Org Prep Daily

October 11, 2007

When the red water comes out

Filed under: industry life — milkshake @ 2:36 am

leeches.jpg

A friend had an unforgettable experience from hiking in Madagascar: a horror called terrestrial leeches. These slug-like creeps wait patiently in trees, bushes and tall plants. They can feel you coming from some distance and they converge and drop onto you from foliage, then bite through the shirt (pants, socks) and sneak in, migrating over your skin towards the juicier body regions where they attach themselves. This is painless - in fact you are not likely to notice the leeches munching on you under the shirt as the leeches exude a potent anesthetic in their saliva. They also inject a thrombin inhibitor that suppresses the blood clotting in the wound - which unfortunately causes you to bleed profusely (though painlesly) from the bite long after the leech has got her fill + dropped off to the ground, happy and slumberous; (this is a leech version of the Thanksgiving dinner - they can live of one good fill for many months). My friend said he knew nothing about these tree leeches until he returned from the hike and found himself covered with his own blood and with some dozen of leechey hitchhikers, attached to various parts…

The leech thrombin inhibitor hirudin is medicinally useful as an anticoagulant. There has been enormous amount of medicinal chemistry and biology done on the blood coagulation cascade. At the previous company we were working on factor VIIa inhibitors (that were supposed to be safer than the anti-thrombin or anti-Xa agents), for treatment of deep vein thrombosis. The thrombosis project got shelved eventually  - one reason was the difficulty with developing good orally-active compounds – but we made some pretty potent i.v. compounds. I have inadvertently found out how potent these compounds actually were: One night working in the lab, I noticed my jeans felt little heavy and sticky so I looked down and saw that the front of one trouser was completely soaked with blood, from the knee down to the sock and I could not find out where all this blood was oozing from! Eventually I noticed a tiny splinter of glass, barely 2 mm across, embedded in the knee and I realized that few hours before I was purifying some final compounds on prep-HPLC and I dropped an empty test tube (after active fraction) and I kneeled down to the floor in order to pick up the splinters - a tiny piece must have stuck to my knee then.   

Here is an example of the VIIa chemical monstrosity we were making  - a true embodiment of the god-awful drug design. But they sure had some long-lasting potency: 

bleeding.gif

________________________________________________________

In US, the TV is now inundated with ads for Plavix. This inhibitor of platelet- aggregation is slightly more effective than aspirin in preventing heart attack (31% vs 23% risk reduction) and therefore widely prescribed as prophylactic over long periods of time. Plavix has more serious complications than aspirin – it causes prolonged bleeding. That makes the ER doctors quite unhappy as there is no available antidote for reversing the effect (like you get with the coumarine-based anticoagulants) and every mid-age weekend biker now seems to be on the drug whether they need it or not. With intracranial bleeding from head trauma, Plavix can provide a heroic and futile excersize for the entire surgery team.

Thanks to Abel Pharmboy for pointing out the story.

6 Comments »

  1. Dad told me that, in the night, especially after rain, if you’re jungle trekking, you can actually hear the little bugger crawling on the leaves, trying to follow you. Terifying…

    Comment by Taitauwai — October 11, 2007 @ 7:11 am

  2. Looks like you could replace bow hunting with a sewing pin and a soda straw – with the trail automatically marked. Interesting possiblities for weaponization as flechette bombs.

    Comment by Uncle Al — October 12, 2007 @ 8:38 pm

  3. there was one point when they replaced the amidine with a 2-aminoisoquinoline to improve absorbtion. did you work on this?

    Comment by Wavefunction — October 14, 2007 @ 9:15 am

  4. Actualy it did: Even pyridinopyrroles and pyridino-pyrimidines without the amino worked – although the binding mode changed slightly. But we got a terrible CYPs problem with those – and we never got to highly potent oral compounds. Part of the problem was also that the management kept changing their mind about what they wanted from us. Another problem was that the compounds were pretty labor-intensive so the progress was relatively slow.

    Comment by milkshake — October 15, 2007 @ 2:20 am

  5. Hearing about the potential horrors of meds like Plavix makes me thankful for the restrictions on drug ads that we enjoy in Canada.

    Comment by Chris — October 17, 2007 @ 12:19 am

  6. Very interesting. I like the discussion and struc-pic of the anticoagulant, but what about the “potent anesthetic” also in the leech saliva? It would be interesting to see more about that, tx.

    Comment by Neil B. — October 18, 2007 @ 10:12 am


RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

The Shocking Blue Green Theme Blog at WordPress.com.

Follow

Get every new post delivered to your Inbox.

Join 136 other followers

%d bloggers like this: