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Bird Flu Drug Mass Production Technique Discovered
creepygeek writes to mention a New Scientist article detailing a new process for creating Tamiflu, an antiviral drug currently thought to be our best defense against the bird flu. From the article: "Making Tamiflu is slow, partly because shikimic is hard to get, but also because one step in the process involves a highly explosive chemical called an azide. As a result, Tamiflu can be made only in small batches of a few tens of litres at a time. But Elias Corey of Harvard University - who won a Nobel prize in 1990 for chemical synthesis - and colleagues have devised a new way to make the drug from two cheap, plentiful petrochemicals, acrylate and butadiene."
From TFA: It's too bad that our 'biggest hope' is not up to the task, as the following articles assert:
It might be better to just stock up on old-fashioned Jewish penicillin.
____
~ |rip/\/\aster /\/\onkey
Can I come out of my air-tight bubble yet?
echo YOUR_OPINION >
If we believe the hype that the bird flu is a real threat to the health of the people of the world... which despite the hype from the media and the upcoming ABC made for tv movie... I have yet to see any credible evidence of despite much looking.
Help Brendan pay off his student loans
Before any useful medical advancement becomes available to the general public. Yes, this is a cynical remark. Is any other kind of a remark merited by the way things work today?
Thanks, but no thanks. I prefer the highly explosive vaccine, thank you very much...
This guy's the limit!
How about education and municipal plans to regarding epidemics? Anti-virals might be the best chance of treating those who have bird flu, but the best practice is to contain the virus early and give the medical community time to develop a real vaccine defense.
I think the most notable thing about this paper is that the last sentances read "It is our hope that the process described herein will be of value in improving the opply of oseltamivir and in reducing the cost. With regard to the latter, the process described herein in in the (unpatented) public domain."
I hear Yogi Bear is quite good at getting baskets full of shikimic. I might have heard wrong, though.
Hey Boo-Boo, let's go grab the shik-a-mic basket, the mi-grr-a-tor-ee birds are coming with the flooo!
Till know aound 50 people worldwide had died of bird flu. I guess more people die being stroke by a lightning. But the worst thing is that nobody knows whether Tamiflu will cure bird flu or not. Meanwhile health authorities all over the wold had been doing massive buys of that medicine ... sounds weird.
I, for one, start a business of selling a new drug that is suppossed to protect you against being struck by a lightning. I'm already taking orders. Anyone?
How long before we see a story about making bioTamiflu out of used vegetable oil from McDonald's?
Who else read this and only saw "highly explosive" and spent 20 mins looking up stuff that exploded.
Bah to your end of the world disease, I was stuff that blows up.
For anyone who believes that it is all hype, or knows little about bird flu, I highly recommend this extremely informative discussion Charlie Rose had with 3 experts on the subject. It is by no means overly technical.
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http://video.google.com/videoplay?docid=234341498
The truth is that it is not hype; just because we know about it well ahead of the time when it will actually affect us doesn't mean that it will not be a threat. The most interesting part of that discussion is the possibility that people with AIDS will be the least likely to be harmed by bird flu, since it is the overactive immune system--in response to the foreign disease--that ultimately kills you.
Now there's yet another thing to drive up the price of oil! Just what we needed!
(yes, that was sarcastic...)
-- Josh Turiel
"2. Do not eat iPod Shuffle."
There aren't too many people around that still remember the 1918 pandemic, but if you have records of your relatives that were alive at the time, odds are at least one of them died of the flu.
"a new way to make the drug from two cheap, plentiful petrochemicals, acrylate and butadiene"
:)
Petrochemical eh? as in petro based? Does this mean gas price is going up more once we start making these drugs?
Are we to trust a random person on /. to look for "credible evidence", or the opinion of several experts actively working on the subject:
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http://video.google.com/videoplay?docid=234341498
Tamiflu won't work. The H5N1 virus can mutate into a form unaffected by Tamiflu. In Vietnam four out of eight avian flu patients who were given the medication died despite the treatment.
w s/20051221/tamiflu_drug_051221/20051221
(CTV NEWS) http://www.ctv.ca/servlet/ArticleNews/story/CTVNe
Many top experts are advising to prepare for the worst. The US gov. is urging people to store food that could last for three months. In the UK mass graves are being planed openly. Forget Tamiflu:
(BBC) http://news.bbc.co.uk/2/hi/uk_news/4869224.stm
"Till know aound 50 people worldwide had died of bird flu."
/. opinions, see this extremely informative discussion with experts:
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The threat is not from this form of bird flu. The threat is from a form that can be transferred from human to human. If that happens, predictions are that it could kill upwards of 70 million people. For informed opinions, as opposed to random
http://video.google.com/videoplay?docid=234341498
Are you done? Watch this:
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http://video.google.com/videoplay?docid=234341498
You mean they discovered patent reform?
"I am the king of the Romans, and am superior to rules of grammar!"
-Sigismund, Holy Roman Emperor (1368-1437)
He may be a genius, but he is a fucking tool as well. He claims credit for the woodward-hoffman rules: Says Corey: "You [Hoffman] cannot deny that despite the possibility of appalling dishonesty at the roots of your collaboration with Bob [Woodward], you elected to close your mind. . .please consider that history many not deal leniently in this matter, taking seriously the possibility not only of Bob's dishonesty, but of your own not unwitting participation in the extension of fraud."
from http://en.wikipedia.org/wiki/Tamiflu and tfa, it seems that the new process which this article is about has been released patent free. IAAOC (I am an organic chemist) and the new synthesis is safer and less dependant on difficult-to-obtain natural precursors. These guys should be applauded for sacrificing a profitable idea for the greater good.
I am one of many. My idea is not unique, nor do I expect my voice alone to sway you. I speak in a chorus of opinion.
"There is always an easy solution to every human problem -- neat, plausible, and wrong."
H. L. Mencken
"Influenza
o The "Asiatic Flu", 1889-1890. Was first reported in May of 1889 in Bukhara, Russia. By October, it had reached Tomsk and the Caucasus. It rapidly spread west and hit North America in December 1889, South America in February-April 1890, India in February-March 1890, and Australia in March-April 1890. It was purportedly caused by the H2N8 type of flu virus and had a very high attack and mortality rate.
o The "Spanish flu", 1918-1919. First identified early March 1918 in US troops training at Camp Funstan, Kansas, by October 1918 it had spread to become a world-wide pandemic on all continents. Unusually deadly and virulent, it ended nearly as quickly as it began, vanishing completely within 18 months. In six months, 25 million were dead; some estimates put the total of those killed worldwide at over twice that number. An estimated 17 million died in India, 500,000 in the United States and 200,000 in the UK. The virus was recently reconstructed by scientists at the CDC studying remains preserved by the Alaskan permafrost. They identified it as a type of H1N1 virus.
o The "Asian Flu", 1957-58. An H2N2 caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957.
o The "Hong Kong Flu", 1968-69. An H3N2 caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today"
None of your other examples prove anything about flu. All it proves it that you never bothered to look up just how dangerous flu pandemics are.
"While they're all threats, they aren't just going to all of a sudden just break out all over the place."
Um, yes actually, that's exactly what will happen with the flu.
"When it explodes, THEN freak out about it, but until then enjoy life."
Yeah, great, why would we be developing effective treatments, exapnding our knowledge of virus pathology, and improving our procedures, when we could be drinking margaritas and listening to reggae.
Newsflash, you lay the groundwork for dealing with outbreaks before they happen. Your stupid plan results in more deaths.
Is this the same Tamiflu that, out of 14 H5N1 avian flu patients who took it, just 2 survived?
1) There probably is no statisically significant data available to determine if tamuflu can stop an epidemic.
2) To rely on only one method is insane. This is just common sense.
3) The assumption is that over time the disease may be come resistant to tamuflu and so other measures are needed (see pt. #2).
4) Tamuflu failed when improper dosages were given.
So to throw out tamuflu would be silly. It would be a good thing to have around, thought the only way to really find out is to have a major outbreak. Only then will we *really* know if it would work.
No time for FUD, I must get on with life.
putting the 'B' in LGBTQ+
Extortion.
putting the 'B' in LGBTQ+
It's nice to see someone still active and innovating after receiving a Nobel prize. The cash reward often results in the recipient living the easy life, as opposed to using it as a tool in pioneering further developments in their field.
"Yes, yes, yes. People have died to bird flu, but the amount dead is comparable to the amount of children dying from hunger in like 2 minutes. So fuck the bird flu. It's just another scam to make someone really rich."
