A paper has just been published that is a real wake up call. I am stunned more of us didn't think about this sooner.
We all remember the Tamiflu frenzy that ensued in 2004 when people first realized the bird flu train might be coming down the tracks. There was a great deal of talk about how Tamiflu (oseltamivir) was the only antiviral capable of saving someone from the virus and it was in short supply. So many people started to stock up:
Fears of an outbreak of bird flu led Americans to hoard the anti-viral medicine Tamiflu in 2005, with prescriptions spiking most sharply when media coverage rose, a study released on Tuesday said.
Filled prescriptions for Tamiflu rose nearly five-fold between September and October of 2004 and the same period in 2005, according to the analysis by the U.S. Centers for Disease Control and Prevention (CDC) and pharmacy benefits manager Medco Health Solutions Inc..
Because there was little or no influenza activity reported during these periods, researchers said the data suggest patients were stockpiling the drug over fears of an epidemic.
The study adds weight to anecdotal reports of patient hoarding a year ago, when governments around the world were scrambling to build up supplies of Roche Holding AG's and Gilead Sciences Inc.'s Tamiflu, one of only two drugs that can treat avian, or bird flu.
[snip]
The report found that Tamiflu prescriptions filled rose to about 134 claims per 100,000 enrollees in 2005, from about 27 prescriptions per 100,000 enrollees in 2004. (Reuters)
This week a report [fulltext .pdf] in the prestigious journal, Environmental Health Perspectives, added a new wrinkle to the Tamiflu question, illustrating once again the complexities of an influenza pandemic. Andrew Singer and his colleagues at the Centre for Ecology and Hydology at Oxford asked a logical question most of us had overlooked: What if everyone who had Tamiflu started taking it all at once?
Lead researcher Dr Andrew Singer, said "An antiviral drug has never been widely used before, so we need to determine what might happen. During a flu pandemic, millions of people will all take Tamiflu at the same time. Over just 8 or 9 weeks, massive amounts of the drug will be expelled in sewage and find its way into the rivers. It could have huge effects on the fish and other wildlife." (NERC)
There is a shitload of Tamiflu already out there. Singer et al. list 3 million treatment courses (10 tablets per course) in the Belgian stockpile; 14 million in France; 16 million in German; 200,000 in Greece; 30 million in Italy; 5 million in The Netherlands; 840,000 in New Zealand;150 million in russia; 10 million in Spain; 14.6 million in the UK; and 81 millioin in the US. Another 5 to 6 million are in a stockpile in case they are needed in a blanket containment attempt somewhere in the world. Each course of treatment is 3/4 of a gram.
What happens when someone takes a Tamiflu tablet? The molecule in the tablet isn't the active form of the drug. It is a prodrug, one able to be absorbed and then converted into the active form by the body's own metabolism. The form in the tablet, oseltamivir phosphate (OP) is absorbed in the gastrointestinal tract and converted to the active neuraminidase inhibitor, oseltamivir carboxylate (OC) by liver enzymes. It is OC that grabs onto the active site of the viral neuraminidase, preventing it from detaching itself after budding through the host cell's membrane after replication.
That's the good part. The bad part is that most of the OC appears to remain intact and is excreted into the environment through the kidneys and feces, after which it appears to be resistant to degradation in the environment.
In other words, in a short amount of time most of those pills will go from us to toilets and then into waterways via sewage discharges. Or so Singer and colleagues believe. It turns out there is little direct information on the fate of environmental Tamiflu. The very fact we don't know more is a damning indictment of our shortsightedness. As often as I've written about it here, this never occurred to me, despite the fact I am well acquainted with the problem of pharmaceuticals showing up in waterways after passing through millions of human pill takers.
What are the possible adverse consequences? Mutations or reassortments and/or recombinations during avian co-infections in a low level Tamiflu environment could produce new drug strains with Tamiflu-resistant neuraminidase genes. Rough calculations of the range of Tamiflu concentrations in wastewater that might result from plausible pandemic scenarios show the estimated levels to be of potential pharmacologic significance. We also have not investigated whether the drug might have serious effects on particular species in the environment. Nobody has looked.
