Wednesday, June 29, 2005

I Just Love This Stuff

One of the older antibiotics known is tetracycline.  Long used as a treatment for syphilis, chlamydia, mycoplasma, intestinal protozoa, cholera, and acne; it is old enough now that a lot of organisms have developed resistance to its effects.  

From Cecil's Textbook of Medicine:
C. psittaci is susceptible to tetracyclines and macrolides but resistant to sulfonamides. Tetracycline has had the greatest clinical use. Psittacosis is the most gratifying of all chlamydial diseases to treat. Defervescence and marked symptomatic relief of systemic signs occur within 24 to 48 hours after starting tetracycline 500 mg four times a day or doxycycline 100 mg twice a day. Treatment should be continued for 10 to 21 days.
"The most gratifying of all chlamydial diseases to treat"?  Frankly, I never though of treating infections as gratifying, but I suppose it is.

Tetracycline is named for the four carbon rings.  Early in the history of pharmacology, it was common to name medicines and classes of medicine according to their chemical structure.  Now it is much more common to name drugs according to their mechanism of action.  
tetracycline chemical structure - chemfinder.cambrigesoft.com
Tetracycline works by binding to ribosomes inside bacterial cells.  The binding is specific to the ribosomes in bacteria; the ribosomes in mammalian cells do not interact significantly with tetracycline.   The binding to ribosomes interferes with protein synthesis.  Tetracycline gets into bacterial cells via an active transport mechanism in the bacterial cell membrane.  Because the ribosomes of mammalian cells are not affected by tetracycline, and mammalian cell membranes prevent tetracycline from entering the cells, tetracycline is harmless to mammals.  In fact, it would not be expected to have any direct effect in mammals, except perhaps to cause allergic reactions. (Harrison's Online, chapter 118).

But things are not always what they seem.  In medicine, there always are surprises.  

Now comes a report that a variant of tetracycline may have a role in the treatment of osteoarthritis (OA).  This is completely unrelated to its action as an antibiotic.  

Doxycycline, as you can see, it related closely to tetracycline; it even has the four carbon rings.

doxycycline chemical structure -- chemfinder.cambridgesoft.com

Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo-controlled, double-blind trial
Kenneth D. Brandt 1 *, Steven A. Mazzuca 1, Barry P. Katz 1, Kathleen A. Lane 1, Kenneth A. Buckwalter 1, David E. Yocum 2, Frederick Wolfe 3, Thomas J. Schnitzer 4, Larry W. Moreland 5, Susan Manzi 6, John D. Bradley 1, Leena Sharma 4, Chester V. Oddis 6, Steven T. Hugenberg 1, Louis W. Heck 5

Arthritis & Rheumatism
Volume 52, Issue 7 , Pages 2015 - 2025
Published Online: 28 Jun 2005


To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment.

In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals.

Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean ± SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 ± 0.42 mm versus 0.24 ± 0.54 mm); after 30 months, it was 33% less (0.30 ± 0.60 mm versus 0.45 ± 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase.

Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.
So doxycycline, a tetracycline-class antibiotic, slows the progression of joint-space narrowing in patients with OA.  In addition, the treated patients had less pain, albeit by only one of the measures.  These patients had OA in one knee but not the other.  The doxycycline had no effect in the OA-free knee.  

To put it mildly, these findings are both unexpected, and difficult to explain, at least for a non-rheumatologist.  It turns out that laboratory experiments had shown an effect in decreasing the rate of destruction of cartilage.  Those experiments had been done with animals, and with isolated human tissue.  Non-rheumatologists would not ordinarily read those journals.

The most obvious significance of this study is that we may be able to develop a treatment for OA that actually alters the progression of the illness.  Current treatments alleviate symptoms, but do not stop the progression of joint damage.  Finding a way to slow the progression would be a significant advance.

One potential problem is that giving antibiotics to the large population of persons with OA, over a long period of time, would promote the development of antibiotic-resistant organisms.  Ideally, we would find a new molecular entity that has no use as an antibiotic, but which retains the anti-arthritic effect of doxycycline.  That would be a multi-billion dollar drug, so long as it did not kill anyone.

The unexpected dual use of doxycycline, however, is not why I find this so interesting.  I think that it is evidence that there is some kind of organizing principle in pathophysiology that the medical profession simply does not understand.  There probably is some kind of abstract, complex mathematical formula that unifies the antibiotic effect of tetracyclines with the antiarthritic effect.  This would be the medical equivalent of the unified field theory that physicists have been gnawing at in the post-Einstein decades.  Of course, physics is relatively simple, compared to pathophysiology.  If the greatest minds in physics have not been able to solve the "simple" physics problem, the likelihood that a solution will be found for the corresponding physiological problem is not great.

On the other hand, if we could figure this thing out, in would open new avenues for drug development.  It would be worth a lot of money.  It also would give fits to the proponents of Intelligent Design.

On a clinical level, there is an important lesson here.  From time to time, patients return to the doctor's office after having been started on a new drug.  They report that something unexpected happened, and are told "that can't happen."  It is important for physicians to recognize that, in some cases, that it can and does happen.  We just don't understand it.

All knowledge comes from observations.  If an observation does not fit the theory, we should not assume automatically that the observation is wrong.  It may be that the theory is wrong, or that we are working with an incomplete theory.

categories: science, medicine, armchair musings
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