watch for long-term mental problems and other health effects
from an anti-malaria drug given to soldiers in Afghanistan and Iraq.

The drug is mefloquine, known by the brand name Lariam, which has been
given to tens of thousands of soldiers since the war on terrorism began.

Some of those soldiers say it has provoked severe mental and physical
problems including suicidal and violent behavior, psychosis, convulsions
and balance disorders. Last year the Food and Drug Administration began
warning that problems might last "long after" someone stops taking it.

The VA warned its own doctors Wednesday that the drug "may rarely be
associated with certain long-term chronic health problems that persist for
weeks, months, and even years after the drug is stopped," according to a
summary of published studies by a VA panel of experts
(more details are at www.va.gov/publ/direc/health, and click on
'Publications' and click on 'Information letters' --IL10-2004-007
http://www.va.gov/publ/direc/health/infolet/102004007.pdf ).

The summary accompanies an "information letter" from the VA's acting
undersecretary for health, Dr. Jonathan B. Perlin, to healthcare
professionals who treat veterans. Veterans' advocates praised the VA
but said the Pentagon seems to have lost track of who has taken the
drug -- making the size of a potentially serious problem unclear.
...........
"We are pleased that the VA is taking a proactive approach to this
situation," said Steve Smithson, assistant director of the American
Legion's National Veterans Affairs and Rehabilitation Commission.
"It is no secret that the military did not do a good job of record keeping
in the first Gulf War," said Smithson. "Early reports on Lariam make me
concerned that we did not learn the lessons from the first Gulf War in that
it is not being documented in health records."

United Press International has reviewed many medical records and has
interviewed dozens of soldiers at eight military bases in the United States
and Europe who said they took the drug. None of the soldiers who said they
took mefloquine had it noted in their medical records.

The VA letter told doctors that a "number of anecdotal and media reports
have suggested that mefloquine has caused more serious effects, including
violent and suicidal behavior, and symptoms similar to Post-traumatic
Stress Disorder." The letter cited reports linking the drug to a wave of
domestic murder-suicides at Fort Bragg, N.C., in the summer of 2002. The
Army has dismissed Lariam as a factor in those murder-suicides.

...........Most recently, UPI reported that a number of soldiers at Fort
Carson, Colo., who returned from Iraq are showing possible signs of
mefloquine
problems. ..........

The Walter Reed Army Institute of Research developed mefloquine in the
1970s after malaria developed resistance to earlier drugs. The Army then
licensed the drug to Swiss pharmaceutical giant Hoffmann-La Roche.
Mefloquine is one of several drugs the Army uses to prevent malaria.

Roche has added increasing warnings about Lariam side effects in the years
since it was approved for use in the United States in 1989. ..........
A Roche spokesman has told UPI that there is "no credible scientific
evidence" linking the drug with "violent criminal behavior." Aggression is
listed under the Adverse Reactions section of the official product label.

In February Dr. William Winkenwerder Jr., the Pentagon's assistant
secretary for health affairs, told Congress that the Army will launch a
study to see whether reports of severe side effects among soldiers are
real. Both he and Army Surgeon General James B. Peake have consistently
said the drug is safe. .........

About 25,000 U.S. soldiers took mefloquine during the Somalia operation, and
a number have complained of long-term mental and physical problems,
including violent and suicidal behavior.
The Army has said it doled out 45,000 mefloquine prescriptions in the year
that ended last October.

The three-page VA letter is accompanied by a 19-page summary of scientific
studies and case reports compiled by an expert group that included medical,
surgical, public-health and pharmacy experts from the department. Some of
the titles among the 61 publications cited are:
"Paranoid psychosis related to mefloquine antimalarial prophylaxis
(prevention)";
"Seizures after antimalarial medication in previously healthy persons";
"Prolonged visual illusions induced by mefloquine (Lariam); a case report."

The letter states that "there are no practical tests for mefloquine, nor
are there any specific tests that can be recommended specifically for
veterans who took mefloquine on active duty."

However, a doctor at the Defense Department's Spatial Orientation Center in
San Diego recently has begun diagnosing a number of service members with
permanent brainstem and vestibular--or balance system--damage that he
believes are due to the drug.

One such diagnosis was given to retired Navy Reserve Cmdr. William
Manofsky, who served in the Iraq war and said he experienced seizures,
balance problems and mental disorders as a result of taking the drug.

Another soldier who has been diagnosed at the center is Staff Sgt.
Georg-Andreas Pogany, a Fort Carson soldier who was attached to a Special
Forces unit in Iraq. He suffered a panic attack after seeing a mangled
Iraqi corpse, he said, and sought help from his superiors. They sent him
back to the United States, where he was charged with cowardice, an offense
punishable by death. That charge was later dropped, but his career is in
limbo. He is currently at Walter Reed Army Medical Center in Washington
undergoing further medical testing and treatment.

Soldiers at Fort Carson say their complaints about problems they believe
were caused by the drug are being ignored by their command and by medical
officials. Several soldiers at the base have told UPI that they are being
pushed out of the military for problems caused by the drug.

In March the Army said it had ruled out mefloquine as a factor in suicides
during Operation Iraqi Freedom in 2003, because only four of 23 confirmed
suicides had occurred in units where the drug was prescribed, and only one
soldier who killed himself tested positive for the drug in his system. In
some units, however, soldiers have told UPI they took the drug, while the
Pentagon has said they did not.

Early this year, the Pentagon said it would no longer use mefloquine in
Iraq, because the risk of malaria is small.
--
(Please send comments to mbenjamin@..., dolmsted@....)

David F. Goldsmith, MSPH, PhD
Associate Research Professor
Department of Environmental & Occupational Health
George Washington University
2100 M Street NW, Suite 203
Washington DC 20052 USA
Tel: 202-994-1734; fax 202-994-0011
cell: 202-549-1019
email: eohdfg@...
website: http://www.OccupationalEpi.com
****************************************************************

http://feinstein.senate.gov/04Releases/r-rumsfeld-lariam4.htm 2004.06.02

http://www.insightmag.com/news/2004/05/16/National/Drug-Causing.Gis.Permanent.Br\
ain.Damage-683426.shtml
4004.05.27

Drug Causing GIs Permanent Brain Damage?
Posted May 27, 2004 By Mark Benjamin and Dan Olmsted

Six U.S. soldiers have been diagnosed by the military with permanent brain
damage from an antimalaria drug used in Iraq and Afghanistan, and health
officials must reassess its safety, a U.S. senator said.

Sen. Dianne Feinstein (D-Calif.), in a letter to Health and Human Services
Secretary Tommy Thompson, said the drug, called mefloquine, has "serious
risks" that have not been adequately tracked by the Pentagon, the Peace
Corps and other government agencies that distribute it.

"I ask that you work with the Food and Drug Administration [FDA] to reassess
the safety of mefloquine," Feinstein wrote Thompson in a letter dated May
24.

Feinstein told Thompson she is concerned that "six service members have been
diagnosed with permanent brainstem and vestibular damage from being given
this drug despite the fact that alternative drugs might have been chosen to
prevent infection."

The FDA last year warned that the drug, also called Lariam, is linked to
reports of suicide, though a connection has not been established. It also
said some psychiatric and neurological side effects have been reported to
last long after taking it. The Pentagon this year announced a new safety
study of the drug, which has been used by some 20 million people worldwide,
and the Department of Veterans' Affairs said it will look at possible
long-term effects on veterans.

According to people familiar with the situation, the six service members
were diagnosed in recent weeks by doctors at the Naval Medical Center in San
Diego. Its Spatial Orientation Lab, a Department of Defense facility,
specializes in balance disorders.

One service member who received a diagnosis is former Navy Reserve Cmdr.
William Manofsky, who became severely ill after taking mefloquine in Iraq
and Kuwait while deployed for Operation Iraqi Freedom. Another soldier with
a mefloquine diagnosis is a Green Beret who served in Afghanistan.

UPI reviewed a copy of Manofsky's medical report from the San Diego lab,
which includes the notation, "Lariam induced," with the word Lariam
underlined.

Earlier this month, Manofsky filed suit against Lariam's manufacturer, Swiss
drug giant Hoffmann-La Roche, for alleged failure to warn of the drug's
risks and for marketing a product it knows is unsafe.

Asked for comment about the lawsuit, Roche spokesman Terence Hurley told
UPI: "We don't comment on pending litigation. Roche believes that the
labeling that accompanies Lariam, and which has been approved by the FDA, is
adequate. Information about the use of Lariam and neuropsychiatric events
has appeared in the product's label since it was approved by the FDA in
1989. ... Roche takes issues of safety very seriously and works with
regulatory authorities on an ongoing basis to ensure recommendations on
product use take into account current scientific and medical evidence."

Manofsky said he became mentally and physically ill after taking the drug,
at one point taking his gun apart because he was afraid he was going to kill
himself. A year after he stopped taking the drug, he still suffers from
severe balance problems, trembling and memory loss.

The diagnoses appear to put the Pentagon, and particularly the Army, in an
unusual position: Military health officials continue to insist the drug is
safe and to prescribe it widely. Army Surgeon General James Peake told a
House subcommittee in February that "we don't think it is as big a problem
as has been made out."

Peake also dismissed any association between the drug and a string of
murder-suicides at Fort Bragg, N.C., in the summer of 2002 by U.S. soldiers
who took Lariam while assigned to units in Afghanistan.