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The threat isn't from the current form of bird flu. People only get that form if they live around chickens--swimming in chicken shit. The threat is if it mutates into a form that can be tranferred between humans. Care to inform yourself, so you don't sound so wrong? Watch this:
http://video.google.com/videoplay?docid=234341498
"...from highly explosive..."
hmmm I see... They plan to eliminate bird flu by making every sick bird explode. clever!
They have a plan
It would be nice to be sure of anything the way some people are of everything.
Corey's synthesis is pretty nifty. It just needs FDA approval and Roche has to adopt it. Given that Roche has had an azide-free route available since 2000, I'm thinking the process change is more than trivial. The Chemical and Engineering News article is much more informative, if you have access to that journal, and you like chemical structures.
Si la vida me da palo, yo la voy a soportar Si la vida me da palo, yo la voy a espabilar
A new vaccine has been developed that targets the part of a flu virus that is conserved between mutations. Admittedly it might not be as effective as a targeted vacciene for a particular strain, but it would likely provide general protection against most flu viruses. So far it's been tested in ferrets (a good human model) and protects against H5N1 avian influenza.
TWW
"Encyclopedia" is to "Wikipedia" what "Library" is to "Some people at a bus stop"
I hope that in your blog, you managed to spell "Martial Law" correctly. Marshal law is a Good Thing(tm), because it means there are police around. (: Martial law is the anarchy type, that you probably meant.
Whoever stated that signature sizes should be limited to one hundred and twenty characters can just go ahead and kiss my
In case you don't want to go look at Wikipedia, azides are high-energy nitrogen-nitrogen bonds that are unstable, hard to make, and hard to handle. There are some (common) metals that can cause azides to form spontaneously combustible (aka hypergolic) compounds, which is a problem if your processing system contains impurities of that metal in the tubing or gaskets.
In contrast, butadiene is a major industrial chemical used in making synthetic rubber, for which we have well-understood handling and manufacturing processes, and acrylates are also large-scale, moderately stable feedstocks for the plastics industry.
Nostalgia's not what it used to be.
Kida explained that people infected with H5N1 have a carbohydrate receptor on cells lining their throats. The receptor -- called alpha 2,3 -- is predominantly found in birds. Avian influenza viruses like to bind to this class of receptors to replicate and cause disease.
. . . . .
Human influenza viruses, however, prefer to bind to another receptor called alpha 2,6, which is dominant in humans.
Kida is now trying to look for H5N1 survivors in Vietnam and Thailand to verify his theory, and if it proves to be true, it could mean that most people simply cannot catch H5N1 easily -- unless the virus mutates.
We will bankrupt ourselves in the vain search for absolute security. -- Dwight D. Eisenhower
Whether the H5N1 thing is hype or not, someone discovering easier ways to synthesise anti-viral drugs is a Good Thing.
;-)
Eventually there IS going to be another flu pandemic, the way the virus mutates and our global society assure us of it, the real question is is it going to kill millions of people or just give everyone a lousy week of work.
Yea, I know this sounds sick, I know I'm rambling, but think about it...
First off, birdflu is a remote possibilty, especially on a pandemic level. It is possible still. We have the fear factor implanted. Fear always equals profit.
AIDS has the fear factor too, but not enough 'wealthy' people get AIDS anymore, so it's not as profitable as it used to be.
Ok, so Tamiflu hasn't been proven tpo have worked as a cure successfully. 2 in 14 people living doesn't sound much better than just dealing with the bird flu without Tamiflu. Tamiflu is not being distributed as a vaccine, nor has it been proven to work as a vaccine. The makers of Tamiflu held out as long as they could to keep profits up, and will rake in even more dough now that they can make it cheaper. Our government(s) support the notion of Tamiflu as our best defense at the moment.
Think any lobbyists had an influence on this?
Treating AIDS was even more profitable though, and if you have AIDS you may fare better with bird flu than the average victim. I bet the pharmaceutical companies have considered it too - for the 'shareholders' of course. BAH.