It's urgent to investigate this, now that it has been called to our attention. Failure to do so is negligence of the worst kind. Unfortunately, that is the kind of negligence we are most familiar with.
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we could store the urine in our prepped water bottles
which we emptied. Then we can pump it into tankers and ship it to siberia, where it freezes to permafrost.
Whatever.
I mean, that problem is really minor compared with the
tamiflu-costs. You could require an extra sewage tax
and punish those who put it into the environment
uncontrolled.
When the pandemic strain is not resistant when it reaches us, then it probably won't become resistant by OC either.
Also, OC were ineffective, we've been told after someone
had the idea to drink the urine to prolong the tamiflu.
Similar problems arose with several antibiotics during the last few decades, if memory serves me right. You're right, Revere, we should have thought about this. What's worse is that it will get into the environment during wave 1, so wave 2, which is likely to be the most lethal, might be much more resistant, too.
Revere, is it plausible to say that this might cause superbugs in the environment? The paper said that basically you could recycle the Tamiflu back into the same person over and over again. Else down to ole tube she goes into septic systems and sewers which are breeding grounds to begin with. The dependence on aerobic bacteria to kill along with the sun might be tamped back and we might be pumping the environment full of the end for all mammals.
"There is a shitload of Tamiflu already out there." Good one Revere, LOL.
Randy: No, not superbugs. Just resistant influenza A or B. The Tamiflu in the environment would be in the active form, OC, which you cannot absorb (it is charged). So you would have to convert it back to OP before it would do you any good. The data that Singer et al. used was for Relenza (no data on Tamiflu) but it suggested there is very little biodegradation in the environment. In other words, it is persistent. Needs more study, though.
While I am concerned at the unforeseen circumstances to organisms within our watercourses I am not particularly bothered by the dangers of Tamiflu resistance developing in wild fowl. As, regretfully, I fear that Tamiflu resistance will quickly develop among the human sufferers of a pandemic H5N1. The have only been about 250 documented cases of human H5N1 and yet we have already seen Tamiflu resistant mutations in Vietnam and Indonesia. In the event of effective human to human transmission it seems inevitable, given the large number of infected sufferers challenged by Tamiflu, that resistant strains will emerge almost immediately and then be selected for. This will lead to a Tamiflu resistant dominant strain, providing ample opportunity for Tamiflu resistant recombination/reassortment with other circulating seasonal flus.
Even though people had been talking about "re-uptake" to try and get enough Tamiflu, and even though I know meds humans take are ending up in the environment, I hadn't thought about aftereffects on our already out-of-balance ecosystem.
http://www.ahrp.org/infomail/04/08/10.php
..."In 2002, the U.S. Geological Survey tested 139 rivers in 30 states and found that 80 percent of streams sampled by showed evidence of drugs, hormones, steroids and personal care products such as soaps and perfumes.
In October, 2003, US scientists reported that Prozac and other pharmaceuticals were polluting US streams and affecting the development of fish and other wild life. According to the National Center for Health Statistics at the CDC, more than 61 million prescriptions for anti-depressants were prescribed by U.S. doctors in 2001. As pointed out, because prescriptions like anti-depressants are for chronic conditions, patients often take them for months and years at a time, making them more likely to build up in wastewater"...
"Marsha Black, an aquatic toxicologist at the University of Georgia found that low levels of common anti-depressants, including Prozac, Zoloft, Paxil and Celexa, cause development problems in fish, and metamorphosis delays in frogs"...
Non-pharmaceutical interventions and contingency planning should have been started with the public first.
At least we've had the time we've had, but waiting for ordered magic solutions with promised money isn't going to get us through a pandemic. (There still is no vaccine against HIV.)
