Optical Isomerism and thalidomide

 

       Thalidomide was a new drug in Europe in the 1960s.  It was quite effective as a sleeping pill and for nausea of pregnancy.  Thalidomide had a disastrous flaw.  It caused bizarre limb defects in newborns.  A hero at the FDA (Federal Drug Administration) delayed its approval in the USA until the problem was recognized.  Thalidomide is a manufactured chemical with two optical isomers, one caused the disaster and the other the benefit.  Only in recent years has it been possible to synthesize these two almost identical types of molecules separately from each other. Plants and animals have all been making them separately since the dawn of time.  For example proteins are all made of l-amino acids; d-amino acids scarcely exist in nature and they are incompatible with life.

       A handful of great innovators have made major contributions to knowledge in unrelated fields.  Galileo pioneered in astronomy by way of telescope making and in structural engineering by way of his efforts in mathematical analysis.  We all know of Louis Pasteur through his contributions in microbiology, including wine making and rabies vaccination.  Louis Pasteur also discovered optical isomerism as a young man in his twenties, a concept which did not even exist until he noticed crystals of cream of tartar, potassium bitartrate, with two different shapes that were mirror images of each other.  With a magnifying glass and tweezers he separated the two sets of crystals from each other.  They had identical physical properties such as melting point and refractive index, but when dissolved, the solutions rotated polarized light in opposite directions.  He correctly attributed this to a carbon atom in its molecule with four different atoms or groups of molecules attached to it. To try to understand optical isomerism imagine a small, round table with three people sitting around it and a fourth person in a chair in the middle of the table, all next to a full length mirror.  The table represents the carbon atom and the people the four different entities attached to it.  Swap any two of the people with each other and all those previously on any individual’s left will appear on that individual’s right and vice versa with the new arrangement like the original image in the mirror.  If you don’t like headaches, make the swap only among the people whose chairs are on the floor. It was a toss-up who sat in the chair on the table in the first place.

       L-dopa, an amino acid active in relieving the symptoms of Parkinson’s disease, was the first bulk chemical synthesized artificially as the single active optical isomer.  This was accomplished in the 1960s by Monsanto.  William Knowles and Ryogi Noyori received the Nobel Prize in Chemistry in 2001 for “asymmetric hydrogenations,” a method capable of making most if not all of these chemicals one isomer at a time.  The FDA has been on top of this situation and is now requiring new such drugs to be marketed as single isomers.  This should avoid some future disasters before they even start to happen.

       Here are some examples of existing substances whose optical isomers have vastly different actions even though most are not disasters like thalidomide:

i)    d-carvone smells like caraway and dill; l-carvone smells like spearmint.

ii)  An enantiomer is one of a pair of optical isomers. Allegra is the single enantiomer of a metabolite of Seldane, a racemic mixture(both isomers in equal quantities).  Seldane has been withdrawn from the market because of (unnecessary) cardiovascular side effects. Both are antihistamines.

iii)  ibuprofen is a racemic mixture; dexibuprofen, its active enantiomer, is on the market in Europe with an effective dose of 50% of ibuprofen and fewer side effects.

iv)  Aleve (naproxen) was developed as a single enantiomer.

v)    l-dopa, previously mentioned as treatment for Parkinson’s disease has an isomer d-dopa which has never been used because it causes deficiency of white blood cells and thus susceptibility to infections.

vi)   Many antibiotics have only one enantiomer produced because they are made by fermentation and even the semi-synthetic ones start with the natural fermentation product. As far as we know the other isomers are inactive. Examples; quinolones (CIPRO was the first member) and all the relatives of penicillin.

 vii)  Lexapro is the active isomer of (racemic) Celexa.  It is effective at 50% of the effective dose of Celexa.

viii) Most beta-blockers such as propranolol are racemic mixtures with one inactive isomer, but l-salotol is a beta-blocker and d-salotol is a type 3 cardiac antiarrythmic drug.

       It is not surprising that such similar chemicals as these isomers should behave so differently in plants and animals compared to their behavior identical to each other with inorganic chemicals.  After all, proteins are constructed of l-amino acids as mentioned above.  In attaching to or otherwise influencing a protein, a drug, synthetic or natural, may be totally active at its functional site,  but inactive at some other site because of its shape not fitting.  Compare with trying to fit a left hand into a stiff right-handed glove. (Total mirror images of proteins made entirely of d-amino acids have never been synthesized).

       Back to  thalidomide:  For decades it has been used in treatment of erythema nodosum complicating lepromatous leprosy.  Now its approval with severe precautions to prevent administration to pregnant women is under consideration for a number of skin conditions and some malignancies especially multiple myeloma. Similar precautions have been in force successfully for patients with leprosy and more surprisingly for another drug, Accutane, used for severe acne. Accutane also causes a high incidence of birth defects.   Ironically all of the precautions we have been discussing would scarcely have been effective if applied to the early development of thalidomide.  Birth defects have not occurred in any experimental animals given thalidomide and many animals have been tested. Also thalidomide is a rare exception in its ability to transform either of its enantiomers into a 50/50 mixture of both of them when dissolved in body fluids and in a matter of minutes.  Other drugs and body components such as amino acids do not change structure in this way.  This general rule of stability is the reason the FDA now promotes the manufacture of new drugs one enantiomer at a time.  Sooner or later this policy will prevent a new tragedy but with different details of course.

       New information creates new questions.  As I was researching this article I wondered how it is known that only one of the thalidomide enantiomers caused the birth defects since they both end up being present so quickly.  Surely some highly respected authority didn’t simply assert it.  But that is what happened with Linus Pauling and vitamin C. 

       The bottom line: do not be the first to use new drugs unless they promise large benefits for previously untreatable serious diseases.

John A. Frantz, M.D.

November, 10, 2003

Vitamins are Good for arthritis

 

I have a friend whose wife is very much into vitamins.  One Friday evening when I was tired and perhaps a little bit irritable, she was giving me the pitch about vitamin supplements.  I replied, “Sure, Nancy, I believe in vitamins if you have arthritis of the jaw.” Her reply: “Oh Doc, I am so glad that you realize that vitamins are good for arthritis.” This taught me a great truth: If you say something offensive to somebody who wants to like you, they may give you another chance (if you don’t blow it by frivolously explaining yourself).  I bit my lip and quit while I was ahead.  I have noticed many lesser examples of this phenomenon since then.