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With states short of Tamiflu, it's time to talk Probenecid again in swine H1N1 flu fight

The news stories are starting to come out of Washington, DC; Baltimore; and soon Sarasota (and that is rare to have that small retirement city mentioned in the same breath with two of the Big Cities on the East Coast!) that states just don't have enough Tamiflu to go around.

And here in sunny Florida, where we did not avail ourselves of the now-expired Federal coupon offer to buy Tamiflu at cheaper prices, people are openly questioning whether the state should, indeed, buy more.

I have a better idea. First, let me set some background.

I do not know if Roche can take enough plants offline, recommission them and start making Tamiflu again in any quantity. recall that Roche made a huge capital investment in more Tamiflu plants in 2005 and 2006, only to see global demand for Tamiflu abate as the concern evaporated regarding a bird flu pandemic. Roche then recommissioned the lion's share of these facilities to make other drugs instead.

Roche also made a huge breakthrough around that time, namely being able to synthesize the key ingredient of the antiviral drug: Something only found in Chinese star anise. Shikimic Acid. According to Wikipedia, Star Anise, under the influence of shimikic acid, fought Iron Man and Wolverine before being brought down by Captain America, who is now his old sidekick Bucky, the Winter Soldier.

No, that's not right. Damn that Wikipedia!  Anyway,Janapese star anise is right out; only Chinese star anise will work. So Chinese farmers began doing what American farmers have been doing with corn; plowing under all other crops to make the big cash (cow) crop. Chinese farmers were making the kind of money American farmers were making! BIG money from star anise, because it also took a long time to reap the fruit.

But then Roche spoiled the party by synthesizing shikimic acid, and now it can be mass-produced more cheaply. Roche will have to recommission those gleaming Tamiflu plants and also begin re-licensing other drug makers to make Tamiflu under license.

Or will they? Roche has been burned by the world's governments once already. I doubt if Roche will be as willing a corporate partner (meaning ready to heavily discount Tamiflu) as they were in 2006 and 2007. And maybe they shouldn't.

The other X-Factor (so you see a pattern here? Wolverine? X-Factor?) is the dreaded Tamiflu Resistance Gene, or the combination of mutations to neuraminidase of gene segments R292K, N294S, and H274Y. Widespread circulations of this set of anti-Tamiflu genes have rendered Tamiflu virtually useless against the non-swine H1N1 that is our seasonal bug.

In fact, a Scientific American article of March, 2009 coincidentally reminded readers of the presence of this gene set. Here's the most striking passage:

A whopping 98 percent of this year's circulating H1N1 flu strains are immune to Tamiflu, compared with only 12 percent during the 2007-2008 flu season. (bold mine)

"We don’t know what's physically happened to the virus to cause it to transmit more rapidly, but something has and even more so this year," says study author Nila Dharan, a fellow in the Centers for Disease Control and Prevention's (CDC)
Epidemic Intelligence Service, which studies major disease outbreaks. Dharan tells ScientificAmerican.com that a spontaneous (natural) genetic mutation – and not overuse of Tamiflu — is to blame. She notes that additional structural changes to the virus (that scientists don’t completely understand) have enhanced the resistant strain's ability to grow and infect people.

The trend is alarming enough that Department of Health and Human Services (HHS) officials have been huddling for the past week to consider whether to adjust the composition of the federal
pandemic flu drug stockpile, of which 40 million treatment courses (80 percent) is Tamiflu, says Robin Robinson, director of the Biomedical Advance Research and Development Authority(BARDA), an HHS arm that manages the stockpile.

I guaran-damn-tee you that in the back/front of every single influenza researcher's mind on this planet is the knowledge that these mutations could, at any time, by reassortment or recombination, get into the present swine H1N1. Mutations have already been seen in H5N1 avian flu, but not in large numbers.

But the movement from 12% to 98% in seasonal H1N1 is striking. And where those mutations first appeared is absolutely head-scratching. Rather than link you to all the blogs I have made on Tamiflu resistance, just search this Blogsite for the words "Tamiflu resistance." You'll read everything from the presence of Tamiflu in the water supply of Sweden to the lack of resistance in the most-prescribed Tamiflu nation on earth -- Japan.

OK, now let's assume you are a policymaker. Here are the facts:

  • You are broke, out of money, laying off workers, cutting services.
  • You have a pandemic-in-the-brewing called swine H1N1. Or H1H1 influenza A. Or "fluffy bunny slippers," according to this insane "let's not-p-off-the-pork-people" White House PC-silliness. Hey, let's just call this "PC FLU?"

But I digress.

  • You also know you don't have enough Tamiflu to really get the job done.
  • And there is this as-widespread-as-Jonas-Brothers-fever anti-Tamiflu gene that is found in 98% of all seasonal H1N1 flu this past season.
  • Did I mention your state is broke?

I have a solution. Back in World War II, largely in the pacific, Corpsmen and medics were stretched to the limit on penicillin. They did not have enough to treat everyone with an infection.

Miraculously, they did have this relatively new anti-gout medicine called Probenecid. They knew one of the side effects of Probenecid was that people didn't pee as much as normal. So someone in some battlefield MASH unit said "What the Hell, let's see if it works," and co-administered Probenecid with penicillin.

And danged if it didn't work! The co-administration of Probenecid with penicillin stretched the effective supply of penicillin by a factor of 2.

