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» LymeNet Flash » Questions and Discussion » Medical Questions » Are currently deployed artemisinins neurotoxic?

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Author Topic: Are currently deployed artemisinins neurotoxic?
Dave6002
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Are currently deployed artemisinins neurotoxic?

Stephen Toovey
Royal Free and University College Medical School, London, UK
Travel Clinic, Cape Town, South Africa

Received 28 April 2006; revised 31 May 2006; accepted 1 June 2006. Available online 7 June 2006.


Abstract

In vitro, animal, and human clinical studies suggest currently deployed artemisinins possess neurotoxic potential. A specific and consistent pattern of brainstem injuries that includes auditory processing centers has been reported from all laboratory animals studied. Hearing loss, ataxia, and tremor are reported from humans. Neurotoxicity appears mediated in part through artemisinin induced oxidative stress in exposed brainstems. In vitro studies suggest that artemisinin neurotoxicity does not manifest immediately upon exposure, but that once commenced it is inevitable and irreversible; extrapolation from in vitro data suggests that 14 days may possibly be required for full development, casting doubt upon some animal safety studies and human necropsy studies. Uncertainty remains over the neurotoxicity of currently deployed artemisinins, and their safety profile should be reviewed, especially in pediatric use. The development of non-neurotoxic artemisinins is possible and should be encouraged.

Keywords: Artemisinin; Artemether; Artesunate; Dihydroartemisinin; Neurotoxicity; Ototoxicity; Malaria; Cancer

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Dave6002
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There is sufficient agreement between in vitro, animal, and human studies to raise concern over the neurotoxicity of Artemisinin in clinical use.

Given that the long term consequences of artemisinin exposure remain unknown, a special concern must be the intended large scale use of these drugs in children, as developing nervous systems may be more prone to insult.

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clairenotes
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I have had serious suspicion about the safety of arteminisin after my own experience with it.

Though I know that other people here have had better outcomes with arteminisin, I have used anti-microbial herbs off and on for 17 years with plenty of healing reactions. Nothing compared to the ones I had with arteminisin.

Slurring speech, migraines, loss of memory... I don't feel these are normal reactions. I did take a larger dose than normal, apparently. I followed guidelines by a well-respected LLMD, but was told later the guidelines were way too high [Frown] . But I notice others have had trouble on way less.

If I take wormwood again, it would only be in the old-fashioned way I used to take it as an herbal tincture, or the loose herb artemesia.

If others decide to take arteminisin... please go slow, use low doses.

Thanks for the research, Dave.

Claire

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Dave6002
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Thanks, Claire for sharing your experience with artemisinin.

Before I thought Arte. was pretty safe, after reading the review paper, which documented plenty of data indicating Arte. may cause damage to the brainstem, I inclined to think we should take it with much caution and at much low dose.

It is true that Arte. is very effective for malaria and has been used by millions of patients without serious side effects. However, these patients were exposed to Arte. just for a short period of time, 7 days, not exceeding one month.

So the side effects of long term usage of Arte on human is still unknown.

Today, my earrings were the worst and I thought Arte. could be the culprit.

So I stopped Arte. and see if my earrings would improve.

I'll do more reading on Arte. safety, in order to decide if I'll take it again.

This paper is a wake-up call for me.


Good luck.

Dave

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polar blast
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hi claire and dave..
I am still not feeling well as I noticed that I am not going to the bathroom at all it has been about 5 days now...I have problems with auditory jumpiness from art and my heart rate and blood pressure has gone up and down...there are differant feeling then I had before and I hope that they are for the good..I dont understand how this could happen when I was under the 3x100 a day...is it becasue I doubled the last two?anyway are you all feeling better..my ears feel raw..also I have been flushing on my face and body..and tremers..my pupils are very small in the light and alot of things dont make sense..will I get better from this?
eric

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kumba
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Hi Dave,
since I just ordered ART I'm a bit alarmed by this post. I have read with interest here, others experiences with ART. conflicting opinions...LOL, nothings straightforward. I will be taking it for Toxoplasmosis, since I don't beleive I was sufficintly treated and all my sx began with this diagnosis. I had a phone consult with Dr. Zhang a couploe of weeks ago and he suggested 100mg three times a day for 3 months. Now reading this article and polarbears ongoing difficulties...Hmmm what to do. I think most studies use very high doses of Art. did this study specify the dose?? Thank you.

