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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« The Research Exemption Lives! | Main | How Safe Is This Stuff? »

June 14, 2005

Fungal Problems

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Posted by Derek

You want a tough therapeutic area to work in? Try antifungals. There are plenty of problems that conspire to make it a real headache.

For one, fungal infections have a way of binning themselves into two categories, marked "pretty trivial" and "pretty life-threatening." Athlete's foot is a good example of the first one, and coccidioidomycosis is a good example of the second. Actually, that disease shows another form of the trivial/deadly dichotomy. Many people with coccidioidomycosis never realize that they had it, or that they had anything at all. It shows up as a mild cough or cold, and then disappears. But in some people, most especially HIV sufferers or other immune-comprimised patients, it's extremely bad news indeed.

So there are large markets where people aren't willing to pay much to be treated, and a number of much smaller, very desperate markets scattered all over the place. That's a tough situation, and the best thing would be to find a real blunderbuss antifungal that would pitch in for all of them.

And there actually is one, but it's a pretty nasty drug. For the worst systemic fungal infections, though, amphotericin B is basically all there is. It's given intravenously, and you have to keep a close watch on the side effects, which run to things like high fever, vomiting, and kidney damage. A less vicious, orally available drug that works as effectively would be a real advance.

It's not like people haven't tried. Fluconazole and Itraconazole are worthy attempts, but they suffer from their own side effect problems. Check out the general information here, and note, for example, the number of drug interactions. The "conazoles" are notorious for interacting with some key drug-metabolizing enzymes, particularly CYP 3A4, and thus sending the blood levels of other medicines all over the place.

And to top it all off, there aren't that many good drug targets in this area, or at least, not any more. There are companies that have bailed out of the whole field for lack of anything reasonable to do. There's some hope that the sequencing of fungal genomes might lead to some new targets, but that hasn't worked out too well with other organisms, and I include humans in that list. We can always hope.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases


COMMENTS

1. Bill Tozier on June 14, 2005 10:49 PM writes...

[there's an unclosed link in there....]

Permalink to Comment

2. Derek Lowe on June 14, 2005 11:11 PM writes...

Fixed - thanks!

Permalink to Comment

3. Sam Jaffe on June 15, 2005 10:20 AM writes...

I know of one very promising antifungal agent: garlic. Don't laugh. There's a guy at the Weizman Institute in Israel who is developing the active components of garlic as a pro-drug (a molecule that can be activated inside the body when needed and which sits dormant the rest of the time [is that the right definition of pro-drug?])He's trying to link it with monoclonal antibodies for chemotherapeutics, but it's greatest promise, he says, is as an antifungal. Garlic's tang (which is due to the molecule Allicin)is exactly that: an anti-fungal. Insects or mice nibble at the garlic and are repelled by the tang, so they don't eat it. But a big gaping wound in the bulb is left by the nibble. The allicin kills any opportunistic fungal attacks.

Permalink to Comment

4. Daniel Newby on June 15, 2005 2:20 PM writes...

In my view, the reason is that fungi and humans are so similar: big, complicated cells with a fairly recent common ancestor. (Don't fungi glue sugars onto their proteins in the same pattern as human cells?) The best drug targets are also present in human cells, so specificity is hard to achieve and side effects are likely. Protozoa, like the organism that causes malaria, have the same problem for the same reasons.

Permalink to Comment

5. Rob Norton on June 16, 2005 9:47 AM writes...

Fungal infections are very difficult to treat, but there are more therapeutic options than you have described and quite a few new compounds under development. Voriconazole is an expanded spectrum triazole that has shown good activity against Candida spp, Aspergillus spp, and some other rare pathogens. One study showed this compound to be superior to amphotericin B in patients with invasive aspergillosis. This compound is available in IV and oral formulations. Caspofungin, micafungin and anidulafungin are "candins" or glucan synthesis inhibitors. These have excellent activity against Candida spp and Aspergillus spp. There are also a few agents under development, including posaconazole and ravuconazole. Also, while fluconazole does have quite a few drug interactions, it is very well tolerated and has an excellent safety profile (good enough to be used as a common treatment for vaginal yeast infections). Fluconazole is also a very effective treatment for coccidioidomycosis. www.doctorfungus.org is a good source for more info on fungal infections

Permalink to Comment

6. Carter Gould on June 16, 2005 3:47 PM writes...

Nice timing...Two days later Pfizer goes and buys Vicuron for $1.9 billion to shore up their antifungal drug portfolio..

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