source:  Clinical Infectious Diseases  1995;21:977-80
title:  Could Nonsteroidal Antiinflammatory Drugs (NSAIDS) Enchance the
Progression of Bacterial Infections to Toxic Schock Syndrome?
author:  Dennis L. Stevens

source:  Science News, Vol. 148-October 7, 1995
author: Lisa Seachrist
title:  Could Common anti-inflammatory drugs allow bacteria to take a deadly

"...'We have seen [these invasive bacterial]
infections for centuries, ' says infectious disease specialist Dennis L.
Stevens of the University of Washington School of Medicine in Seattle.   'What
seems to be unique now is that we are seeing a significant number of otherwise
healthy individuals getting these infections.'
   " That trend has scientists asking why the bacterium suddenly turned mean?
Some maintain tht the bug has become more
 virulent .  Stevens agrees but also suggests that commonly used
antiinflammatory drugs such as ibuprofen may have played a part.
    "' I've been impressed [looking at] the several hundred case reports that I
have studied that a significant number of individuals either took the [drugs]
or were prescribed them and 24 to 36 hours later suddenly had shock and organ
    "....Occasionally strep takes on a more destructive personality.   If
bacteria invade the bloodstream--for example, from the throat or a cut in the
skin--strep can find its way to the subcutaneous tissue, or fascia, that
surrounds the muscle.
    "At that point, a race ensues between the body's immune system and the
multipling bacteria. Antibodies recognize foreign proteins on the bacteria and
use a variety of signaling compounds, known as cytokines, to call in white
blood cells; these engulf and digest the bacteria.  But the bacteria
manufacture a variety of toxins that help break down tissue, aiding the
bacteria's spread through the fascia and into other parts of the body.
  " If the immune system wins, a person may develop a slight fever without ever
realizing he or she had an infection  If the bacteria win, people develop
necrotizing fasciitis, the ballyhooed 'flesh eating bacteria disease' or group
A streptococcal toxic schock syndrome, a potentially fatal combination of shock
and organ failure, with sometimes devastating results.
     "....Stevens argues that if a new and more virulent strain of
streptococcus had emerged, invasive strep infections would have been far more
widespread.  For instance, a new strain of influenza is always associated with
    "He suspects some specific factor unrelated to the bacterium is making
people more susceptible.  Known factors include chicken pox and trauma, but a
series of anecdotal reports, beginning in the mid_1980s, has drawn attention to
the link between patients suffering either necrotizing fasciitis or toxic
schock syndrome and pain relievers known as nonsteroidal antiinflammatory drugs
(NSAIDS) such as ibuprofen.
    "In March, researchers from the University of Otago Medical School   in
Dunedin, New Zealand, published in the New Zealand Medical Journal accounts of
seven cases of necrotizing fasciitis, five of them associated with NSAIDs.  'We
have seen an increase in necrotizing fasciitis, and perhaps the very frequent
use of these agents is responsible for this increase, ' says study author
Robert Walker.
    "In Canada last winter, Lucien Bouchard, leader of the Quebec separatist
movement suffered what he thought was a pulled leg muscle.  He took NSAIDs and
later suffered a case of necrotizing fasciitis that resulted in the amputation
of his leg.
    "The United Kingdom's National Health Service has begun to monitor cases of
necrotizing fasciitis.  Consulting microbiologist Michale Barnham reports that
at least 10 cases have been linked to the drugs.
    "NSAIDs have proved invaluable for treating disease such as rheumatoid
arthritis and for reliving the aches of athletic  injuries.  But Stevens
maintains that the very mode of action that makes them so effective puts people
at risk of invasive strep infections.
    "NSAIDs work by dampening inflammation --a vital part of the body's
defenses against microbial invaders.  In the October Clinical Infectious
Diseases, Stevens outlines the hypothesis that NSAIDs can mask an infection and
stymie the immune system.
    "...As a result, 'patients mask their clinical symptoms with the NSAIDs and
prevent a proper diagnosis,'  argues Stevens. Furthermore, overproduction on
TNF allows the bacteria to spread more easily and contributes to shock and
organ failure. 
    "Stevens suggests, for example, that at the timeLucien Bouchard pulled a
muscle, he may  also have had strep circulating in his bloodstream.  When he
damaged the muscle, blood leaked into the injured area and the bacteria took
hold.  NSAIDs lessened Bouchard's own ability to fight the infection.
    "An interesting 'ecological' link between NSAIDs and invasive strep
infection occurred last year in the form of an increase in cases of necrotizing
fasciitis among children infected with the chicken pox.  Benjamin Schwartz of
the CDC  points out that the increase coincides with the introduction of
suspensions of ibuprofen for pediatric use.  Parents might give their children
the medication to calm fever, pain, and itching associated with chicken pox,
but in doing so it makes it easier for bacteria from the skin  to enter the
body via the disease's open sores...
    "Conducting a study ...remains the only way to truly determine whether a
link exists."   Cold Day in Hell considering the amount of money made off these
drugs.   " .....Such an endeavor  ...will be tremendously difficult and
costly............"  No profits in $$$$$$$$$ only in lives!
   " In the meantime, Stevens and Walker argue against the use of NSAIDs when a
bacterial infection may be the root of the problem.  Stevens notes that people
who have ' increasingly severe muscle pain accompanied by fever and chills
should see their doctor.'  And they should not take NSAIDs until they've
received antibiotics to treat the bacterial infection..............
   " The researchers agree that, in general, NSAIDs pose no dangers and that
they remain vital treatment tools. But because they reduce fever, they can mask
underlying bacterial infections.
    "The tip-off to these dangerous but extraordinarily rare invasive strep
infections, Walker reiterates, is severe pain disproportionate to any injury."
---- Sounds like something that can happen with Lyme disease--an underlying
bacterial infection that would remain that way if the powers that be had their
  "Despite the utility of NSAIDs, Walker cautions weekend athletes to take the
drugs with care. 'These drugs are used because of their profound effects on the
immune system,' says Walker.
'They're not just some innocuous candy-lollies.' "
source: (Marie Kroun)