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Lymetoo
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David said, "So I stopped Arte. and see if my earrings would improve."

could you explain????????

--------------------
--Lymetutu--
Opinions, not medical advice!

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Penn92
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Well, my 10yo daughter has been on 100mg artemisinin daily since mid-June and has had no problems.

I have been on 100mg 2x daily since early October and, other than a herx on day 2- day 6 involving tight shoulders and neck and minor spasms in shoulder and neck muscles, the worst thing I can say is it causes an occasional mild headache. My air hunger has improved vastly and I'm pretty pleased with it overall.

--------------------
Getting older is when we would rather not have a good time
than have to get over it. - Oscar Wilde

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Dave6002
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quote:
earrings would improve.
Haha... who wrote this?
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Dave6002
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The following review article has oposite opinion. Have to read it yet:

Toxicology Letters
Volume 167, Issue 2 , 1 December 2006, Pages 162-164

Letter to the Editor

Are currently deployed artemisinins neurotoxic?

George O. Adjeia, Bamenla Q. Gokaa, Jrgen A.L. Kurtzhalsa and Toufigh GordiCorresponding Author Contact Information, a, E-mail The Corresponding Author

aState University of New York at Buffalo, Department of Pharmaceutical Sciences, Buffalo, United States

Received 22 August 2006. Available online 12 September 2006.

Keywords: Neurotoxicity; Artemisinin; Malaria

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micul
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Artemisinin is very safe. Most people don't have any problems with it. Cancer patients take it non stop for years without side effects. Some people take up to 3000 mg a day without a problem.

The article in the first post only states "MAY" have some toxicity. Which means that they haven't proven any. There are other studys that show how safe it is also. Of course there are always going to be those people that have a bad reaction to it. But that's the same for any med whether it's Biaxin, Zith, Mino...you name it. Some will herx on it and raise a question about it's safety. I've been taking it for 2 yrs in high doses without any major problems that didn't subside when it was discontinued for a few days, and I will continue to use it.

[ 28. November 2006, 09:23 PM: Message edited by: micul ]

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Dave6002
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Conclusion from the article:

Some of the key evidence that has been cited in the aforementioned review to support ``available human clinical evidence supports currently available artemisinins, alone or in combination with partner drugs as being neurotoxic'' misrepresent the conclusions of the authors of the original articles.

Therefore, it cannot be considered unbiased on whether these important classes of antimalarials are neurotoxic or not.

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Dave6002
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Reply to Letter to the Editor

Are currently deployed artemisinins neurotoxic? Reply to Adjei et al.

S. Tooveya, E-mail The Corresponding Author

aRoyal Free and University College Medical School, London, UK

Received 5 September 2006. Available online 12 September 2006.

Keywords: Malaria; Artemether-lumefantrine; Neurotoxicity; Artemisinin; Artemether; Artesunate; Dihydroartemisinin; Ototoxicity

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Dave6002
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The reply was well-written and both sides agree that there is doubt about the safety of currently deployed artemisinins.
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Dave6002
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No hearing loss associated with the use of artemether-lumefantrine to treat experimental human malaria

Matthew B.B. McCalla, Andy J. Beynonb, Emmanuel A.M. Mylanusb, Andre J. A.M. van der Venc and Robert W. Sauerweina, Corresponding Author Contact Information, E-mail The Corresponding Author

aDepartment of Medical Microbiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
bDepartment of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
cDepartment of General Internal Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

Received 22 December 2005; revised 24 February 2006; accepted 27 February 2006. Available online 30 June 2006.


Summary

Artemisinin derivatives are becoming the first-line treatment for uncomplicated malaria in areas with widespread resistance to chloroquine. Although generally safe and well tolerated, it has been suggested from animal experiments, and more recently from one human study with artemether-lumefantrine, that these compounds are potentially neurotoxic, affecting particularly the brainstem auditory pathways. We report here the auditory analyses of 15 volunteers who underwent an experimental human malaria infection and were treated with artemether-lumefantrine. The subjects underwent audiological examination before the start of the study, during infection, and after treatment. Examination included standard tone audiometry, high frequency tone audiometry and auditory brainstem response (ABR). No effects on hearing loss that were deemed to be caused by drug treatment were found using tone audiometry. ABR analysis similarly failed to demonstrate any auditory pathway damage in the volunteers after treatment. We have thus not found any clear evidence of a detrimental effect on the auditory system by artemether-lumefantrine treatment in uncomplicated malaria. Our results support the continued implementation of artemisinin derivatives in the fight against drug-resistant malaria.