"There was absolutely no statistical correlation between Lariam use and
those suicides," Peake said.

But the Army announced it will study possible Lariam side effects, including
suicide, as a result of the controversy. The study could take up to two
years, according to William Winkerwerder Jr., assistant secretary of defense
for health affairs.

In March another Special Forces soldier committed suicide after taking
Lariam in Iraq and returning home to Monument, Colo. William Howell's wife
believes Lariam triggered his bizarre behavior, in which he stuck a gun in
her face and threatened to kill her before shooting himself. She accused the
Army of not looking into whether the drug had played a role -- the same
charge made by friends of the soldiers involved in the Fort Bragg incidents.

Howell's death in Colorado brought the number of suicides among Special
Forces soldiers during the war on terrorism to five. At least four of the
five took Lariam on deployments just prior to committing suicide, according
to the Army.

Mark Benjamin and Dan Olmsted write for UPI, a sister news organization of
Insight.

http://www.insightmag.com/news/2004/04/27/National/Va.Probes.LongTerm.Effects.Of\
.Malaria.Drug-657827.shtml
2004.04.12

VA Probes Long-Term Effects of Malaria Drug
Posted April 12, 2004 By Mark Benjamin and Dan Olmsted

A decade after veterans first began complaining, the Department of Veterans'
Affairs (VA) says it will review an antimalaria drug given to thousands of
U.S. troops fighting the war on terrorism to determine if it could cause
long-term health and mental problems.

The review comes six weeks after the Pentagon announced its own study of
whether the drug, called Lariam, has caused mental illness and suicide. The
two studies suggest the government's concern about possible effects of the
drug is quickening after years of defending it as safe.

"There has been a lot of attention to possible long-term health problems,
including the possibility of an association with suicide and violent
behavior among service members," VA spokeswoman Karen E. Fedele told United
Press International.

A VA "white paper" on Lariam provided by Fedele says the department "will
need to develop a well-grounded response to concerns among veterans, their
families, Congress, the media and others about possible long-term health
effects among Operation Iraqi Freedom and Operation Enduring Freedom
veterans from taking the antimalarial drug mefloquine (Lariam)."

UPI reported in May 2002 that mounting evidence suggests the drug, known
generically as mefloquine, has triggered such severe mental illness that in
a number of cases it has led to suicide. In an ongoing investigation, UPI
quoted soldiers who served in Somalia and elsewhere beginning in the early
1990s who said the drug had caused long-term problems.

Jeanne Lese of Lariam Action, an activist group,
[ http://www.lariaminfo.org/ info@... ] said: "Somalia vets
have been contacting us for years, saying they're not the same since the
war. They talk of outbursts of rage, anxiety, paranoia, depression, and many
have overwhelming suicidal urges. All of them had at least one friend commit
suicide in Somalia or after. But when they ask if the drug could be making
them sick, they are told Lariam is 'approved by the Food and Drug
Administration [FDA]' so it can't be at fault. The patient is the problem,
not the drug."

The FDA last year ordered that anyone prescribed the drug be given a written
warning that it can cause depression, psychosis, aggression, hallucinations,
paranoia and thoughts of suicide, and that problems may continue "after
Lariam is stopped." The FDA also cited rare reports of suicide among people
taking the drug but said it didn't know if the drug was responsible.

Pentagon officials have said during the last several months that use of
Lariam in Iraq is limited and that the drug does not cause suicide. "I can
tell you we are using almost no Lariam there," Virginia Stephanakis, a
spokeswoman for the Army Surgeon General's office, told UPI in November.

"We don't believe there is any connection between Lariam and suicide," Army
spokeswoman Martha Rudd said in January. "There is nothing to indicate that
is a factor."

But after a Special Forces soldier who took the drug in Iraq committed
suicide after returning to Fort Carson, Colo., last month, a medical
official told the Colorado Springs Gazette that "we had 80,000 people [in
Iraq] on it and only had a few problems." Separately, the paper also
reported that in the year ending this past October, 45,000 U.S. service
members worldwide were prescribed Lariam by the military.

In December, the Pentagon revised their Lariam warning for military
clinicians to say that "rare instances of suicide" have been reported but
that no statistical association has been established, and that "symptoms may
continue long after mefloquine use has been stopped." In February, the
Pentagon announced it would launch its own scientific study of whether
Lariam has in fact triggered mental illness and suicides among troops.

The VA white paper said the department "should review the literature on
mefloquine relative to long-term health effects, with an emphasis on any
effects that may persist after the drug is stopped." It said a Lariam
working group should include the department's directors of surgery and
neurology and "identify experts and recommend how to proceed."

Lariam was invented by the Army to help it fight in parts of the world where
malaria is rampant. It has been taken by tens of thousands of soldiers and a
total of 5 million Americans since it was approved for use in the United
States in 1989.

The VA white paper noted that the Pentagon "has widely prescribed mefloquine
for U.S. service members in Southwest Asia to protect against endemic
malaria." In the summer of 2002, several soldiers who took the drug while
serving in Afghanistan killed their wives and committed suicide at Fort
Bragg, N.C. UPI reported that they showed signs of Lariam toxicity, but the
Army concluded the drug was not responsible in that cluster of deaths.

Veterans' advocate Steve Robinson, a former Army Ranger, said the VA review
was necessary. "We are pleased that the VA will raise its awareness of the
link between Lariam, its deleterious side effects and the psychological
injuries coming out of the war in Iraq," said Robinson, executive director
of the National Gulf War Resource Center. "The VA should make available the
most current scientific tests if veterans believe they have suffered as a
result of taking this drug."
[ http://www.gulfweb.org/ ]

Robinson pointed to the case of former Navy Lt. Cmdr. William Manofsky, who
served during Operation Iraqi Freedom and says taking Lariam caused brain
damage including violent shaking that continues a year after he stopped
taking the drug. Manofsky recently retired on disability, and the Navy
acknowledged that was partly due to Lariam.

In an e-mail exchange with Manofsky last week, the VA's Mark A. Brown, the
official in charge of reviewing health threats to soldiers, said he agreed
that "this is an issue that clearly needs to be looked into." He said the VA
is "concerned that so many veterans took this drug. ... If there are any
serious long-term health effects that persist even after the drug is
stopped, then this would affect a lot of veterans."

Mark Benjamin and Dan Olmsted write for UPI, a sister news organization of
Insight magazine.

http://www.indiana.edu/~primate/larrefs.html mefloquine medical references

*************************************************************************

http://www.va.gov/publ/direc/health/infolet/102004007.pdf

DEPARTMENT OF VETERANS AFFAIRS
Veterans Health Administration Washington DC 20420
IL 10-2004-007 In Reply Refer To: 13 June 23, 2004

UNDER SECRETARY FOR HEALTH'S INFORMATION LETTER
POSSIBLE LONG-TERM HEALTH EFFECTS FROM THE MALARIAL
PROPHYLAXIS MEFLOQUINE (LARIAM)

1. Purpose. This Under Secretary for Health's Information Letter provides
information to clinicians who examine and provide care to veterans who may
have taken mefloquine as a malaria prophylaxis while on active duty in
Southwest Asia during Operation Iraqi Freedom (OIF) and Operation Enduring
Freedom (OEF).

2. Background
a. During OIF and OEF, the United States (U.S.) Department of Defense (DOD)
provided mefloquine (Lariam) to some U.S. service members to protect them
against endemic malaria.

b. Mefloquine is approved by the U.S. Health and Human Services Food and
Drug Administration (FDA) for protection against malaria, and since the late
1980s it has become widely recommended for malaria chemoprophylaxis.
Mefloquine can cause common mild side effects including vivid dreams and
mild psychiatric symptoms, which can be sufficiently uncomfortable as to
affect compliance.
In addition, a number of anecdotal and media reports have suggested that
mefloquine has caused more serious effects, including violent and suicidal
behavior, and symptoms similar to
Post-traumatic Stress Disorder (PTSD).
These media accounts link reports of such behavior to mefloquine use among
returning OIF and OEF veterans, for example, homicides and suicides among
five service members returning to Ft.
Bragg, NC, in the Summer of 2002.
Concerns that mefloquine might cause violent behavior is not new; a Canadian
soldier accused of homicide claimed that taking mefloquine, while deployed
to Somalia in 1992, had caused his violent behavior.

c. Adding to this concern, the DOD warning label "Information for
Clinicians" for mefloquine (taken essentially from the equivalent FDA
label), includes the following:

"Rare instances of suicide in patients taking mefloquine have been reported
but no studies have demonstrated a statistical association between
mefloquine use and suicide, suicidal ideas, suicide attempts, or any other
violent behavior.
Patients with a history of psychiatric illness may be vulnerable to
mefloquine-related psychiatric symptoms, and the package insert recommends
against prescribing (it) to patients with a history of psychiatric or
alcohol problems.
Often, potential neuropsychiatric side effects are the greatest concern for
patients.
Side effects may include anxiety, paranoia, depression, agitation,
restlessness, mood changes, panic attacks, forgetfulness, hallucinations,
aggression, and psychotic behavior.
Symptoms may continue long after mefloquine use has been stopped.
If neuropsychiatric symptoms occur, mefloquine use should be discontinued in
favor of other prophylactic medications or