Anyway, how long before we see them come up with the idea of treating AIDS with bird flu. They'll probably figure out a way and place to test it - get some moderate success - convince the public via it's corrupt politicians it's fiarly failsafe and make it happen. Treatment immunity will be granted swiftly. BOOM. The AIDS cure (aka birdflu derivitive) will mysteriously mutate and spread, passing bird-flu worldwide in a matter of months.
The billions of dollars in Tamiflu stockpiles will be useless and the public will demand a solution, any solution.
A 'Get AIDS Quick' solution will of course be ready for mass consumption, and most likely for free. The drug pushing son-of-a...... er 'pharmaceutical companies' will be happy to give you AIDS free in order to get you hooked on the lifetime of AIDS cocktails, won't they?
It's always about PROFIT.
I have problems with these mortality figures. It's very easy to determine who died from bird flu - you have a body, death certificate, medical records, etc. It is NOT easy to work out who has had the bird flu and has survived in the general populace - not all sick people will have seen a doctor and some may not even have developed symptoms. Without doing a massive study looking for bird-flu antibodies, the mortality figures are almost certainly overblown, maybe by orders of magnitude. This applies whether we are talking about the impact on birds or on humans.
Cheers,
Toby Haynes
Anything I post is strictly my own thoughts and doesn't necessarily have anything to do with the opinions of IBM.
Anybody else notice that ABS is 'Acrylonitrile Butadiene Styrene' & this drug can be made from 'acrylate and butadiene'. I don't want recycled lego's being shoved up my arm thank you very much.
If I try on my tinfoil hat for a moment, it seems that the only winner in a Tamiflu stockpiling situation will be the manufacturer. We can be almost certain that the "next big pandemic" will blind side us. That is, after all, the nature of pandemics. It'll be a mutated form of *something*, probably something quite benign.
While all of those things are terrible and kill millions each year, and have done for a very very long time (with the exception of AIDS), NONE of them have the potential to wipe our 70 million people in the space of 6 months.
There are several companies which have been developing H5N1 (bird flu) vaccine for a while. The (unnamed) company I work for is one. We actually have a massive stockpile of the stuff, but there are a couple of problems with developing H5N1 vaccine at this stage of its pandemic (FYI, it's Pandemic Stage 4, out of 6 possible stages, with 6 being a global catastrophe).
First, the H5N1 virus we know today is not a serious threat to humans. In order to progress to Pandemic 5, it must mutate so that it is contagious human-to-human. That is the criteria for stage 5. It might no longer even be H5N1 (these represent the proteins which are present of the surface of the virus, by the way). With that mutation comes the uncertainty of whether current H5N1 vaccines will have reduced, or even zero efficacy against the new virus.
Further, there is no good way to test even current H5N1 vaccines in humans. We know they do a decent good job of protecting birds and livestock, but that doesn't mean that they are really able to protect humans. I don't see many people signing up for a clinical trial to be exposed to a virus that, if the clinical trial is unsuccessful, would kill the majority of the people in the trial (people who are otherwise healthy).
We honestly can only hope that what we have today will be both effective in humans, and also effective against the mutated virus that represents stage 5.
The problem is not producing enough vaccine, we can mass produce it now. This company having some new approach is nothing more than a press release stating that they caught up with the rest of the vaccine industry.
Slay a dragon... over lunch!
Care to share the information?
Also I think you'll find that "Tamiflu" is the name of a drug, not the name of a company.
Primarily contacted by voluntary behavior that almost everyone in the entire world has been told to avoid.
malaria,
Previously controlled by DDT, before it was removed from the market by (later disproven) fear.
hunger, lack of fresh water and overall stupidity of the general population
Assuming you meant "ignorance" instead of "stupidity", all three of those are political issues. Feel free to suggest solutions that will satisfy all affected groups.
Bird flu, on the other hand, has the potential to tear through high functioning societies. No amount of education, pesticide, food, or water can stop it. There's a reason people are afraid of the word "pandemic".
Dewey, what part of this looks like authorities should be involved?
In my college years as a Microbiologist, my teachers always ranted and raved about how bad pandemics were.
t m
I didnt fear anything until I saw the statistics of one of the pandemics..
Here is a link from the cdc - about the 1918 Avian Flu Pandemic
http://www.cdc.gov/ncidod/eid/vol12no01/05-0979.h
"The "Spanish" influenza pandemic of 1918-1919, which caused 50 million deaths worldwide.."
Hundreds of millions were infected and millions died... Bird Flu is a real threat.
http://www.odemagazine.com/article.php?aID=4267
Thank you for pointing this video out. Charlie Rose has assembled a great panel, which had a great discussion of bird flu. The full version is very much worth the 99 cents.
Sure! And remember that at one time cigarettes didn't kill you, and only gay people got AIDS.
Today, only birds can transmit bird flu. As the disease and our understanding of it evolve, there's a very strong possibility that this will change.
Dewey, what part of this looks like authorities should be involved?
As I read it, he was generous with the new production proceedure, because anyone using it already owed royalties.
As I read the article, he was generous with the new production proceedure, because anyone using it already owed royalties.
Nobody is claiming the current virus is the actual threat to humans. The actual threat comes if/when this virus mutates into a form that can be transferred between humans. Then you're talking about almost a hundred million possible deaths....
Suppose a medicated person is sick for less time and sheds fewer virus particles.
Suppose tamiflu has almost no effect, such that an infected person infects 0.99 others if treated with tamiflu and 1.01 others without it. In one case the epidemic dies out, in the other case it spreads.
Using a more realistic illustration, the difference between 1.4 and 1.6 is a difference that could buy time and spread out the load on hospitals.
...but it's also been shown to be extremely profitable.
---
And if your idea for fighting bird flu is with chicken soup, we truly are screwed.
That would just be stupid.
What do you take me for, a moron?
I'll be fighting the bird flu with bird soup thank you very much!
*mumbles something about crazy liberals*
Less Talk. More Stab.
>Sooner or later there WILL be another flu with the ability to kill millions.
Virologists estimate that these come in ~50 year cycles as the people with immunity die of old age and herd immunity disappears.
They're unsure whether H5N1 is going to be the one that breaks loose or whether it will be a later one, but we are overdue.
Tamiflu is oil! That's why we invaded Iraq!
-Darkshadow (There was a thing called Heaven; but all the same they used to drink enormous quantities of alcohol.)
http://chronicle.com/colloquy/98/suicide/backgroun d.htm
If Slashdot were chemistry it would look like this:Cadaverine
Even if Tamiflu becomes cheap and widely available, it'll probably suffer the same fate as Amantadine. It is another anti-viral medication. Thanks to the Chinese feeding it to their chickens, it's useless against bird-flu.
I'd like to know at what rate is H5N1 evolving and when it could mutate into a form transmissable by humans? I'm assuming it's a matter of time before it happens not a question of if.
"You'll get nothing, and you'll like it!"
Lasser fever could combine with Athletes foot to develop a deadly plague! How many what if's are there. Stick to the facts and leave Clairvoyancy for Weirdos. The fact is that Bird flu does not easily transfer from Human to Human. The expert Viroligists rightly have to investigate a worst case synario. I however do not.
Doesn't anyone think this is a strange conicidence that Donald Rumsfield who was Health and Human Services Secretary during the Gerald Ford Adminstration was given a medal for controling the outbreak of the Swine Flu in 1976 in Burlington County, NJ?
Does anyone think that it is a strange conicidences that Donald Rumsfield is now the Defense Secretary during the GW Bush Adminstration and is going to make a winfall profit from the sale of Tamiflu now that Avian Flu has appeared in neighborhing Camden County, NJ?
Avian Flu is American Bioterrorism manufactured by the government of United States of America so that a few rich WASPs can get away with murder and make a profit from it.
I am level headed by the way. This is not some paranoia rant from some loony wearing a tin-foil hat, it is the honest to God awful truth. Search reliable internet sources!
The Rapture is NOT an exit strategy.
Corey pretty much is a self aggrandizing douchebag. Has had a couple suicides in his lab, doesn't feel bad about it. Claims to get 99% yields in some of his chemical reactions, after purification (next to impossible). Has done some brilliant things despite that though. Note to some readers...acrylate and butadiene reacted together to form a new chemical compound are not going to have the same properties as the starting materials. Most of our drugs/plastics use petroluem feed stock at some point in their production. It'll be lot's of fun when we run out of oil!