A few years ago, people with long memories and concern over Tamiflu stocks began speculating about the effectiveness of Tamiflu and Probenecid. I have written about this many time before, but the definitive blog on the subject in my inventory is this shoulda-won-a-Pulitzer story:

Killing two birds with one stone

A portion of Roche's study of the use of probenecid in 2002 comes from the blogsite Smart Economy, and the story can be found at: http://smarteconomy.typepad.com/smart_economy/2005/11/smart_wartime_t.html.

Dr. Michael Greger, a person whom I communicate with occasionally, wrote in his seminal work Bird Flu: A Virus of our own Hatching:

Roche found that probenicid doubled the time that Tamiflu spent circulating in the human bloodstream, effectively halving the dose necessary to treat someone with the flu. Since probenicid is relatively safe, cheap, and plentiful, joint administration could double the number of people treated by current global Tamiflu stores. “This is wonderful,” exclaimed David Fedson, former medical director of French vaccine giant Aventis Pasteur. “It is extremely important for global public health because it implies that the stockpiles now being ordered by more than 40 countries could be extended, perhaps in dramatic fashion.”2495

So let's review:

  • Probenecid is safe.
  • It keeps the medicine in the body longer.
  • It will effectively double our supply of Tamiflu overnight.
  • It will free up Relenza for use exclusively by police, fire, EMT, emergency room staff, and otehr first responders.
  • It will reduce the incidence of painful gout in Tamiflu takers.
  • It will reduce the amount of Tamiflu that makes its way into the groundwater, thereby making it the "green" solution.

In short, the co-administration of Tamiflu with Probenecid is a solution that bears very close, careful scrutiny. 

Always glad to help.

Reader Comments (7)

Scott, despite the chemical-sounding name, shikimic acid is a very common plant compound. It's in...well, most of the plant kingdom I'd bet. It's a starting compound to making all kinds of plant compounds. The star anise story could be substituted by dozens of other plant drug stories (i.e., yew bark and taxol) where they used the raw plant because they hadn't figured out how to synthesize it. What usually happens is the farmer or collector of wild plant material invests and produces lots of material and then the buyer comes back and says, Oh sorry, we don't need any more, and the producer gets left holding a big bill and lots of material no one wants anymore.

May 1, 2009 | Unregistered Commenterphytosleuth

Oh geez. Just read up on Probenecid. Oh dare I say it? I am so bad. Okay, I wonder if grapefruit juice would have the same effect. Oh now I've started an urban legend. Stop me.

May 1, 2009 | Unregistered Commenterphytosleuth

It reduces gout, too? I'm convinced.

Way to go, Scott!

May 1, 2009 | Unregistered CommenterDean B

Cheers, Scott! A fascinating and thought provoking read... Yeah, we ARE all worried about "Oseltamivir Resistance" entering into 2009 A(H1N1) and H5N1 in a manner similar to seasonal H1N1.

Wonder why Roche haven't mentioned their probenicid + Tamiflu co-administration studies in any recent press releases!?! It would make sense to educate us on the efficiency measures we could take in the event of...

May 3, 2009 | Unregistered CommenterJonathon Singleton

H5N1 Originates in Alaska:


May 4, 2009 | Unregistered CommenterRobert S. Finnegan

Thank you for this informative and easy to read report. I live in Jakarta and we have been holding our breath. I was going to buy (attempt to) a large stock of Tamiflu to give to the poor. This has saved me a lot of money and most likely save lives should it reach pandemic level. Jakarta is a city of on average nine million people, all crammed together. A pandemic here would most likely kill half the population.

I know virtually nothing about these viruses except their designation and origins and this article has increased my viral knowledge greatly. Thanks again.

Robert S. Finnegan
Tebet, Jakarta

May 4, 2009 | Unregistered CommenterRobert S. Finnegan

This great stuff(!) when you consider that the government is allowing the ADJUVANTS THIMEROSAL and SQUALENE to be used in the h1n1 vaccines! For those of you who don't know about adjuvants or about thimerosal and squalene they have been directly linked to autism,add,adhd,aspergers syndrome,downs syndrome, birth defects,gulf war syndrome and more recently guillian-barre syndrome. Thimerosal was federally banned in 1998 and squalene was banned in October of 2004. OUR government recently passed legislation to protect them and the drug manufacturers from any liability concerning the h1n1 vaccines...including death. The government says the vaccines are safe...then why did they pass this legislation? AUTISM in OUR children has gone from 1 in 10,000 children in 1980 to 1 in 150 today.A child will receive 48 doses of 14 vaccines by the age of 6, and they will have over 35 by the time they finish the 12th. grade. These adjuvants are accumulative and some of their components never leave the body....causing toxicity and hypoxia. The same government that is allowing these adjuvants to be used is the same one that is trying to get a national health care plan. Just think... our boys on the beltway will be deciding which banned or experimental drug our American people will be taking next, while big pharm will oblige them for a few billion more of our tax payers dollars...this currant round is costing the tax payers over 7 billion for a hyped influenza that has only killed 556 people in the U.S. so far this year, while the seasonal influenza has killed over 13,000! The winter statistics will follow that of Argentina, New Zealand and Australia....no change...just hype!My statistics come from the C.D.C., W.H.O. and the National Institutes of Health. Thank you for considering my observations...PHILesq

September 2, 2009 | Unregistered CommenterPHILesq

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