IL 10-2004-007 June 23, 2004 page 2

measures.
Potential side effects that can impair reaction time and thinking include
sensory and motor neuropathies, encephalopathy, convulsions, psychosis,
nightmares, dizziness, and confusion. Studies indicate that these may occur
in 1 in 2,000 to 1 in 13,000 people who receive prophylactic mefloquine."

d. VHA held a meeting April 13, 2004, to discuss possible responses to this
issue. The meeting included representatives from the Office of Public Health
and Environmental Hazards and Office of Patient Care Services'
Medical-Surgical,
Mental Health, and Pharmacy Benefits & Management, and other VHA leaders and
experts in neurology, mental health, infectious disease, and toxicology.
The group concluded that the Department of Veterans Affairs (VA) needed a
well-grounded response to current concerns among veterans, their families,
Congress, the media, VA health care providers, and others about possible
long-term health effects and disability among OIF and OEF veterans from
taking mefloquine.
In particular, VHA health care providers will need concise and accurate
medical information about mefloquine health effects to answer questions and
concerns of veterans who are returning from deployments in Southwest Asia.

e. To develop guidance on possible long-term and chronic health effects from
mefloquine, this group conducted a literature review of more than sixty
reports that included
eight surveys of travelers,
34 case reports of adverse events,
two Cochrane reviews,
seven epidemiological studies including clinical trials and prospective
studies, and
nine general reviews of multiple case reports, which included manufacturer
and FDA warning label summaries.
The most recent Cochrane review (2004) examined ten clinical trials
involving 2750 adult participants, five of which were field trials, mainly
of male soldiers.

3. Guidance
a. The following summary is to assist VA health care providers when they are
providing care to veterans who may have taken mefloquine while on active
duty.
Since there are no practical tests for mefloquine, nor are there any
specific tests that can be recommended specifically for veterans who took
mefloquine while on active duty,
medical care needs to focus upon occupational health issues:
e.g., taking a thorough military and medical history,
including taking of mefloquine, along with a basic medical examination that
includes appropriate laboratory tests relating to the veteran's complaints
and medical findings.

b. Review of available literature (see Att.A for references and summaries)
suggests that certain health effects may be associated with mefloquine,
some of which may persist after the drug is stopped.
Self-reported symptoms in "travelers surveys" include:
insomnia, mood impairment, depression, "strange thoughts," altered spatial
perception, sleeping disturbances, fatigue, dizziness and other
neuropsychiatric effects,
lasting in some instances more than 2 months.
Clinical trials and epidemiological studies suggest that reported side
effects are not common,
are self-limiting, and include:
depression, panic attacks, anxiety, insomnia, vertigo, nausea and headache,
and strange or vivid dreams.
However, such studies have only limited power to detect more rare and
serious adverse events.

c. The most severe and persistent adverse effects appear in "case reports."
In those instances, consistent with the nature of a case report,
the relevant signs and symptoms began while mefloquine was being taken,
and persisted in some reports for weeks, months or even years after the
drug was stopped. NOTE: Mefloquine has a long half-life in humans of 15 to
30 days.
Adverse effects that are reported to persist for significant periods after
the drug is stopped,
or that could be associated with long-term health effects,
include the following which lists in decreasing frequency the cases;
NOTE: The reported number of individual cases and the number of published
reports for that health effect are shown in parenthesis;
i.e., 16/12 means that there were sixteen reported cases and twelve
published reports.

(1) Anxiety, paranoia, hallucinations, depression, suicidal ideation,
cognitive and other neuropsychiatric symptoms (16/12),

(2) Acute and paranoid psychosis (10/9),

(3) Convulsions, grand mal seizures, coma and abnormal
electroencephalography (EEG) (9/4),

(4) High frequency sensorineural hearing loss and tinnitus, with partial or
no remission (3/1),

(5) Acute lung injury with diffuse alveolar damage (2/1),

(6) Elevated liver function tests or fatty liver (2/2),

(7) Multifocal myoclonus (1/1),

(8) Fatal toxic epidermal necrolysis (1/1),

(9) Trigeminal sensory neuropathy (1/1),

(10) Atrial flutter (1/1), and

(11) Mefloquine overdose induced encephalopathy (1/1).

d. Veterans need to be informed that seeking care for possible
mefloquine-related conditions does not constitute a claim for compensation.
NOTE: Veterans wishing to file a compensation claim need to be referred to a
Veterans Benefits Counselor, or advised to contact the appropriate VA
Regional Office at 1-800-827-1000.

4. Contact. Questions regarding this information letter may be addressed to
the Environmental Agents Service (131) at (202) 273-8579.

S/ Arthur S. Hamerschlag for Jonathan B. Perlin, MD, PhD, MSHA, FACP
Acting Under Secretary for Health DISTRIBUTION: CO: E-mailed 6/23/04
FLD: VISN, MA, DO, OC, OCRO, and 200 - E-mailed 6/23/04 IL 10-2004-007

June 23, 2004
ATTACHMENT A
SUMMARY OF LITERATURE ON POSSIBLE LONG-TERM CHRONIC HEALTH EFFECTS FROM
MEFLOQUINE

1. To develop guidance on possible long-term health effects from mefloquine,
a Veterans Health Administration (VHA) expert group that included
representatives from the Office of Public Health and Environmental Hazards
and Office of Patient Care Services' Medical-Surgical, Mental Health, and
Pharmacy Benefits & Management, and other VHA leaders and experts in
neurology, mental health, infectious disease, and toxicology, conducted a
literature review that located
seven health surveys of travelers,
thirty-four case reports of adverse events,
two Cochrane reviews,
six epidemiological studies including clinical trials and prospective
studies, and
nine general reviews of multiple case reports including manufacturer and
Food and Drug Administration (FDA) warning label summaries.
In addition the two Cochrane reviews (the most recent dated 2004) examined
ten clinical trials involving 2750 adult participants.
Five of those were field trials, mainly of male soldiers.
The following table, sorted by study-type, then by date, summarizes this
information.

Title, Authors, Reference Date Study Type - Subjects Major Findings

"Low body mass index is associated with an increased risk of
neuropsychiatric adverse events and concentration impairment in women on
mefloquine,"
van Riemsdijk MM, Sturkenboom MC, Ditters JM, Tulen JH, Ligthelm RJ,
Overbosch D, Stricker BH;
British Journal of Clinical Pharmacology, 2004; 57(4): 506-12.
2004 Survey of 151 Dutch travelers from 1999 to 2000 before and up to 3
weeks (pretravel) after taking mefloquine
Significant impairment of mood state observed subjects with body mass index
(BMI) < or = 20 kg m(-2);
Stratification for gender showed that the total mood disturbance in females
in the lowest BMI category significantly increased by 8.42 points
[95 percent confidence interval (CI) 3.33, 13.50],
whereas BMI did not affect the risk in males;
Stratification for history of use of mefloquine showed that the risks were
highest in first-time users;
An sustained attention performance test showed reaction time in women with a
BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95 percent CI
7.80, 37.20),
whereas reaction time in men showed a slight and nonsignificant decrease.
CONCLUSION: Risk factors for mefloquine-associated neuropsychiatric adverse
events and concentration impairment are female gender, low BMI, and
first-time use.
The frequency of neuropsychiatric effects is highest in women with a BMI <
or = 20 kg m(-2).

"Many travelers suffer of side-effects of malaria prophylaxis,"
Rietz G, Petersson H, Odenholt I;
Lakartidningen, 2002 Jun 27; 99(26-27): 2939-44.
2002 Survey of about 500 Swedish travelers before and after their trip, with
62 percent response rate
Travelers taking any malarial prophylaxis reported greater rate of symptoms
compared to controls (59 percent vs. 41 percent), and that their trip had
been negatively affected by their symptoms;
Neuropsychiatric symptoms most common among mefloquine takers but the
difference was not significant;
Travelers taking mefloquine more frequently associated their symptoms with
that drug;
travelers most worried about taking malaria prophylaxis prior to the trip
reported symptoms more often than those not feeling any anxiety.

page A-1 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Neuropsychiatric events during prophylactic use of mefloquine before
traveling,"
van Riemsdijk MM, Ditters JM, Sturkenboom MC, Tulen JH, Ligthelm RJ,
Overbosch D, Stricker BH;
European Journal of Clinical Pharmacology, 2002 Sep; 58(6): 441-5.
2002 Survey 179 Dutch travelers from 1999 to 2000 before and for three weeks
after taking mefloquine (prior to traveling)
Females reported adverse events more frequently than males ( P=0.005);
Small but significant increase in the score on the domain fatigue [0.74
points, 95 percent confidence interval (CI) 0.18, 1.30 exclusively in
females and not in males;
Firsttime users increased 2.81 points (95 percent CI 0.70, 4.92) on mood
state test, and among those,
women showed the largest increase of 4.58 points (95 percent CI 0.74, 8.43).
The use of mefloquine was associated with neuropsychiatric adverse effects.
Females encountered neuropsychiatric effects more frequently than males,
which could be confirmed by validated psychological tests.
Neuropsychiatric effects were more common in first-time users than in
individuals who had used mefloquine before.

"Reported side effects to chloroquine, chloroquine plus proguanil, and
mefloquine as chemoprophylaxis against malaria in Danish travelers,"
Petersen E, Ronne T, Ronn A, Bygbjerg I, Larsen SO;
Journal of Travel Medicine, 2000 Mar-Apr; 7(2): 79-84.
2000 Survey of self reports among 5,446 Danish travelers from 1996 to 1998
5,446 Danish travelers surveyed (76.3 percent response) on drug compliance,
hospitalization and premature termination of travel, following use of
chloroquine, chloroquine plus proguanil, or mefloquine;
Compliance significantly better for mefloquine users (83.3 percent among
short term travelers re. 76.3 percent among chloroquine plus proguanil
users);
84.8 percent, 59.3 percent and 69.5 percent reported no symptoms using
chloroquine, chloroquine plus proguanil, and mefloquine, respectively;
0.6 percent, 1.1 percent and 2.8 percent reported "unacceptable" symptoms,
respectively; Compared to chloroquine, mefloquine users had a significantly
higher relative risk (RR) of reporting depression, RR 5.06 (95 percent CI
2.71 - 9.45),
"strange thoughts," RR 6.36 (95 percent CI 2.52 - 16.05) and
altered spatial perception, RR 3.00 (95 percent CI 1.41 - 6.41).
CONCLUSION: Overall mefloquine is tolerated at least as well as chloroquine
plus proguanil and shows better compliance, however, symptoms related to the
central nervous system are more prevalent in mefloquine users and when
symptoms develop, they are perceived as more severe.

"Neuropsychiatric problems in 2,500 long-term young travelers to the
tropics,"
Potasman I, Beny A, Seligmann H;,
Journal of Travel Medicine, 2000 Jan; 7(1): 5-9.
2000 Survey of neuropsychiatric problems and previous psychological
consultation of 2,500 young travelers to tropical countries
Out of 1,340 respondents, 151 (11.3 percent) reported they had
neuropsychiatric problems (NPP) during travel compared to 2.3 percent who
needed psychological consultation before travel (probability (p) <.001);
In a follow up, 117 of 151 responded to a study questionnaire (mean age 24.4
years, 54.7 percent female, mean stay abroad 5.3 months) the most common
reported NPP were
sleeping disturbances (52.1 percent), fatigue (48.7 percent) and dizziness
(39.3 percent).;
33 (2.5 percent) reported severe symptoms,
16 (1.2 percent) had symptoms lasting more than 2 months;
7 had pure or mixed depressive symptoms;
Consumption of recreational drugs admitted by 22.2 percent;
Mefloquine used significantly more often by those who suffered NPP, compared
to the entire cohort (98.2 percent vs. 70.7 percent; p<.001);
CONCLUSIONS: Long-term travel to the tropics was associated, in this cohort,
with a considerable rate of neuropsychiatric symptoms.
The majority of the responding travelers were females, used mefloquine as
prophylaxis, and at least one fifth used recreational drugs.

page A-2 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Adverse effects associated with antimalarial chemoprophylaxis,"
Corominas N, Gascon J, Mejias T, Caparros F, Quinto L, Codina C, Ribas J,
Corachan M.;
Medicina Clinica, 1997 May 24; 108(20): 772-5.
1997 Survey of 1,054 Spanish travelers who traveled from 1992 to 1994
Self reports among 1,054 travelers taking various malarial prophylaxis
including mefloquine;
18.4 percent reported adverse reactions including
12.4 percent on chloroquine, 17.2 percent on chloroquine + proguanil, and
20.3 percent on mefloquine (differences not significant);
Neuropsychiatric reactions more frequent in the mefloquine group (p < 0.01);
Gastrointestinal reactions less common in the chloroquine group (p = 0.04);
Transitory eye disorders more frequent in the chloroquine + proguanil group
(p = 0.01);
Travelers with adverse reactions in mefloquine group had significantly lower
weight than those who did not present them (p < 0.01);
Mefloquine has greater neuropsychiatric toxicity and is worse tolerated in
low weight patients.

"Neuro-psychiatric effects of antimalarials,"
van Riemsdijk MM, van der Klauw MM, van Heest JA, Reedeker FR, Ligthelm RJ,
Herings RM, Stricker BH;
European Journal of Clinical Pharmacology, 1997; 52(1): 1-6.
1997 Survey 394 Dutch travelers taking mefloquine, within 14 days of return,
compared to travelers taking other malarial prophylaxes
Questionnaire consisted of questions regarding use of alcohol, smoking,
general health, medical history, tropical diseases during the trip, and
other medicines, and contained an extensive list of general complaints
regarding all body systems at four levels of severity.
A modified and validated version of the Profile of Mood States was included.
RESULTS: In the study period, 2541 persons visited the Travel Clinic, of
whom 1791 (70 percent) were both eligible and willing to co-operate.
Of these 1791, data were obtained from 1501 (84 percent).
Insomnia was most frequently encountered in users of mefloquine and mouth
ulcers in proguanil users.
After adjustment for gender, age, destination, and alcohol use, the relative
risk for insomnia to mefloquine versus non-users of antimalarials was 1.6,
and the excess risk was 6 per 100 users over an average period of 2 months.
There were no significant differences between groups in depression, anxiety,
agitation, and confusion.
Stratification by gender demonstrated that insomnia was more common in women
on mefloquine, but not in men.
Also, women more frequently mentioned palpitations as an adverse event.
After adjustment for age, destination, and alcohol use in women, the
relative risks for insomnia and palpitations to mefloquine versus non-use of
antimalarials were 2.4, and 22.5, respectively. When travelers were
specifically asked for the adverse reactions they had experienced,
anxiety, vertigo, agitation, and nightmares were significantly more
frequently mentioned by mefloquine users.
CONCLUSION: Insomnia was more commonly encountered during use of mefloquine
than proguanil or during non-use of antimalarials.

page A-3 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Comparison of adverse events associated with use of mefloquine and
combination of chloroquine and proguanil as antimalarial prophylaxis: postal
and telephone survey of travelers," Barrett PJ, Emmins PD, Clarke PD,
Bradley DJ;
British Medical Journal, 1996; 313: 528-8.
1996 Survey of 1214 British travelers from 1993 to 1995 who received advice
from the travelers telephone health line run by the Medical Advisory
Services for Travelers Abroad.
Travelers received a questionnaire upon returning from their trip.
27 percent of travelers taking mefloquine reported neuropsychiatric adverse
events.
The traveler sought medical advice in 2.2 percent of the cases and 0.3
percent required hospital attention.
Of those taking chloroquine and proguanil, 16 percent reported
neuropsychiatric adverse events with 0.9 percent requiring medical advice
and 0.1 percent hospital attention.
Of those reporting any adverse event with mefloquine, 5.1 percent
discontinued antimalarial prophylaxis and 0.7 percent switched to another
agent.
The corresponding numbers for chloroquine and proguanil were 6.3 percent and
0.3 percent. Disabling neuropsychiatric adverse events included
hallucinations, panic attacks, dissociation from reality, confusion,
difficulty concentrating, depression, anxiety, emotional instability
depression, anxiety, personality changes, and nightmares.

Centers for Disease Control & Prevention (CDC)
National Center for Infectious Diseases, Travelers' Health, Information for
the Public: Prescription Drugs for Malaria, accessed 4-21-04 at
www.cdc.gov/travel/malariadrugs.htm
2004 Review -- Travelers Advisory from CDC
The most common side effects reported by travelers taking mefloquine include
headache, nausea, dizziness, difficulty sleeping, anxiety, vivid dreams, and
visual disturbances.
Mefloquine has rarely been reported to cause serious side effects,
such as seizures, depression, and psychosis.
These serious side effects are more frequent with the higher doses used to
treat malaria; fewer occurred at the weekly doses used to prevent malaria.
Mefloquine is eliminated slowly by the body and thus may stay in the body
for a while even after the drug is discontinued.
Therefore, side effects caused by mefloquine may persist weeks to months
after the drug has been stopped.
Most travelers taking mefloquine do not have side effects serious enough to
stop taking the drug.
Travelers Who Should Not Take Mefloquine. The following travelers should not
tak mefloquine and should ask their health care provider for a different
antimalarial drug
a. Persons with active depression or a recent history of depression
b. Persons with a history of psychosis, generalized anxiety disorder,
schizophrenia, or other major psychiatric disorder
c. Persons with a history of seizures (does not include the type of seizure
caused by high fever in childhood)
d. Persons allergic to mefloquine

Mefloquine is not recommended for persons with cardiac conduction
abnormalities (for example, an irregular heartbeat).

page A-4 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

CDC National Center for Infectious Diseases,
Travelers' Health, Information for Health Care Providers, Prescription Drugs
for Malaria, accessed 4-21-04 at www.cdc.gov/travel/malariadrugs2.htm.
2004 Review -- Physicians Advisory put out by CDC
Mefloquine is contraindicated in persons allergic to mefloquine and in
persons with active depression or a previous history of depression,
generalized anxiety disorder, psychosis, schizophrenia, other major
psychiatric
disorders, or seizures.
Not recommended for persons with cardiac conduction abnormalities.
Mefloquine primary prophylaxis should begin 1-2 weeks before travel to
malarious areas.
It should be continued once a week, on the same day each week, during travel
to malarious areas, and for 4 weeks after the traveler leaves such areas.
Mefloquine has been associated with rare serious adverse reactions
(including psychoses or seizures) at prophylactic doses; these reactions are
more frequent with the higher doses used for treatment.
Other side effects that occur with prophylactic doses include
gastrointestinal disturbance, headache, insomnia, abnormal dreams, visual
disturbances, depression, anxiety disorder, and dizziness.
Mefloquine is contraindicated for use by travelers with a known
hypersensitivity to mefloquine and in persons with active depression or a
history of depression, or in persons with generalized anxiety disorder,
psychosis, schizophrenia, or other psychiatric disturbances.
Mefloquine is contraindicated in persons with a history of seizures (not
including the type of seizure caused by high fever in childhood).
Mefloquine is not recommended for persons with cardiac conduction
abnormalities.