The effects of selected drugs, including chlorpromazine and non-steroidal
anti-inflammatory agents, on polyclonal IgG synthesis and interleukin 1
production by human peripheral blood mononuclear cells in vitro.
Martinez F, Coleman JW
89337194 Clin Exp Immunol 1989 May;76(2):252-257
We tested a range of drugs for their effects on in vitro polyclonal IgG
synthesis by human peripheral blood mononuclear cells (PBMC) stimulated with
the lectin pokeweed mitogen (PWM). The test drugs were selected on the basis of
reported disruptive effects on immune function in vivo. IgG production between
day 4 and days 7 or 8 of culture was measured by biotin-streptavidin sandwich
ELISA. The anti-psychotic agent chlorpromazine (0.55-1.7 microM) enhanced IgG
synthesis to approximately double control levels. In contrast, the
non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, piroxicam,
ibuprofen and aspirin inhibited IgG synthesis by up to 50%, with a rank order
of potency that reflects their activity as inhibitors of cyclo-oxygenase.
Phenytoin, procainamide, propylthiouracil, methimazole, D-penicillamine and
D-penicillamine-L-cysteine all failed to modulate IgG synthesis at non-toxic
concentrations. The potentiation and inhibition of IgG synthesis by
chlorpromazine and indomethacin, respectively, was observed only when the drug
was present during the first 24 h of culture. Neither chlorpromazine nor
indomethacin, at non-toxic concentrations, affected PHA- and PWM-stimulated
proliferation of PBMC. In addition, chlorpromazine, indomethacin and piroxicam,
at concentrations which produced maximal modulation of IgG synthesis, and
D-penicillamine and D-penicillamine-L-cysteine at 10 microM failed to influence
production of interleukin-1-like activity. We conclude that chlorpromazine and
NSAIDs, although they exert opposite effects on IgG synthesis, act at an early
stage of B cell differentiation that appears to be independent of interleukin 1
synthesis and early proliferative events.
#89337194 The effects of sel. drugs .. & NSAID on IgG.tif#
Here are the very short conclusions of other references below:
1 Spiers et al (1993): fenclofenac suppress and slows leucocyte regeneration
after irradiation (rats)
2 de Souza et al (1993): Bb itself impair lymfocyte proliferation and IL-2 and
IL-4 production (mice)
3 Martinez et al (1989): the NSAIDs indomethacin, piroxicam, ibuprofen and
aspirin inhibited IgG synthesis by up to 50%,
4 Hoffmann (1986): Peritoneal macrophages facilitate strong antibody production
by B cells, synergizing with IL-1 and IL-2. Indometacin blocks this effect of
the macrophages, suggesting that it is mediated by cyclo-oxygenase pathway and
5,6 Jelinek et al (1985): the results support the conclusion that PGE2 at
physiologically relevant concentrations can influence human antibody responses
by means of a direct inhibitory action on the responding B cell or an indirect
one on the production of necessary T cell factors."   -1 -1
Central nervous system side effects of nonsteroidal anti-inflammatory drugs.
Aseptic meningitis, psychosis, and cognitive dysfunction. Hoppmann RA, Peden
JG, Ober SK
91290953 Arch Intern Med 1991 Jul;151(7):1309-13
A review of the literature regarding central nervous system side effects of the
nonsteroidal anti-inflammatory drugs (NSAIDs) revealed three general
categories: aseptic meningitis, psychosis, and cognitive dysfunction. Aseptic
meningitis is found most commonly in patients with lupus treated with
ibuprofen, but it should be considered in any patient with meningitis if the
patient has used NSAIDs. Psychosis, although infrequently reported with NSAIDs,
should be suspected in an elderly patient started on a regimen of indomethacin
who acutely develops disorientation, paranoia, or hallucinations. Finally,
there appears to be some potential for memory dysfunction and attention
deficits in elderly patients treated with NSAIDs. Until further studies are
available on the incidence and severity of these cognitive changes, physicians
should use low doses of NSAIDs in the elderly and remain alert to the
possibility of such adverse side effects. ibuprofen, sulindac, naproxen,
#91290953 Central nervous system side effects of NSAID.tif# 

