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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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October 8, 2012

Nasty Drug Molecules: Amphotericin B

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Posted by Derek

You've probably seen the headlines about fungal meningitis showing up, caused (it appears) by contaminated injectable steroid supplies. As soon as I heard these stories, I wondered what you treat this condition with, and my first thought was "Amphotericin B, most likely". And so it appears.
amphotericin%20jpeg.jpg
That compound still seems to be the usual answer for the nastiest fungal infections, a role it's occupied for decades. That's not by choice. It's an awful compound in many ways, as illustrated by that Wikipedia article linked above:

Amphotericin B is well known for its severe and potentially lethal side-effects. Very often, a serious acute reaction after the infusion (1 to 3 hours later) is noted, consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. This reaction sometimes subsides with later applications of the drug, and may in part be due to histamine liberation. An increase in prostaglandin synthesis may also play a role. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the induced effect of the drug.

Organ damage is also distressingly common, and patients who are dying of a systemic fungal infection can suddenly find themselves dying instead of kidney or liver failure. As you'd imagine from that structure, it has to be given intravenously, unless you're treating an oral infection. (Note that it's quite similar to the common topic medicine nystatin). The drug works, as far as anyone can tell, by opening pores in cell membranes, particularly associating with sterols. It seems to have a greater affinity for ergosterol (found in fungi) over cholesterol, which gives it whatever therapeutic window it has.

People have tried for years to replace Amphotericin B, but it remains with us. If you're taking it, you are probably in a bad way.

Comments (22) + TrackBacks (0) | Category: Infectious Diseases


COMMENTS

1. darwin on October 8, 2012 8:07 AM writes...

With this being an old school Rx, I wonder what the history was behind its selection and development. Not a chemist, but I wouldnt predict Pharma throughputs hosting a lot of structures like this in their libraries.

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2. Lindsay on October 8, 2012 8:34 AM writes...

The linked wikipedia article explains that it was isolated from Streptomyces.

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3. lynn on October 8, 2012 8:35 AM writes...

It's a potent natural product with a broad spectrum of action. It was, basically, the first systemic antifungal agent. Discovered in 1955, it was in many by 1957 and introduced in the clinic in 1960. In the old days of antibiotic discovery, compounds went from discovery to the clinic in incredibly short time(due to little regulatory oversight). These didn't come from Pharma libraries but from freshly prepared actinomycete fermentations that Pharma screened for antifungal activity - and, indeed, polyenes are found ubiquitously.

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4. lynn on October 8, 2012 8:45 AM writes...

...that's "it was in man by 1957"

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5. Luysii on October 8, 2012 9:22 AM writes...

The chemical subtlety of natural products is beyond belief. According to PNAS vol. 109 pp. 2234 - 2238 '12, Amphotericin B works by binding to the ergosterol of the fungal membrane (other antibiotics -- fluconazole and the azole drugs ) work by inhibiting ergosterol synthesis.

Now look at the structures of ergosterol and cholesterol and imagine how you would come up with a compound to bind to one and not the other. I doubt that it would look anything like Amphotericin B.

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6. Dave on October 8, 2012 9:25 AM writes...

I'd just point out that the structure from Wikipedia is a little deceptive as the stereobond at the anomeric carbon of the mannose is very ambiguous (due to the way that the wedge is used). The structure should have a beta-D-mannopyranose (see http://www.chemspider.com/Chemical-Structure.10237579, for a clearer depiction).

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7. Dave on October 8, 2012 9:45 AM writes...

The image on Wikipedia has now been revised

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8. Curious Wavefunction on October 8, 2012 9:56 AM writes...

#5 luysii: One word - 3D.

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9. anon the II on October 8, 2012 11:00 AM writes...

These days chemists tend to use wikipedia a lot for structural information. It would be real nice if somebody, who really has a good handle on how to use solid, hashed and wedged lines to convey stereochemistry, would go in and fix the structures. You could start at "Polyene antimycotic" wiki page since it's structure for Amphotericin B is different from the Amphotericin B wiki page. Maybe it will all be OK by the time this message posts.

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10. Anonymous on October 8, 2012 11:26 AM writes...

"Organ damage is also distressingly common, and patients who are dying of a systemic fungal infection can suddenly find themselves dying instead of kidney or liver failure."

Yes. In the clinical setting, it has earned the nickname 'amphoterrible.'

Newer lipid formulations have helped a bit.

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11. Dave on October 8, 2012 12:52 PM writes...