U.S. Department of Health & Human Services, U.S. Food and Drug
Administration,
FDA News, P03-52, July 9, 2003, "FDA Creates Medication Guide for Lariam."
Accessed 4-21-04 at www.fda.gov/bbs/topics/NEWS/2003/NEW00921.html
2004 Review -- FDA Medication Guide
FDA developed the Lariam (mefloquine) Medication Guide in collaboration with
the drug's manufacturer, Roche Pharmaceuticals of Nutley, NJ, to help ensure
patients understand the risks of malaria, and the rare but potentially
serious psychiatric adverse events associated with use of Lariam.
Sometimes these psychiatric adverse events may persist even after stopping
the medication. Some rare reports have claimed that Lariam users think about
killing themselves.
There have been rarer reports of suicides, although FDA does not know if
Lariam use was related to these suicides.

page A-5 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Mefloquine for preventing malaria in non-immune adult travelers, Review,"
The Cochrane Database of Systematic Reviews, Copyright 2004 The Cochrane
Library, Volume (1),
Croft, AMJ; Garner, P.
2004 Review - Cochrane review of We included 10 trials involving 2750
nonimmune adult participants. Five were field trials, mainly male soldiers.
Also reviewed 516 published case reports of mefloquine adverse effects, 63
percent involved tourists and business travelers
Mefloquine prevents malaria, but has adverse effects that limit its
acceptability.
Evidence from non-randomised studies shows mefloquine has potentially
harmful effects in tourists and business travellers.
No-one knows if mefloquine is well or poorly tolerated.
Many of the standard textbooks of tropical medicine assert that mefloquine
is well tolerated in prophylaxis and that the only side effects of
importance are neuropsychiatric reactions or seizures, experienced by around
one in 10,000 users.
This much-cited estimate of the frequency of neuropsychiatric side effects
from mefloquine is based not on experimental data, but on spontaneous
reports of severe adverse events in mefloquine users, and undoubtedly
underestimates the true incidence of undramatic but nevertheless unpleasant
side effects from mefloquine.
The main problem with mefloquine is that its tolerability is a major concern
of the public, with questions raised repeatedly in the news media.
Yet evidence to reassure the public, or confirm their fears, is not
available.
Withdrawals during clinical trials of mefloquine group were consistently
higher in four placebo controlled trials (odds ratio 3.56, 95 percent
confidence interval 1.67 to 7.60).
In five trials comparing mefloquine with other chemoprophylaxis, no
difference in tolerability was detected.
There were four fatalities attributed to mefloquine.

Roche Pharmaceuticals "Dear Healthcare Professional" letter about mefloquine
side effects, "Copyright © 2003 by Roche Laboratories Inc. All rights
reserved," at
www.fda.gov/cder/foi/label/2003/19591s19lbl_Lariam.pdf ,
2003 Review -- Manufacturer's warning letter to clinicians
"Lariam can rarely cause serious mental problems in some patients.
The most frequently reported side effects with Lariam, such as nausea,
difficulty sleeping, and bad dreams are usually mild and do not cause people
to stop taking the medicine.
However, people taking Lariam occasionally experience severe anxiety,
feelings that people are against them, hallucinations (seeing or hearing
things that are not there, for example), depression, unusual behavior, or
feeling disoriented.
It has been reported that sometimes, in some patients, these side effects
continue after Lariam is stopped.
Some patients taking Lariam think about killing themselves, and there have
been rare reports of suicides.
We do not know if Lariam was responsible for these suicides.
Do not take Lariam to prevent malaria if you have 1) depression or had
depression recently; 2) recent mental illness or problems, including anxiety
disorder, schizophrenia or psychosis; 3) seizures; 4) allergic to quinine or
quinidine 5) Heart disease; 6) Pregnancy; 7) Breast feeding; or 8) Liver
problems."

"Adverse effects of the antimalaria drug, mefloquine: due to primary liver
damage with secondary thyroid involvement?"
Croft AM, Herxheimer A; BioMed Central Public Health, 2002 Mar 25; 2(1): 6.
2002 Review of 516 published case reports - Cochrane Review
Postulate many mefloquine adverse effects are a post-hepatic syndrome caused
by primary liver damage;
"Mefloquine syndrome" presents in a variety of ways including
headache, gastrointestinal disturbances, nervousness, fatigue, disorders of
sleep, mood, memory and concentration, and occasionally frank psychosis.
Previous liver or thyroid disease, and concurrent insults to the liver (such
as from alcohol, dehydration, an oral contraceptive pill, recreational
drugs, and
other liver damaging drugs) may be related to the development of severe or
prolonged adverse reactions to mefloquine.

page A-6 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Drug interactions with antimalarial agents,"
Griffin JP;
Adverse Drug Reactions and Toxicological Reviews, 1999 Mar; 18(1): 25-43.
1999 Review of case reports
Case reports enumerates "common" side effects including
nausea, vomiting, dizziness and vertigo, loss of balance, headache, sleep
disorders, diarrhea and abdominal pain;
More rare serious side effects include: 1) psychiatric effects as including
depression, anxiety, confusion, psychosis, paranoia, aggression and
agitation;
2) Neurological effects including convulsions, sensory and motor
neuropathy, paraesthesia, tinnitus, tremor, ataxia and visual disturbances,
and encephalopathy has been reported;
3) Cardiovascular effects including blood pressure changes, syncope,
bradycardia, extrasystoles, cardiac conduction defects including
atrioventricular block;
4) Skin rashes including urticarial rashes, pruritis, hair loss and
Stevens-Johnson syndrome;
5) Hematological effects including leucopenia and thrombocytopenia; and
6) Liver enzyme changes.
No discussion of how long these effects might last after the drug is
stopped.

"Dermatological Adverse Effects with the Antimalarial Drug Mefloquine: a
Review of 74 Published case Reports,"
Smith HR, Croft AM, Black MM;
Clinical and Experimental Dermatology, 1999, 24; 249-254.
1999 Review of 74 case reports on mefloquine dermatological effects
published between 1983 and 1997
There is good circumstantial evidence that mefloquine can cause mild and
occasionally severe adverse dermatological effects in health travelers and
in hospital patients with malaria.
These effects are mostly self-limiting and rarely require treatment.
Pruritus is the most frequent dermatological reaction and
maculopapular rash is also common.
Stevens-Johnson syndrome and toxic epidermal necrolysis have all been
associated with mefloquine.
The incidence of dermatological adverse effects with mefloquine may be
between 4 to 10 percent
for short-term use and
as high as 30 percent for prolonged use.

"CNS adverse events associated with antimalarial agents. Fact or fiction?;"
Phillips-Howard PA, ter Kuile FO;
Drug Safety : An International Journal of Medical Toxicology and Drug
Experience,
1995 Jun; 12(6): 370-83.
1995 Review Mefloquine therapy causes dose-related transient dizziness; and
serious central
nervous system (CNS) events occur in 1:1200 Asians and 1:200
Caucasians/Africans;
Risk factors include dosage, concomitant drug use/interactions, previous
history of a CNS event and disease severity;
Retreatment (within a month) increases the risk in Asians 7-fold;
Irreversible effects are extremely rare and usually associated with
overdosing or prior history of a serious CNS event.

"Mefloquine prophylaxis: an overview of spontaneous reports of severe
psychiatric reactions and
convulsions,"
Bem JL, Kerr L, Stuerchler D;
The Journal of Tropical Medicine and Hygiene, 1992 Jun; 95(3): 167-79.
1992 Review of adverse reaction reports since 1991 (about 1 year)
by the manufacturer Hoffmann-La Roche.
59 serious neurologic and psychiatric adverse reaction reports reviewed:
26 convulsions, 12 depressions, 20 psychotic episodes, and one toxic
encephalopathy;
none were fatal;
Only patient population identified at increased risk of developing these
serious reactions are persons with a history of seizures or manic-depressive
illness.