We talked about the reuse of tamiflu several months ago on fluwikie and it was the consensus and I believe even Roach was contacted at the time; that tamiflu is destroyed by first pass liver degradation hence the pro-drug design. So even if the rivers are full of it and the animals are ingesting it, its not actually getting into their system. So by my understanding this is a non issue. I would be more concerned with all the humans taking it incorrectly and causing increased resistance that way.
We could use the wastewater to irrigate spinach. Can't ya just taste the irony in this situation?
max: I don't know what that concensus was based on. The EHP paper examined the question of metabolism and concluded that there is little transformation of the active form, which is highly water soluble. Nor does there suggest there will be much adsorption to soil or biodegradation.
The drug cannot be destroyed by first pass liver or it wouldn 't work, since it is taken orally and thus goes through the portal system to the liver first. In fact, it is activated by the liverr. It is transformed to the carboxylate active form via hepatic esterases. From that point on the scant data don't suggest a lot of change.
The issue of other species is also something that must be considered, given the other examples we have had recently (e.g., diclofenac killing vultures in India).
Seems like we are using a chemical compound on humans that we don't know alot about...in the absence of some pharmaceuticals that we know work and would save millions of lives in a pandemic...doesn't make much sense to me.
Aren't antivirals questionable to begin with against H5N1? It seems to me that stockpiling them is the one thing that people and governments can do easily so that's the "big plan". I could have acquired my own stash, but logic says if I unknowingly get exposed and delay taking them it's not much help.
The mass drug dump in the water is quite a surprise, didn't occur to me either. But, I have been thinking about prions and how the latest finding that CWD is apparently transmitted in saliva, which can get in the water and presumably resists degradation. Ack...
styu: No one knows for sure whether they will work and if they do, if they will continue to work. But evidence suggests they do work now if given in adequate dose and promptly. I wouldn't be especially eager go say they are useless at this point, nor to depend upon them to save us. I don't think either position is defensible given current evidence.
I'm really happy to see the feedback on the EHP paper. Oseltamivir carboxylate does not need to be in the blood stream of ducks to be an effective antiviral (i.e., inhibit the neuraminidase), it just needs to reach the virus before it detaches from the infected cell. In ducks, the avian influenza virus replicates in the gut, hence, exposure to contaminated riverwater is all that is needed to generate tamiflu resistance. My guess is that 'used' tamiflu (i.e., from urine) could treat humans if you could somehow get the urine to the virus infected region...as that would be a horrible experience, my guess is you shouldn't try. Using your blood is the best way to get the drug to the infected cells, so stick with taking the prodrug (Tamiflu)!
I've also come across a number of papers that indicate that neuraminidase is not exclusive to the influenza virus, but can also be found in many bacteria. As the relesae of an antiviral can potentially effect bacterial attachment, it is safe to say there are many unknowns about the release of this active drug into the environment. The last part was not included in the EHP paper.
It will be interesting to see if any of the countries considering heavy use of oseltamavir in their planning respond to this paper by altering their plans.
Australia recently held a human pandemic influenza exercise which the media are reporting went really well (although if it was anything like the human health side of the combined human/veterinary public health exercise last year, that's codespeak for an absolute shambles...) and the scenario would most likely have included oseltamavir use (particularly for first responders. Given the environmental sensitivities of the general population here, it will be interesting to see if this raises any interest.
I have been working on a project (about 2 and some years) at UCLA with a friend for a San Diego (in the county of, not the city... and a small city within the county) reservoir and treatment plant that supplies drinking water. We collected invertebrates, wetland plants, fish, and water from various parts of the urds and other man made retaining ponds and wetlands. Rain water and road run-off go into these man made wetlands instead of directly contaminating the drinking water. The processed water is then filtered and treated and then released into the reservoir. Our job was to see how effective wetlands are in taking up the toxins and other substances.
