E-DRUG: Dipyrone/metamizol revisited (5)
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Dear all
Although dipyrone is not marketed in European countries
because of the its potential bone marrow toxicities
(especially agranulocytosis), it has been used in Japan even
now by prescription only medicine.
OTC drugs which contain dipyrone was banned because it caused
many sudden death in the past due to anaphylactic shock or other
causes and because it became an social problem in Japan in 1965.
Those OTC drugs were oral preparations but it contained
about 300-500mg of dipyrone in an ampoule with a little ethanol.
It was absorbed very well.
Other type of cause of deaths were called as
- Abnormal toxic syndromee(by specialists of forensic medicine0.
According to the modern knowledge, it may be a fulminant type of Reye's syndrome related to the use of NSAIDs as antipyretics, or einfluenza related encephalopathy with multi-organ failure related to the use of NSAIDs.
According to my personal view, it should be called as a type of viral severe sepsis or a septic shock with multi-organ failure induced by over produced cytokines enhanced by NSAIDs.
Although task force of Japanese Ministry of Health Welfare (MHW) did not mention the relationship between Reye's syndrome and NSAIDs including diclofenac Na, mefenamic acid and dipyrone before 1998, some of their studies had already indicated the epidemiological relationship between both at least in 1992.
In 1999 other task force reported the epidemiological relation between case mortality due to influenza related encephalitis/encephalopathy and NSAIDs use such as diclofenac Na and/or mefenamic acid: odds ratio for mefenamic acid was 4.6 (95% CI: 1.03-20.49, p=0.049) and
for diclofenac was 3.05 (95%CI: 1.01-9.21, p=0.045).
Later the use of diclofenac Na and/or mefenamic acid became contraindicated to use for influenza infected children in Japan, but it is not prohibited to use in other viral infection and
bacterial infection. Other NSAIDs such as ibuprofen and dypirone (both oral and injection) is not prohibited. Moreover, NSAIDs including diclofenac Na, mefenamic acid and dipyrone
(including injection) is not prohibited to use for the fever of adult infection.
But I have been consulted with at least 5 adult cases of fulminant type of Reye's syndrome or influenza (virus infection)-related encephalitis/encephalopathy with multi-organ failure.
Acording to the task force of MHLW (Now Ministry of Health,
Labor and Welfare) 30 percents of the influenza related encepahalitis/encephalopathy including necrotizing encephalopathy was considered to be related to NSAIDs use.
Some animal studies indicate that NSAIDs antipyretics increase mortality rate of infected animals: Bacterially infected rabbits treated with sodium salicylate increased compared with saline treated infected rabbits.
Another study using virus infected rabbits indicated that treatment with mefenamic acid at a dose which did not induce death of animal also increased death than control with no NSAID.
Lowering by antipyretics of infected animals increase not only mortality rate, but also increased number of bacteria, viruses and interferons (one of the cytokines).
Cytokines including TNF may induce tissue damage of multi-organ including brain, liver, kidney and so on, even in the absence of bacteria or viruses in the damaged tissue. And these cytokines with or without endotoxins may play a role in inducing Reye's syndrome, encephalopathy in necrotizing pancreatitis and necrotizing encephalopathy.
Paracetamol do not enhance the induction of cytokines and is proven as much safer antipyretics than salycilates and other NSAIDs.
Bearing in mind the evidence that paracetamol is a much safer alternative antipyretic, these evidences of risk suggests that there is good reason to stop using NSAIDs including dipyrone
at least in children with fever (and it may be true for adults), especially of viral origin as soon as possible. It must be the most powerful measure to eradicate Reye's syndrome and to reduce fatality from influenza related encephalitis/encephalopathy
in Japan. It may also be true in Africa.
Dypirone decreases the body temperature but it never decrease virus. On the contrary, it may increase viruses and other microorganisms due to block of the inflammatory process (= tissue repair mechanism) of body.
The more effective in antipyretic the more dangerous for deterioration of infection and may be the cause of death.
For these reasons, I also conclude dypirone should not be used as antipyretics in infection of both viral and bacterial origin and of both in children and adults and both in Japan and in Africa.
References
1) Study on correlation between acute encephalitis of unknown
cause with severe sequelae and drugs. Report of the Task Force
Study for 1990 to 1992, published in March 1994.
2) Study on correlation between acute encephalitis of unknown
cause with severe sequels and drugs. Report of the Task Force
Study for 1996, published in March 1997.
3) Bernheim HA, Kluger MJ. Fever: effect of drug-induced
antipyresis on survival. Science (1976) 193:237-9
4) Vaughn LK, Veale WL, Cooper KE. Antipyresis: its effect on
mortality rate of bacterially infected rabbits.
Brain Res Bull (1980) 5: 69-73
5) Kurosawa S. Kobune F, Okumura K, Sugiura A. Effect of
antipyretics in rinderpest virus infection in rabbits.
J Infect Dis (1987) 155: 991-7
6) Vaughn LK, Veale WL, Cooper KE. Effects of antipyresis on
bacterial number in infected rabbits.
Brain Res Bull (1981) 7: 175-80
7) Treon SP, Broitman SA. Monoclonal antibody therapy
in the treatment of Reye's syndrome.
Med Hypotheses (1992) 39: 238-42
8) Mizuguchi M. Acute necrotizing encephalopathy of childhood:
a novel form of acute encephalopathy prevalent in Japan and Taiwan.
Brain Dev (1997) 19: 81-92
HAMA, Rokuro MD Chairman
Non-Profit Organization "Japan Institute of Pharmacovigilance"
publishing ISDB-full-membership Drug Bulletin
"Kusuri-no-Check" (JCheck-up Your Pills to Save Your Life
Deputy Editor: The Informed Prescriber
HAMA Rokuro <gec00724@nifty.com>