"Neuropsychiatric side effects after the use of mefloquine,"
Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, Kern W,
Pohle HD;
Am The Journal of Tropical Medicine and Hygiene, 1991 Jul; 45(1): 86-91.
1991 Review of case reports
Reviewed neuropsychiatric side effects in German patients after treatment
with mefloquine;
Reactions consisted mainly of seizures, acute psychoses, anxiety neurosis,
and major disturbances of sleep-wake rhythm;
Effects occurred after both therapeutic and prophylactic intake;
Estimated that one of 8,000 mefloquine users suffers from such reactions
(one of 215 among therapeutic users, one of 13,000 among prophylaxis users).

page A-7 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"The acute neurotoxicity of mefloquine may be mediated through a disruption
of calcium homeostasis and ER function in vitro,"
Dow GS, Hudson TH, Vahey M, Koenig ML;
Malaria Journal, 2003 Jun 12; 2(1): 14.
2003 Mechanistic study Investigated the possibility that the acute in vitro
neurotoxicity of mefloquine might be mediated through a disruptive effect of
the drug on endoplasmic
reticulum (ER) calcium homeostasis.
Mefloquine was found to disrupt neuronal calcium homeostasis and induce an
ER stress response at physiologically relevant concentrations, effects that
may contribute, at least in part, to the neurotoxicity of the drug in vitro

"The risk of severe depression, psychosis or panic attacks with prophylactic
antimalarials,"
Meier CR, Wilcock K, Jick SS;
Drug Safety : An International Journal of Medical Toxicology and Drug
Experience, 2004; 27(3): 203-13.
2004 Epidemiologic study. A population-based observational study using a
database of medical records to quantify and compare the risk of psychiatric
disorders during or after use of mefloquine with the risk during use of
proguanil and/or chloroquine, or doxycycline
The study population was drawn from the large UK-based General Practice
Research Database (GPRD).
Subjects were aged from 17-79 years and were exposed to mefloquine,
proguanil, chloroquine or doxycycline (or a combination of these drugs) at
some time between 1990 and 1999.
We performed a person-time and a nested case-control analysis to assess the
risk of developing a first-time diagnosis of depression, psychosis or panic
attack during or after use of these
antimalarial drugs.
RESULTS: Within the study population of 35 370 subjects (45.2 percent
males), we identified 580 subjects with a first-time diagnosis of depression
(number of subjects (n) = 505),
psychosis (n = 16) or panic attack (n = 57) and two subjects committed
suicide.
The incidence rates of first-time diagnoses of depression during current use
of mefloquine, proguanil and/or chloroquine, or doxycycline, adjusted for
age, gender and calendar year, were 6.9 (95 percent CI 4.5-10.6), 7.6 (95
percent CI 5.5-10.5) and 9.5 (95 percent CI 3.7-24.1)/1000 person-years,
respectively.
The incidence rates of psychosis or panic attacks during current mefloquine
exposure were 1.0/1000 person-years (95 percent CI 0.3-2.9)
and 3.0/1000 person-years (95 percent CI 1.6-5.7), respectively,
approximately 2-fold higher (statistically nonsignificant) than during
current use of proguanil and/or chloroquine, or doxycycline.
The nested case-control analysis encompassed 505 cases with depression and
3026 controls,
16 cases with psychosis and 96 controls, and 57 cases with a panic attack
and 342 controls. Current use of mefloquine was not associated with an
elevated risk of developing depression.
In a comparison between patients currently using mefloquine with all past
users of antimalarials combined, the risk estimate was elevated for current
users of mefloquine for both
psychosis (odds ratio (OR) 8.0, 95 percent CI 1.0-62.7; p < 0.05) and
panic attacks (OR 2.7, 95 percent CI 1.1-6.5; p < 0.05).
CONCLUSION: The absolute risk of developing psychosis or panic attack
appears low with all the antimalarials tested.
No evidence was found in this large observational study that mefloquine use
increased the risk of first-time diagnosis of depression when compared with
the use of other antimalarials investigated in this study.

page A-8 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a
focus on neuropsychiatric adverse events,"
van Riemsdijk MM, Sturkenboom MC, Ditters JM, Ligthelm RJ, Overbosch D,
Stricker BH;
Clinical Pharmacology and Therapeutics, 2002 Sep; 72(3): 294-301.
2002 Epidemiologic study, prospective, doubleblind, randomized study on
neuropsychiatric adverse events and concentration impairment during
prophylactic use of mefloquine or atovaquone plus chloroguanide
119 Subjects (mean age 35 years) followed from baseline screening to 7 days
after leaving malaria area, measuring changes in mood disturbance and
neurobehavioral indices including sustained attention, coding speed, and
visuomotor accuracy;
Significant deterioration in depression, anger, fatigue, vigor, and total
mood disturbance domains occurred during use of mefloquine but not during
use of atovaquone plus chloroguanide;
Stratification on sex showed between-treatment differences in female
patients but not in male patients;
In both treatment groups, sustained attention deteriorated after travel,
especially with increased duration of stay.
CONCLUSIONS: Prophylactic use of mefloquine was associated with
significantly higher scores on scales for depression, anger, and fatigue and
lower scores for vigor than prophylactic use of atovaquone plus
chloroguanide.

"Neurological, cardiovascular and metabolic effects of mefloquine in healthy
volunteers: a double-blind, placebo-controlled trial,"
Davis TM, Dembo LG, Kaye-Eddie SA, Hewitt BJ, Hislop RG, Batty KT;
British Journal of Clinical Pharmacology, 1996 Oct; 42(4): 415-21.
1996 Epidemiologic study, Double-blind, randomized, placebocontrolled
trial -- 106 healthy adult subjects over 4 weeks
Mefloquine did not alter calcium homoeostasis but produced a mean 0.5 mmol
l-1 fall in serum glucose over the study period (p < 0.001) and relative hyp
erinsulinaemia;
Symbol digit modalities, and digit forwards and backwards test scores
similar in active and placebo groups across the three assessments, as were
lying/standing blood pressure and high-tone hearing loss;
Electrocardiographic QTc interval prolongation and diarrhea were mild but
transient side-effects of mefloquine (p < 0.01);
Neurological symptoms comparable in two groups throughout study;
No evidence of drug toxicity in eleven subjects who withdrew.
Concluded mefloquine prophylaxis does not appear to produce low-grade but
debilitating neurological symptoms or to alter the results of sensitive
tests of cerebral function, but it might contribute to hypoglycaemia and
cardiac dysrhythmias.

page A-9 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Tolerability of malaria chemoprophylaxis in nonimmune travellers to
sub-Saharan Africa: multicentre, randomised, double blind, four arm study,"
Schlagenhauf P, Tschopp A, Johnson R, Nothdurft HD, Beck B, Schwartz E,
Herold M, Krebs B, Veit O, Allwinn R, Steffen R;
British Medical Journal,, 2003 Nov 8; 327(7423): 1078.
2003 Clinical trial; randomized, double blind, with placebo, 623 subjects
receiving various malaria prophylaxis including mefloquine
Many subject reported adverse events (even in the initial placebo group);
none were serious;
Chloroquine and proguanil trial had highest mild to moderate adverse events;
followed by mefloquine (64/153; 42 percent, 34 percent to 50 percent),
doxycycline, and atovaquone and proguanil (p = 0.048 for all);
Mefloquine and combined chloroquine and proguanil arms had the highest
proportion of more severe events (n = 19; 12 percent, 7 percent to 18
percent and n = 16; 11 percent, 6 percent to 15 percent, respectively),
whereas the combined atovaquone and proguanil and doxycycline arms had the
lowest (n = 11; 7 percent, 2 percent to 11 percent and n = 9; 6 percent, 2
percent to 10 percent, respectively: p = 0.137 for all);
Mefloquine arm had the highest proportion of moderate to severe
neuropsychological adverse events, particularly in women (n = 56; 37
percent, 29 percent to 44 percent versus chloroquine and proguanil, n = 46;
30 percent, 23 percent to 37 percent; doxycycline, n = 36; 24 percent, 17
percent to 30 percent; and atovaquone and proguanil, n = 32; 20 percent, 13
percent to 26 percent: p = 0.003 for all);
Highest proportion of moderate or severe skin problems were reported in the
chloroquine and proguanil arm (n = 12; 8 percent, 4 percent to 13 percent
versus doxycycline, n = 5; 3 percent, 1 percent to 6 percent; atovaquone and
proguanil, n = 4; 2 percent, 0 percent to 5 percent; mefloquine, n = 2; 1
percent, 0 percent to 3 percent: P = 0.013).
CONCLUSIONS: Combined atovaquone and proguanil and doxycyline are well
tolerated antimalarial drugs;
Broader experience with both agents is needed to accumulate reports of rare
adverse events.

"Unexpected frequency, duration and spectrum of adverse events after
therapeutic dose of mefloquine in healthy adults,"
Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A,
Kollaritsch H; Acta Tropica, 2002 Feb; 81(2): 167-73.
2002 Clinical trial; 22 healthy volunteers monitored 21 days with
therapeutic mefloquine (750 and 500 mg at 6 hour (h) intervals)
Unexpected high frequency of side effects of any grade reported by all 22
subjects;
Most common were vertigo (96 percent), nausea (82 percent) and headache (73
percent); Subjects with severe vertigo (73 percent) required bed rest and
specific medication for 1 to 4 days;
More females than males reported severe adverse reactions;
Majority (77.3 percent) participants (f: 8/12, m: 9/10) showed symptom
resolution within 3 weeks (510 h) after drug administration;
Biochemical and hematological findings stayed within the normal range of
values, but showed nevertheless a
significant rise of Na, Cl, Ca, bilirubin, GGT and LDH.

page A-10 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects
Major Findings

"Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune
travelers: results from a randomized, double-blind study,"
Overbosch D, Schilthuis H, Bienzle U, Behrens RH et al.
Clinical infectious diseases, 2001; 33: 1015-21
2001 Clinical trial; randomized, doubleblind, with placebo evaluating
frequency of adverse events.
976 travelers from the Netherlands, UK, Canada, and S. Africa traveling to
malaria endemic areas for up to 28 days.
Individuals were monitored 7, 28, and 60 days after travel.
Treatment emergent neuropsychiatric events occurred in 29 percent of
travelers randomized to mefloquine and in 14 percent randomized to
atovaquone-proguanil (p=0.001).
Events included strange or vivid dreams, insomnia, dizziness, visual
difficulties, anxiety, and depression.
Most adverse events were considered mild.
Treatment was discontinued due to neuropsychiatric events in nineteen
subjects
receiving mefloquine, in five receiving mefloquine placebo, and in three
receiving atovaquone-proguanil.