We then took the plants from the man made wetlands and grew them in Nalgene 6x4x4 foot pots, filled them with water and mosquito fish. Various dragonflies started breeding and midges and occasional mosquito. We then spiked the pots with PAHs, mercury, oragno-phosphates, and anti-epileptic drugs, antibiotics, Tylenol, some other substances that I am not familiar with, and other health care products.
From there we sampled the water everyday before dawn and once a month in the afternoon for four months. Then we ripped up the plants, took out the second sample of fish and dragon flies (the first before spiking), mud, and root samples (separating root hairs from main roots).
It was quite an undertaking and we ran out of money to do all of the molecular tests and digestions so we preserved the water, fish, dragonflies, plants (leaves, roots and stems), and algae for when we do get more funding. But, what we did find was very interesting.
Some plants are far more effective in the uptake of anthropogentic material then other plants. The dragon flies tend to sequester more of the chemicals including the health care products and medicines then the fish. We figured this would be a limited fate because fish and birds eat the insects. Cattails are the least effective plant in the uptake of all substances and bulrushes are the best. Cattails tend to have a quick die off and so return what ever is taken up into the plants, back into the water. Bulrushes grow slower but seem from our numbers even to take up more per stem vs. cattails.
The micobiology group did all of the methylmercury and bacterial assays.
My friend is now working at ACE but we hope to finish this important project. The first part of the project was published last year with IWA. If you can get the paper the title is 'The Ecological Value of Constructed Wetlands for Treating Urban Runoff' by Pankratz et al.
Now the question of retention of Tamiflu in treatment plants which process effluent and then turn the water back into a water body.... I would worry about communities that are down stream from rivers. .... we have a ton of things to do...
What about encouraging the combination of tamiflu and probenecid? As I understand it (I'm no expert), probenecid may reduce the amount of tamiflu excreted from the body in urine. Therefore, the result of the combination might be that more tamiflu is retained in the body (potentially extending the effective tamiflu supply) and less tamiflu is excreted into the environment.
Chuck, The irony is in the spinach...iron..y . I need some sleep.
When they used the "blanket containment" method to stop the outbreak in Indonesia a couple of months back, giving tamiflu to all the people living in the village where the outbreak occured, might that have caused these "Mutations or reassortments and/or recombinations during avian co-infections in a low level Tamiflu environment could produce new drug strains with Tamiflu-resistant neuraminidase genes." you propose? (And I'm guessing you meant new viral strains, not new drug strains). Have their been any indications of tamiflu resistant H5N1 cropping up in that area since the inital outbreak and treatment?
Its interesting 'someguy' mentions combining Tamiflu with probenecid as one of the reviewers of the EHP paper mentioned that as well. It turns out it would help retain the antiviral but it comes at at cost. (1) Tamiflu has side effects which are minimised due to rapid excretion; (2) you would need BUCKET LOADS of probenecid produced in a very short time to treat the millions of people potentially infected with pandemic influenza; and (3) you might have a problem with the environmental release of probenecid (or metabolites).
On a separate note, is anyone aware of published (or not) evidence that in China people dose a rag with vinegar and put it on a radiator, effectively volatilising the acid into the home which kills the virus (as the influenza virus is sensitive to pH above 9 and below 5). I heard this from a colleague but she couldn't remember where she heard this. it would be cheap, easy, and environmentally friendly with no side effects except a smelly home. It beats getting pandemic influenza! Of course you need to practice 'social distancing' to avoid getting the virus from your neighbor who is taking Tamiflu!
http://dmd.aspetjournals.org/cgi/content/full/28/7/737 This links to a study on tamiflu that shows that the active metabolite has poor absorption hence the prodrug design.
I also looked up the amount needed for an active concentration (its listed on google somewhere) I believe it was 35uM to be effective. Even at this minute concentration the amount of dilution in body of water would be so enormous as to render any tamiflu present essentially useless.
max: Did you read the EHP paper? Their calculations don't suggest it is so negligible. Paper is Open Access at the link given in the post.