Keywords: Malaria; Artemether-lumefantrine; Artemisinin; Neurotoxicity; Hearing loss

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Dave6002
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Neurotoxic mode of action of artemisinin

Schmuck, Gabriele; Roehrdanz, Elke; Haynes, Richard K; Kahl, Regine

Pharma Research Center, Bayer AG, D-42096, Wuppertal, Germany; e-mail [email protected]

Abstract

We recently described a screening system designed to detect neurotoxicity of artemisinin derivatives based on primary neuronal brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity Res. 2:37-49, 2000). Here, we probe possible mechanisms of this brain stem-specific neurodegeneration, in which artemisinin-sensitive neuronal brain stem cell cultures are compared with nonsensitive cultures (cortical neurons, astrocytes). Effects on the cytoskeleton of brain stem cell cultures, but not that of cortical cell cultures, were visible after 7 days. However, after a recovery period of 7 days, this effect also became visible in cortical cells and more severe in brain stem cell cultures. Neurodegeneration appears to be induced by effects on intracellular targets such as the cytoskeleton, modulation of the energy status by mitochondrial or metabolic defects, oxidative stress or excitotoxic events. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range in all three cell cultures, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Artemisinin additionally induces oxidative stress, as observed as an increase of reactive oxygen species and of lipid peroxidation in both neuronal cell types. Interestingly, an induction of expression of AOE was only seen in astrocytes. Here, manganese superoxide dismutase (MnSOD) expression was increased more than 3-fold and catalase expression was increased more than 1.5-fold. In brain stem neurons, MnSOD expression was dose dependently decreased. Copper-zinc superoxide dismutase and glutathione peroxidase, two other antioxidant enzymes that were investigated, did not show any changes in their mRNA expression in all three cell types after exposure to artemisinin. [Journal Article; In English; United States; MEDLINE]

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Dave6002
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Hi, kumba,

the following abstract may answer some of your question:
quote:
I think most studies use very high doses of Art. did this study specify the dose??
Artemisinin neurotoxicity: neuropathology in rats and mechanistic studies in vitro

Kamchonwongpaisan, S; McKeever, P; Hossler, P; Ziffer, H; Meshnick, S R

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, USA

Abstract

Despite the wide use of artermisinin and its derivatives, concerns have been raised about their potential neurotoxicity. Accordingly, studies were undertaken on rats treated with high doses of arteether and on mouse neuroblastoma cells (Neu2a) treated with 3H-dihydroartemisinin. Rats uniformly developed neurologic symptoms following intramuscular administration of 50 mg/kg/day of arteether for 5-6 days. Acute neuronal necrosis associated with vacuolization and focal axonal swelling in the neuropil was observed in specific areas of the brain, especially the vestibular nuclei and red nuclei. Scattered swollen neurons were also evident in the cerebellar nuclei and the reticular formation. No neurologic symptoms, neuronal nuclei necrosis, nor gliosis was observed in rats administered 25 or 30 mg/kg/day for six or eight days. In vitro, Neu2a cells took up much less 3H-dihydroartemisinin than Plasmodium falciparum-infected red blood cells when incubated under identical conditions for 4 hr with 4.2 microM 3H-dihydroartemisinin. This selective uptake may explain why the artemisinin derivatives are selectively toxic to malaria parasites. Autoradiograms of sodium dodecyl sulfate-polyacrylamide gels run from 3H-dihydroartemisinin-treated cells showed that neuronal proteins with molecular weights of 27, 32, 40, and 81 kD were alkylated, although not nearly as strongly or rapidly as the P. falciparum proteins. The results indicate that while artemisinin derivatives have neurotoxic effects in rats and alkylate proteins in neuroblastoma cells, these effects only occur at high doses or after prolonged exposure. [Journal Article; In English; United States; MEDLINE]

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charlie
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"intramuscular administration of 50 mg/kg/day of arteether for 5-6 days".(rats are a bit smaller than we are, and we don't shoot up on the stuff)

"The results indicate that while artemisinin derivatives have neurotoxic effects in rats and alkylate proteins in neuroblastoma cells, these effects only occur at high doses or after prolonged exposure".

somehow this really doesn't worry me much....Two of us in this household have taken it for years.

and it didn't affect me affect me affect me

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