"Serious adverse events of mefloquine in relation to blood level and
gender,"
Schwartz E, Potasman I, Rotenberg M, Almog S, Sadetzki S;
The American Journal of Tropical Medicine and Hygiene, 2001 Sep; 65(3):
189-92.
2001 Clinical trial; Mechanistic
Evaluated association between mefloquine serum levels and serious side
effects, with seventeen patients presenting to emergency rooms or travel
clinics with symptoms suggesting serious adverse effects of mefloquine and
twenty-eight controls (healthy people, still taking mefloquine after travel;
Mean age patients and controls was 31.5 +/- 11.6 years and 34 +/- 12.2
years, respectively; More women among the patients (76 percent versus 40
percent, respectively; p = 0.03);
Most complaints related to central nervous system (13 of 17);
five patients interrupted their trip and two were hospitalized;
No difference in mefloquine blood levels found comparing patients to control
groups;
No significant difference found between blood mefloquine levels among men
and women; mefloquine blood levels do not correlate with severe adverse
events;
Women more susceptible than men, despite having similar blood levels of the
drug.

"Paranoid psychosis related to mefloquine antimalarial prophylaxis,"
Fuller SJ, Naraqi S, Gilessi G;
Papua and New Guinea Medical Journal, 2002 Sep-Dec; 45(3-4): 219-21.
2002 Case report - one subject
A 39-year old marine biologist medically evacuated from New Guinea with
paranoid ideation and irrational behavior; Taken mefloquine 2 weeks earlier;
No history of illicit drug use or other medications; On admission
disoriented, speech rambling, agitated and fearful of medical staff;
Afebrile; No unusual lab tests;
Diagnosed with acute psychosis secondary to mefloquine, which resolved over
the next 2 to 3 days; Patient admitted suffered from endogenous depression
for 19 years and had taken meds for that.

"Mefloquine-induced paranoid psychosis and subsequent major depression in a
25-year-old student,"
Dietz A, Frolich L;
Pharmacopsychiatry, 2002 Sep; 35(5): 200-2.
2002 Case report - one subject
Patient developed paranoid psychosis followed by depression after taking
mefloquine for a vacation; Recovered fully within 9 months of receiving his
first dose of mefloquine.

page A-11 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Multifocal Myoclonus Associated with Mefloquine Chemoprophylaxis,"
Jimenez-Huete, A, Gil-Nagel, A, and Franch O;
Clinical Neuropharmacology, 25; 5 243, 2002.
2002 Case report - one subject
Case report of a 54 year old Spanish woman developed multifocal myoclonus
during mefloquine prophylaxis;
Presented with abnormal movements in four limbs;
Cerivastatin started 10 months earlier for treatment of
hypercholesterolemia;
8 weeks previously started prophylactic mefloquine,
and two weeks later during a trip noticed sudden brief shock-like irregular
muscular contractions that appeared without pattern in all four limbs,
and were more intense at the end of the day;
Complained of slight frontal headache, dizziness and slowness of thinking;
No known exposures including recreational drugs and friends were
asymptomatic;
Continued taking mefloquine 3 more weeks while symptoms increased until she
could not drive a car;
On the 6th week treatment stopped mefloquine and symptoms rapidly abated;
Neurological exam 2 weeks later showed infrequent irregular non-synchronous
brief muscular contractions in her proximal and distal upper limbs,
consistent with multifocal myoclonus;
No brain lesions by magnetic resonance imaging (MRI) and EEG normal;
Blood tests showed only slight hypercholesterolemia;
Follow up exam 2 weeks later showed no abnormal signs.

"Pulmonary toxicity with mefloquine,"
Udry E, Bailly F, Dusmet M, Schnyder P, Lemoine R, Fitting JW;
The European Respiratory Journal, 2001 Nov; 18(5): 890-2.
2001 Case report - two subjects
Case 1: Patient developed acute lung injury within hours following
mefloquine treatment for a low-level P. falciparum, which was halofantrine
resistant;
Extensive microbiological investigation remained negative;
Video-assisted thoracoscopic lung biopsy demonstrated diffuse alveolar
damage;
Progress was favorable without treatment;
Case 2: Patient experienced acute lung injury and diffuse alveolar damage
related to mefloquine; Glucose-6-phosphate dehydrogenase deficiency was
present in the former (but not the later, suggesting that it is not a
predisposing condition) case and was thought to contribute to the
lung injury.

"Mefloquine-induced trigeminal sensory neuropathy,"
Watt-Smith S, Mehta K, Scully C; Oral Surgery,
Oral Medicine, Oral Pathology, Oral Radiology, and EnDODontics, 2001 Aug;
92(2): 163-5.
2001 Case report - one subject
Patient with sudden-onset trigeminal sensory neuropathy of the lip
associated with taking mefloquine.

"Cognitive and neuropsychiatric side effects of mefloquine,";
Javorsky DJ, Tremont G, Keitner GI, Parmentier AH;
The Journal of Neuropsychiatry and Clinical Neurosciences, 2001 Spring;
13(2): 302.
2001 Case report - one subject
52 year old woman no psychiatric history used mefloquine prophylactically
once a week for 3 weeks prior and during a trip to Africa;
Previously used mefloquine 4 years without problems;
During return flight developed anxiety, paranoia, visual hallucinations,
confusion and depressive symptoms;
Outpatient treatment continued to show suicidal ideation, other
neuropsychiatric symptoms, and
cognitive disturbances 3 months after last dose of mefloquine;
Hospitalized for inpatient psychiatric treatment;
Mildly elevated TSH, positive past exposure to hepatitis A, normal brain
MRI, medical history was no help;
Drug therapy led to improvement over 4 days;
after briefly living with a relative following discharge returned to
independent functioning.

page A-12 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Danger of malaria self-treatment. Acute neurologic toxicity of mefloquine
and its combination with pyrimethamine-sulfadoxine,"
Nicolas X, Granier H, Laborde JP, Martin J, Talarmin F;
La Presse medicale, 2001 Sep 29; 30(27): 1349-50.
2001 Case report - one subject
A patient did not follow the prescribed mefloquine dosage and developed
acute neurological disorders after overdosing;
Patient developed mefloquine related encephalopathy.

"Bipolar disorder after mefloquine treatment,"
Even C, Friedman S, Lanouar K;
Journal of Psychiatry & Neuroscience, 2001 May; 26(3): 252-3.
2001 Case report - one subject
50 year old man took mefloquine for a vacation in the Far East, developed
after his second 250 mg dose depressive symptoms that interrupted his trip;
Two weeks later he ended up in a psychiatric hospital with worsening
depressive symptoms,
suicidal ideation and elusions of guilt and economic ruin (still taking
mefloquine);
received electroconvulsive therapy over 11 days!
He was given drugs for depression for 6 years!

"Prolonged visual illusions induced by mefloquine (Lariam): a case report,"
Borruat FX, Nater B, Robyn L, Genton B;
Journal of Travel Medicine, 2001 May-Jun; 8(3): 148-9.
2001 Case report - one subject
[Neuropsychiatric symptoms in preventive antimalarial treatment with
mefloquine: apropos of 2 cases];
Lebain P, Juliard C, Davy JP, Dollfus S;
L'Encephale, 2000 Jul-Aug; 26(4): 67-70.
2000 Case report - two subjects
Severe neuropsychiatric reactions in two patients following chemoprophylaxis
with mefloquine;
Case 1: 43 year old woman developed severe depression with visual and
auditive hallucinations and a paranoid delusion; Treated by clomipramine and
risperidone;
Case 2: 55 year old man presented twice with acute psychosis with confusion
following mefloquine prophylaxis; Treated with halopridol.

"Mefloquine-induced psychosis,"
Havaldar PV, Mogale KD;
The Pediatric Infectious Disease Journal, 2000 Feb; 19(2): 166-7.
2000 Case report - one subject
Case report of mefloquine induced psychosis in a 7-year old Indian child.
Hospitalized and diagnosed with cerebrial malaria, quinine treatment failed,
mefloquine treatment started.
On third day of mefloquine treatment he had loss of sleep and irrelevant
talk, and the following day had hallucinations, which worsened.
All symptoms of psychosis subsided within 24 hours of stopping mefloquine.

"Seizures after antimalarial medication in previously healthy persons,"
Schiemann R, Coulaud JP, Bouchaud O;
Journal of Travel Medicine, 2000 May-Jun; 7(3): 155-6.
2000 Case report - one subject
Case of a grand mal seizure after chloroquine prophylaxis followed by
mefloquine therapy in a 19 year old girl who contracted malaria while on
vacation,
while taking chloroquine and proguanil;
Therapy was with mefloquine 1,500 mg, and on the same day she suffered a
grand mal seizure.