This is a very good and well thought out response. Fairly convincing as well (sources would have been nice, but are not necessary since the facts you cited have been pointed out in other posts and I've heard them before). However, I still don't think it will be as large of a disaster as the media predicts. Even if 100 million people die (world wide), that's still a small fraction of the world population of over 6 Billion. Is it tragic? Yes. Will it be a huge catastrophe to the country/world/human population? I don't think so. Should we prepare for it? Of course! I don't think researchers and such should ignore the situation. I just don't think the general populous needs to freak out about it (at least not yet). Will I blame the government if they aren't prepared for this? No. I didn't blame them for not being prepared for Hurricane Katrina, so why would I blame them for this? They're response was a bit half-assed, but there's only so much they could have done (doesn't matter if it would have been a Democrat or Liberterian or whoever else in the White House--there are limitations to what our bloated government can do). Disasters happen and they're unpredicatble (to a degree), so why point the finger of blame? Blame is just an excuse to get out of doing things to fix things yourself.
Read my blog posts on usability.
Did anyone else read that and have the reaction, "Maybe we shouldn't be burning our limited supply of ingredients for life-saving medicines?"
If it's for-profit but free, you're not the customer -- you're the product (e.g., the Slashdot Beta's "audience").
can die of cancer.
SLASHDOT: news for people who can't concentrate on work or have no life at all and got tired of yelling back at the TV.
Stop paying attention to hysterical news reports about bird-flu.
You seriously have no understanding of the situation. I suggest you actually watch the video I linked to. Go ahead, spend the 99 cents. It'll stop you sounding like an idiot.
"Despite this astonishingly low number Charlie Rose, news media in general and you carry on about the inescapable bird flu pandemic that is 'certain to kill us all'. Lions and tigers and bears, oh my!"
The threat is not from the current form of bird flu. The threat is if/when bird flu mutates into a form that can be transmitted between humans. Then we're looking at devastation, unless we prepare ourselves. The 50-100 people who got it now don't have a human-to-human strain, so it doesn't matter. They are just unfortunate to have to come into contact with a lot of birds, for whatever reason. But, feel free to keep quoting this low number as if it has anything to do with the actual threat.
"Bird Flu Drug Mass Production Technique Discovered"
Er, no, it was invented. Unless you think that all knowledge is lurking out in in the magicsphere just waiting for someone to stumble over it. In which case, can we eliminate the patent office, please?
You guys must think the flu is SUPERMAN. Hell, I'm Superman. My doctors gave me all that stuff and I haven't been sick from a cold or flu for 16 YEARS. I did get a nasty bronchitis 3 months ago but come to find out they were also overdosing me on thyroid medicine.
THAT I DO NOT RECOMMEND. It makes your allergies stronger well, no that isn't quite right. It makes your Immune System reaction to allergic substances much stronger. Closes your nostrils, your bronchial tubes somewhat. Anyway, Clinoril or 5-10 aspirin take your pick. The acid content burns up the flu. Vitamin C does a similar acid bath on bloodstream viruses.
Anyhow it beats heck out of doing nothing waiting for the undertaker.
Back in 1981, shortly after reagan got into office, the CDC approach him requesting 25-50 million to start plans to stop the spread of a funny disease. It was not known what it was, but it was known that it was tied to gay bath houses. Reagan denied the funds even though top people were going in literally begging for them. Back then, less than a 1000 people had it. It could not have been stopped, but we could have been cut WAY back (perhaps would have stopped 80-90% of thise infected). Had we got aggresive in the early stages, the USA might have had only 1/2 to as much as 1/10 of the infections/loses that we now have. In addition, the USA pays out billions each year on the medicince for those infected as well as for research. Had we been willing to spend just 25 million on it, we would be saving billions each year.
You speak of spending money wisely, and here is a disease process that once it gets lose can either cause wide spread panic or we can be read for. Keep in mind that the 1919 flu which killed millions, was the bird flu.
Simple preperations can lower our costs and save loads of lives.
I prefer the "u" in honour as it seems to be missing these days.
The major physician of Russia, the one who forbidden the import of Georgian wines because of "too much" pesticides it contains, said that Tamiflu does not really cure the birds flu. At least no better than anything else. He also argued that medical corporations goes too far in advertising "cures" to serious diseases like birds flu or AIDS, just to earn more money.
Taking into account that Tamiflu costs about 1000% more than thing like Paracetamolum (which doesn't cure anything either, but advertised as "a cure for flu") I can believe him.