Someguy and Andrew: first question. As soon as one stops taking Probenecid, all oseltamivir would be released, or not?
If yes, it's only a delay.
Secondly, Probenecid isn't just like some harmless vitamine C stuff, isn't it? It may have several serious side effects and I am curious anyone has ever taken it deliberately in a higher dosage in order to retain an antibiotic at high level in the body. Not to speak the little experience we have in general in retaining Tamiflu by use of Probenecid.
Andrew Singer, I've read in the past during epidemics in Asia, of stores running out of vinegar, from people boiling it on the stove to try and keep from getting sick.
M in H. Re the Tamiflu resistant strains. Not a doc of course but they first indicated that it was screwing with the testing on "cases" which initally werent testing out, then they did. Then the conjecture was that even after they automatically dumped Tamiflu on them in huge doses, they still died.
Resistant strains? Without research we wont know but it will become flamingly evident if it comes and they throw the Tamiflu blanket out and it doesnt work. Their last thoughts will be... I spent 200 bucks on some crap that makes me psychotic, doesnt work, and makes the flu even worse down the road for my family and friends. One saving grace and Revere will get a charge out of it is that Roche will suffer dramatically and by proxy Rumsfeld...
Mary in Hawaii - I'm fairly certain tamilu has never been measured in the environment, which is to say, noone looked. Hence, it's impossible to say that blanketing an area has already had an effect in Indonesia.
Randolph - I'm hesitant to come down against Roche on this one as the regulations that are in place for drug approval do not seriously consider Ecotoxicology as terribly important. If you have an incling of toxicology background, you'll have a laugh at the European Medicines Agency (EMEA in paper) document that states the Ecotox done on Tamiflu...its a joke (free on the web--google search it or look in paper, the link is there). The joke is on us, as the regulations are simply not in place to do a better job, hence, Roche and others dont bother. What was clearly short-sighted of all parties involved is that, unlike most other drugs, Tamiflu always had the potential to be used on a very very large scale (i.e. pandemic situations), however, the drugs are not assessed any more due to their potential use patterns, as such. The regulators should reassess Tamiflu and future drugs in light of their potential scale of use. My two cents (or pence for any Brits watching). What's also amusing, is that Tamiflu was initially poorly marketed and virtually nooone used when it was released. If my memory serves me, Giliad (the inventor of the drug who sold the marketing rights to Roche) was in the process of a legal battle with Roche for poor marketing (i.e. no sales)...but, bird flu came in 2003 and the rest is history! I suspect they are pretty happy with how it worked out, now.
OK, dumping large amounts of drug into the water is probably not the best idea in the world, but under the scenario envisaged by this paper (massive Tamiflu use on a worldwide scale), introduction of a new neuraminidase gene (or a new strain) from waterfowl is not likely to be our greatest concern -- the problem will only occur during a full-scale pandemic in which the more immediate threat is from human-to-human transmissible virus. The bigger question is whether the use leads to selection of highly transmissible resistant strains of the pandemic virus itself.
On the whole, this issue seems rather a distraction.
You stated :
''There is a shitload of Tamiflu already out there. Singer et al. list 3 million treatment courses (10 tablets per course) in the Belgian stockpile; 14 million in France; 16 million in German; 200,000 in Greece; 30 million in Italy; 5 million in The Netherlands; 840,000 in New Zealand;150 million in russia; 10 million in Spain; 14.6 million in the UK; and 81 millioin in the US''
This again shows the vast ignorance of people. Many on this post. Up to 20 % ( confirmed ) and possibly more of this is Relenza.
As I've stated many times before Tamiflu and Relenza may be NAs they are NOT the same.
Get educated please.
I'll follow up my recent post by showing what the United States Government is saying. This probably doesn't fit your agenda though.
''The current goal with future procurements is to bring that ratio to 80:20. Theoretically, there is less risk of resistance with Relenza compared with Tamiflu. Also, the most common Tamiflu resistant mutant is susceptible to Relenza. Thus, both Tamiflu and Relenza are being procured to ensure both of these medications are available if needed.
Q: How many regimens of antivirals will be procured at the state and federal levels?
A: The HHS goal is to have 81 million antiviral regimens available for the U.S. population. Of this 81 million, 50 million regimens will be procured and stored in the SNS. Of this 50 million, approximately 44 million regimens will be held for pandemic usage by states and 6 million reserved for domestic containment efforts. HHS will subsidize state purchases of up to 31 million treatment courses of Tamiflu and Relenza, apportioned to States based on population.''
http://www.bt.cdc.gov/planning/coopagreement/pdf/fy06guidance_qa2.pdf
M. Randolph Kruger
Maybe this article will be of help. Even though Glaxo sponsored it is still good science I believe.
This didn't get much media. Actually only this article that I could find.
http://www.bloomberg.com/apps/news?pid=20601102&sid=apT0bMPgell0&refer=…
Marc: You make an excellent point, although there could now be significant use during seasonal flu or as a blanket containment attempt because of a largish cluster (like the one in Karo). And as you say, the dumping massive amounts into the environment is probably not the best idea. Whether the substantial leak of NA inhibitors into the environment will have any effect on selective pressure is unclear, although you are probably right -- but I am disturbed it wasn't thought of more seriously, if even to finally say, "not a problem except in a pandemic and then it would be the least of our problems." There is also the question of non-target species (again, diclofenac and vultures comes to mind).
cpg: I don't have a tamiflu agenda, but the agenda of the post was to call attention to the EHP paper that we should be thinking about environmental impacts, whether it is is oseltamivir or zanamivir or something else. At first this seems like a second order problem and given the size of the first order ones, probably not worth thinking about. But I think the EHP paper demonstrated that it could plausibly be a bigger problem and we would do well to think about it and find out how bad the problem is -- or isn't.
Revere
Didn't mean to say 'agenda' in relation to environmental impacts. Only Classic Tamiflu vs Relenza debate. You have got to admit it's tamiflu or bust on this forum. Right or wrong !!!
Cheers
The reason we're talking about tamiflu is because it was the drug most/all countries (that have a stockpile) are stockpiling. Since writing the paper, a number of countries have also begun a small stockpile of Relenza, which is probably as much to do with marketing by Glaxo as it has anything to do with public health. Some of the physical characteristics of Relenza and how it interacts in the environment were used to model tamiflu in the EHP paper as data on tamiflu is scarce (Relenza has been around longer than tamiflu, hence, a bit more info is available on it). There is no reason to believe that the story would have been any different had Relenza been the one that is being stockpiled. The fact that Relenza is used in 5 mg quantities, 15 times less per dose than tamiflu, would make a bit of difference, but it's a smaller dose as it's effective at inhibiting viral replication a lower IC50. Meaning you get a biological response using less drug.
"attack rate": a successful wargame is a failure. You want to find what the problems are, so if it goes well you don't learn much. But the worthwhile failure looks bad.
If we do not have a pandemic in the next five years or so and all that stockpiled Tamiflu expires... Disposing of it will be a nightmare for plenty of govts.
My name is Maura Logan and i would like to show you my personal experience with Tamiflu.
I am 63 years old. Have been on Tamiflu for 5 days now. Formerly had no negative feelings about "Big Pharmaceutical" but this medication has changed my mind. Definitely needed more extensive testing by the FDA.
I have experienced some of these side effects-
Horrible itching started after 8 pills (fourth day) and has lasted for six more days--and counting. Also suffering insomnia, and mood swings--crying and sour temper. Dr. wasn't even sure I had the flu (headache, severe body ache, exhaustion but no cold symptoms). Med seemed to help, but the after-effects are totally miserable. Hugely expensive med and not worth the risk. Absolutely HATE, HATE, HATE this medication!
I hope this information will be useful to others,
Maura Logan