Anti-inflammatory medication after muscle injury. A treatment resulting in
short-term improvement but subsequent loss of muscle function.
Mishra DK, Friden J, Schmitz MC, Lieber RL
96027815 J Bone Joint Surg Am 1995 Oct;77(10):1510-9
We studied the effect of flurbiprofen, a non-steroidal anti-inflammatory drug,
on muscles that had been subjected to exercise-induced injury. The muscles of
the anterior compartment in the limbs of rabbits were cyclically activated as
the ankle was simultaneously moved through passive plantar flexion every two
seconds for thirty minutes. This treatment imposed acute passive lengthening
(eccentric contractions) of the maximally contracted muscles of the anterior
compartment. After the eccentric contraction-induced muscle injury, one group
of rabbits was treated with oral administration of flurbiprofen, two times a
day for six days, while the other group of rabbits served as untreated
controls. The contractile, histological, and ultrastructural properties of the
muscles were measured before the initial exercise and at three, seven, and
twenty-eight days afterward. The group that was treated with flurbiprofen
demonstrated a more complete functional recovery than the untreated controls at
three and seven days but had a deficit in torque and force generation at
twenty-eight days. The administration of flurbiprofen also resulted in a
dramatic preservation of the intermediate filament protein desmin. After three
days, the proportion of fibers of the extensor digitorum longus that lost
desmin-staining was significantly greater in the untreated controls than in the
treated animals (34 +/- 4.1 compared with 2.9 +/- 1.7 per cent) (p < 0.001), a
finding that supports the concept of a short-term protective effect. However,
the muscles in the treated animals still mounted a dramatic regenerative
response, as indicated by the expression of embryonic myosin. Early in the
recovery period (at three days), significantly fewer fibers of the extensor
digitorum longus (2.2 +/- 1.4 per cent) expressed embryonic myosin in the
treated animals than in the untreated controls (11.8 +/- 1.9 per cent) (p <
0.001). However, at seven days, the expression of embryonic myosin by the
muscles from the treated animals (19.5 +/- 11.9 per cent) actually exceeded
that of the muscles from the untreated controls (16.2 +/- 4.1 per cent). This
finding suggests either a delayed or an ineffectual regenerative response by
the muscles in the treated animals.
Comment in: J Bone Joint Surg Am 1997 Aug;79(8):1270-1 

Anti-inflammatory doses of ibuprofen: effect on neutrophils and
exercise-induced muscle injury.
Pizza FX, Cavender D, Stockard A, Baylies H, Beighle A
99205044 Int J Sports Med 1999 Feb;20(2):98-102
The purpose of the study was to determine the effect of anti-inflammatory doses
of ibuprofen on neutrophils, neutrophil O2* production, and markers of muscle
injury. Males (n=10) performed 2 bouts of one-arm eccentric exercise on
opposite arms separated by three weeks. Subjects received 2400 mg x d(-1) of
ibuprofen or a placebo 5 d before exercise and during 10 d of recovery.
Measurements were made before the treatments, pre-exercise, at 4 h, and at 1,
2, 3, 4 and 10 d post-exercise. Circulating neutrophil counts were similar
between the treatments at the sampling points. Neutrophil counts were higher
(p<0.05) for ibuprofen and were elevated (p<0.05) at 4h post-exercise relative
to pre-exercise in both treatments. Stimulated neutrophil O2* production was
lower for ibuprofen relative to placebo at pre-exercise and was increased
(p<0.05) at 4 h and 4 d of both treatments. CK activity at 3 d post-exercise
was lower (p<0.05) for ibuprofen relative to placebo. Isometric strength,
soreness, tenderness, and arm angles were similar between the treatments. In
conclusion, anti-inflammatory doses of ibuprofen reduced CK activity but not
the neutrophil response or other indirect markers of muscle injury during
recovery from eccentric arm exercise.