@anon the II, Sadly, the image on http://en.wikipedia.org/wiki/Polyene_antimycotic, would also seem to be incorrect (it is close) but still differs at the anomeric postion - the alpha anomer is shown rather than the beta anomer.
I will see if I can update this image too.

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12. anon the II on October 8, 2012 1:36 PM writes...

@ Dave

It looks like you've fixed the Amphotericin B's. Want to have a go at the Nystatin's also? I checked PubChem just to be sure and unfortunately, you get both.

By the way, how do you get an .svg from Chemdraw? Nevermind, I see it's an option on the PC but not on the mac. I hate it when that happens.

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13. anon the II on October 8, 2012 2:44 PM writes...

While I should have been working, I figured out how to edit wikipedia and managed to fix the structure of Nystatin so that it, at least, matches the one in PubChem CID 11286230.

I feel powerful now.

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14. Anonymous on October 8, 2012 3:29 PM writes...

I usually use ChemID, I think the structures are a lot more reliable. The web address is:

http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp

It is also pretty good with garbeled code numbers.

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15. gippgig on October 8, 2012 3:57 PM writes...

Note that the amphotericin B structure shown above has the wrong enantiomer of the sugar (mycosamine). (I've been battling with incorrect structures since I got interested in antibiotic chemistry way back when I was a kid. Always check the original reference rather than relying on a database; databases (not just chemical) are invariably riddled with errors. For the structure of amphotericin B from x-ray crystallography see JACS 93 4560. Incidentally, the Wikipedia entry for amphotericin B states that amphotericin A differs by having a double bond between the 27th & 28th carbons; it actually differs by having a single bond between C-28 & C-29 (like nystatin; Journal of Antibiotics 38 175).
By the way, what is the fungus that is causing the meningitis outbreak? I haven't seen it identified in any of the reports.

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16. microbiologist on October 8, 2012 4:26 PM writes...

In answer to 15: The fungus is Aspergillus, according to stories in the Boston Globe.

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17. bradpalm1 on October 8, 2012 5:17 PM writes...

Even worse news is that ampho B typically has a hard time crossing the blood-brain-barrier and afflicted patients may need intrathecal therapy as well. I suspect these patients are being treated empirically with IV ampho B and voriconazole or IV ampho B and flucytosine due to these other molecules relative improved ability to cross an inflamed blood-brain barrier.

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18. Coffee Lover on October 8, 2012 6:11 PM writes...

Talking to the family ID doc, Voriconazole is now the preferred treatment.

Apparently the symptoms from Amphotericin led docs to call it "shake and bake" (rigors and fever) or amphoterrible.

Permalink to Comment

19. bradpalm1 on October 8, 2012 8:44 PM writes...

Likely IV voriconazole to start if Aspergillus meningitis is suspected with ampho B added on if clinical deterioration becomes evident. As far as ampho B associated rigors are concerned, it's always tough to tell whether they're due to infusion of the drug or transient bacteremia/fungemia in the patient. Interestingly, we still use IV meperidine (Demerol) to suppress these uncomfortable rigors despite the added risk of drug neurotoxicity as well. Quite a complicated mess.

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20. Vader on October 9, 2012 12:52 PM writes...

What are the odds that a drug like Amphotericin B could make it though FDA approval nowadays? Is the process less rigorous when There. Is. No. Better. Therapeutic. Option?

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21. exGlaxoid on October 16, 2012 2:59 PM writes...

Dr. Sid Hecht at UVA (and SKB) made 100's of Amphotericin B analogs trying to find better ones and I don't know if anything ever came out of it. They are dreadful to work with, make, take, or even think about from all I have seen. It would make more sense to me to start fresh from a screening hit than to make more of them, unless someone really understood their mode of action. But the FDA might not approve a new drug unless it was nearly perfect, a standard not applied to older drugs. But few companies want to invest in anti-fungal research now, given the lack of return on the investment. Maybe this will spur some new research, but doubtful.

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22. Don Swartz on March 21, 2013 5:59 PM writes...

As someone who has been on Amph B at times for over a year, I would like to point out that the lipid and lyposomal versions have none of the side effects of the original. The onset of rigor, in my case was a direct result of AB, and treated with Tylenol, a high dose of Benadryl, and lots of heat. These precautions need to be applied right when the infusion starts since the AB takes about an hour or so to kick in. But since they came out with lyposomal AB, those precautions are not as necessary. My first encounter with AB was on my 40th birthday, after valve replacement. The nurse administered AB without any treatment. An hour later I had passed out from shaking and breathing so hard. I was later told that it took four people to keep me in the bed with the rails up. I was lucky I didn't burst a seam. This is not a fun drug and should not be taken lightly

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