"Mefloquine-induced acute hepatitis,"
Gotsman I, Azaz-Livshits T, Fridlender Z, Muszkat M, Ben-Chetrit E;
Pharmacotherapy, 2000 Dec; 20(12): 1517-9.
2000 Case report - one case
Patient with elevated liver function tests attributed to heart failure
experienced acute elevation of liver transaminases 6 weeks after taking
mefloquine 250 mg per week; Cessation of the drug caused test results to
return to normal.

"Long-lasting neuropsychiatric side-effects following mefloquine
prophylaxis. A case after six weeks of initiating and lasting six months,";
Bygbjerg IC, Ronn AM;
Ugeskrift for Laeger, 1999 Mar 8; 161(10): 1422-3.
1999 Case report - one subject
Case of severe neuropsychiatric side-effects arising six weeks after
initiating mefloquine prophylaxis, requiring repeated hospitalization, and
NOT resolving completely after 6 months, in a previously healthy 30 year-old
female.

"Neuropsychiatric side effects of malarial prophylaxis with mefloquine
(Lariam),";
Minei-Rachmilewitz T;
Harefuah, 1999 Jul; 137(1-2): 25-7, 87.
1999 Case report - one subject
39-year-old woman who developed acute psychosis after being given mefloquine
prophylaxis.

page A-13 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Acute paranoid hallucinatory psychosis following mefloquine prophylaxis
(Lariam),"
Kruger E, Grube M, Hartwich P;
Psychiatrische Praxis, 1999 Sep; 26(5): 252-4.
1999 Case report - one subject
Case-report of a patient suffering for the first time from an acute paranoid
psychosis induced by mefloquine prophylaxis.

"Mefloquine and ototoxicity: a report of 3 cases,"
Fusetti M, Eibenstein A, Corridore V, Hueck S, Chiti-Batelli S;
Clinica Terapeutica, 1999; 150: 379-382.
1999 Case report - 3 subjects
Three cases of high-frequency sensorineural hearing loss and tinnitus
following malaria prophylaxis with mefloquine;
one patient had partial remission of hearing loss after stopping mefloquine;
the remaining two cases the symptomatology remained unchanged;
no patients reported improvement of tinnitus.

"Acute fatty liver after malaria prophylaxis with mefloquine,"
Grieco A, Vecchio FM, Natale L,
Gasbarrini G; Lancet, 1999 Jan 23; 353(9149): 295-6.
1999 Case report - one subject

"A severe adverse reaction to mefloquine and chloroquine prophylaxis,"
Lysack JT, Lysack CL, Kvern BL;
Australian Family Physician, 1999 Apr; 28(4): 310.
1998 Case report - one subject
A 23 year old man no history neurological or psychiatric illness ingested
three weekly 228 mg doses mefloquine malaria prophylaxis while in India;
Experienced increasingly severe adverse reaction after each dose, including
symptoms of paranoia, hallucinations, and suicidal ideation;
Discontinued mefloquine switched to chloroquine, but symptoms acutely
intensified and became debilitating;
Severe symptoms persisted for 12 months following the discontinuation of
both antimalarial drugs.

"Convulsions during prophylactic use of mefloquine,"
Heeringa M, Kuster JA, Meyboom RH, Bouvy M;
Nederlands Tijdschrift voor Geneeskunde, 1999 Jan 30; 143(5): 273-4.
1999 Case report - 6 subjects
Six patients reported with convulsions attributed to prophylactic use of
mefloquine;
five had no neurological history;
one had history of epilepsy but had had no convulsion during the preceding
5-years;
convulsions occurred 1 to 23 days after mefloquine treatment began, and
treatment was discontinued after convulsions;
four patients with follow-up showed full recovery from convulsions.

"Case study: neuropsychiatric symptoms associated with the antimalarial
agent mefloquine," Clattenburg RN, Donnelly CL;
Journal of the American Academy of Child and Adolescent Psychiatry, 1997
Nov; 36(11): 1606-8.
1997 Case report - one subject
Report on acute neuropsychiatric symptoms in a 10-year-old boy subsequent to
his return from travel abroad in Africa, where he had taken the antimalarial
agent mefloquine; 4-week course of cognitive-behavioral therapy effectively
treated this disorder.

"Fatal toxic epidermal necrolysis associated with mefloquine antimalarial
prophylaxis."
McBride SR, Lawrence CM, Pape SA, Reid CA;
Lancet, 1997 Jan 11; 349(9045): 101.
1997 Case report - one subject
"Psychopathological phenomena in long-term followup of acute psychosis after
preventive mefloquinine (Lariam) administration."
Meszaros K, Kasper S;
Der Nervenarzt, 1996 May; 67(5): 404-6.
1996 Case report - one subject
Report long-term observation of a patient suffering for the first time an
acute psychosis following mefloquine prophylaxis

"Atrial flutter with 1:1 conduction after administration of the antimalarial
drug mefloquine," Fonteyne W, Bauwens A, Jordaens L;
Clinical Cardiology, 1996 Dec; 19(12): 967-8.
1996 Case report - one subject
63-year-old male patient with atrial flutter in whom mefloquine use was
associated with 1:1 AV conduction;
responded to therapy with digoxin and sotalol;
patient had a history of palpitations.

page A-14 IL 10-2004-007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Acute glomerulonephritis without fever: an unusual presentation of malaria
on mefloquine prophylaxis,"
Martinez-Ocana JC, Serra A, Bonet J, Fernandez-Crespo P, Caralps A;
Nephron, 1996; 73(2): 372.
1996 Case report - one subject

"Neuropsychiatric reactions with mefloquine chemoprophylaxis,"
Croft AM, World MJ;
Lancet, 1996 Feb 3; 347(8997): 326.
1996 Case report -- summary

"Acute psychosis after mefloquine. Report of six cases."
Sowunmi A, Adio RA, Oduola AM, Ogundahunsi OA, Salako LA;
Tropical and Geographical Medicine, 1995; 47(4): 179-80.
1995 Case report - six subjects
Self-limiting psychosis characterized by acute onset of visual and auditory
hallucinations and poor sleep developed in six adults between 8 and 24 hours
after oral administration of 750-1500 mg of the antimalarial mefloquine.
All patients had no personal or family history of psychosis and were
neurologically and mentally normal before mefloquine ingestion.

"Adverse reaction to mefloquine associated with ethanol ingestion,"
Wittes RC, Saginur R;
Canadian Medical Association Journal, 1995 Feb 15; 152(4): 515-7.
1995 Case report - one subject
A 40 year old man no history of neuropsychiatric illness took one 250-mg
tablet mefloquine weekly for malaria prophylaxis while in Tanzania;
No adverse reaction following first two doses, but with his third and his
fourth dose he consumed about half a litre whisky;
On those two occasions he experienced hallucinations, paranoid delusions and
suicidal ideation;
Subsequently continued taking mefloquine, but abstained from alcohol ethanol
and had no recurrence of psychiatric symptoms.

"Mefloquine-induced grand mal seizure during malaria chemoprophylaxis in a
non-epileptic subject,"
Pous E, Gascon J, Obach J, Corachan M;
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995
Jul-Aug; 89(4): 434.
1995 Case report

"Acute brain syndrome after mefloquine treatment,"
Ronn AM, Bygbjerg IC;
Ugeskrift for Laeger, 1994 Oct 10; 156(41): 6044-5.
1994 Case report - one subject, treated for P. falciparum.
Patient rehospitalized 12 days after mefloquine treatment with fever,
nausea, dizziness and headache;
15 days after treatment generalized convulsions and coma;
EEG severely abnormal; discharged 37 days after mefloquine treatment,
but two months before the EEG and patient were normal.

"Acute psychosis after mefloquine: a case report,"
Sowunmi A;
East African Medical Journal, 1994 Dec; 71(12): 818-9.
1994 Case report - one subject
A self-limiting psychosis characterized by visual and auditory
hallucinations and isomnia occurred in a 17-year old male after mefloquine
administration for presumed chloroquine resistant falciparum malaria.

"Encephalopathy and memory disorders during treatments with mefloquine,"
Marsepoil T, Petithory J, Faucher JM, Ho P, Viriot E, Benaiche F;
Rev Med Interne. 1993; 14(8): 788-91.
1993 Case report - two subjects
Case 1: excessive mefloquine therapy lead to an acute psychotic state that
ultimately regressed without treatment;
Case 2: Patient suffered a transient memory failure following prophylactic
mefloquine treatment.

"Psychotic episode caused by prevention of malaria with mefloquine. A case
report,"
Folkerts H, Kuhs H;
Der Nervenarzt, 1992 May; 63(5): 300-2.
1992 Case report - one subject
Developed psychosis, dizziness, confusion and delusions, which were more
intensive and remained longer than previously reported.

page A-15 IL 10-2004007 June 23, 2004
Title, Authors, Reference Date Study Type - Subjects Major Findings

"Recurrent psychiatric manifestations during malaria prevention with
mefloquine. A case report," Rodor F, Bianchi G, Grignon S, Samuelian JC,
Jouglard J;
Therapie, 1990 Sep-Oct; 45(5): 433-4.
1990 Case report - one subject
A 22 year old woman without psychiatric antecedent took mefloquine for a
journey in a chloroquine resistant area;
First tablet induced an acute psychiatric syndrome that lasted 5 days;
Following the second tablet the patient attempted suicide by drowning.

2. Summary. Medical literature, and in particular case reports, indicate
that mefloquine may rarely be associated with certain long-term chronic
health problems that persist for weeks, months, and even years after the
drug is stopped.

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