Post Your Cases > Rescue from bilirubin and kernicterus?
Doug,
What a great idea. I immediately did a literature search and was pleased to find a considerabe amount of published material on the chemistry of bilirubin itself (completely separate from the biochemistry of its synthesis, degradation and excretion). Looks to me from the structure and pD that it might partition into a lipid emulsion (pD is high, so it should; but the two carboxylates might make it too negative; the surface of the lipid particles is very negative and this accounts, I believe for the attraction of cationic amphiphiles like bupivacaine). Tho there are some data that suggest it doesn't dissolve in triglycerides, I think on balance it is certainly worth an in vitro (read..in the beaker) test. Hold on the IRB and animals 'til after we show it partitions into lipid. Let's go for it!
I remember in college there was a brilliant physics student who suffered from severe kericterus or the ravages thereof. She had such severe athetosis it difficult for her to speak and almost impossible to walk. I had enormous respect for her ability to rise above it all.
So, let's test your theory!
Guy
What a great idea. I immediately did a literature search and was pleased to find a considerabe amount of published material on the chemistry of bilirubin itself (completely separate from the biochemistry of its synthesis, degradation and excretion). Looks to me from the structure and pD that it might partition into a lipid emulsion (pD is high, so it should; but the two carboxylates might make it too negative; the surface of the lipid particles is very negative and this accounts, I believe for the attraction of cationic amphiphiles like bupivacaine). Tho there are some data that suggest it doesn't dissolve in triglycerides, I think on balance it is certainly worth an in vitro (read..in the beaker) test. Hold on the IRB and animals 'til after we show it partitions into lipid. Let's go for it!
I remember in college there was a brilliant physics student who suffered from severe kericterus or the ravages thereof. She had such severe athetosis it difficult for her to speak and almost impossible to walk. I had enormous respect for her ability to rise above it all.
So, let's test your theory!
Guy
April 28, 2008 |
[Guy Weinberg]
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Kernicterus, like local anesthetic toxicity, is rare but devastating.
The in vitro test was done years ago, Pediatrics 3/85, 75:443-455. Apparently, the carboxyl groups are mostly kept inside the folded molecule. I don't think there is anything on the outside of the molecule to attract it to negatively charged lipid particles, though.
10% Intralipid has a half-life of about 15 minutes in term babies after a 1 ml/kg bolus, Journal of Pediatrics 7/77, 91:134-137. Would the lipid particles last long enough?
Ideally, the lipid would acutely decrease brain bilirubin to help protect the brain, and then allow more bilirubin to be removed with the subsequent exchange transfusion.
I have written to a researcher who recently published an article testing minocycline as a neuroprotective agent in an animal model of kernicterus, a model that might work for this idea. No word back from him yet.
The in vitro test was done years ago, Pediatrics 3/85, 75:443-455. Apparently, the carboxyl groups are mostly kept inside the folded molecule. I don't think there is anything on the outside of the molecule to attract it to negatively charged lipid particles, though.
10% Intralipid has a half-life of about 15 minutes in term babies after a 1 ml/kg bolus, Journal of Pediatrics 7/77, 91:134-137. Would the lipid particles last long enough?
Ideally, the lipid would acutely decrease brain bilirubin to help protect the brain, and then allow more bilirubin to be removed with the subsequent exchange transfusion.
I have written to a researcher who recently published an article testing minocycline as a neuroprotective agent in an animal model of kernicterus, a model that might work for this idea. No word back from him yet.
April 29, 2008 |
Doug Derleth
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You've put your finger on the question: "what is the best animal model to test your theory?". Note, that my theory of electrostatic attraction is just that. I'm putting together a proposal to analyze LA-lipid interaction by nmr. Meantime, that's just a guess and based on my initial reading of the bilirubin literature, I think your theory is sufficiently plausible to warrant further work.
The PK issue is obviously important as it affects how/when you would do the exchange transfusion and also the question of disposition of the bilirubin that isn't lost to exchange. I can think of a few other options, too, Doug. Why don't you email me when you have time:
guyw@uic.edu
The PK issue is obviously important as it affects how/when you would do the exchange transfusion and also the question of disposition of the bilirubin that isn't lost to exchange. I can think of a few other options, too, Doug. Why don't you email me when you have time:
guyw@uic.edu
April 29, 2008 |
[Guy Weinberg]
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Bilirubin is very lipid soluble. What if a bolus of lipid emulsion were given shortly before an exchange transfusion to prevent kernicterus in a severely jaundiced newborn? Would more bilirubin come out with the removed blood? Would more bilirubin come out of the brain? Would this affect clinical outcomes? There would be some concern about increased free fatty acids affecting albumin binding of bilirubin. (Give more albumin, too?) This potential treatment might be tested in an animal model. I'm going to see if I can get any kernicterus experts interested in this possible treatment. Any thoughts on this?