Dr Vinayak Joshi, Dr Sridhar VKE, Dr L.M. Golub, discussed
the questions asked. The answers to the question are as below
Question: Pinak Kapadia
Sir, it was an enlightening discussion, and the lucidity
of the essay made it seem like an easy conversation to understand. Thank You. I have a few queries sir: As long as the patient
is taking SDD and with adequate maintenance, his periodontal disease has been shown not to progress. What happens if he stops
it? The collagenase levels may return to pre-treatment and destruction may ensue. Plus, what would happen if a patient skips
the dose, for say-a month or so? And if subantimicrobial dosage be used for local drug delivery purposes, what should be the
dosage required, and will it be useful? Sir, thanks a lot for the lecture.
Periodontal
disease cannot be completely cured but must be controlled by repeated periodontal maintenance therapy (scaling and polishing
etc). According to the American treatment planning protocol the periodontal patient needs to be recalled once every 3-4 months
for a diagnostic checkup and maintenance therapy. The SDD should be administered for a minimum of 3 months and maximum of
9 months daily therapy. On the subsequent recall visit if the patient shows the presence of active disease in form of bleeding
on probing or loss of attachment then the SDD is adjunctively administered along
with the routine mechanical therapy till the next recall visit in 3 months period. This adjunctive administration of SDD can
continue up to a maximum of 9 months and then a 3 month of drug holiday is given, and if the disease continues to show progression
then the SDD can be safely administered for a 2nd cycle and combined, perhaps with therapeutic such as local delivery
of antimicrobials etc..
We have known that ( according to literature) that
short term regimen of SDD i.e. 1 month or less will reduce collagenases significantly but the reduced collagenase will comeback
to high level if the patient stops SDD. However there is also literature showing that if the patients take the SDD for 3 months
or more the drug shows substantivity, i.e. after stopping drug administration, the benefit of the drug persists for at least
until the next 3 month recall appointment.
The basic principle of the Local drug delivery is
to eliminate the putative periodontal pathogens which have the potential to invade deep into the tissue and are not eliminated
by mechanical therapy (examples: Atridox, Periochip, Arestin). So local application of antimicrobials is known to be almost
100times more effective than systemic administration of antibiotic (e.g. 100 mg per day Doxycycline) and also avoids other
adverse effects of high dose systemic antimicrobial administration. The SDD (i.e. 20mg Doxycycline capsules) on the contrary
were not designed to act as antimicrobials and the nonantibiotic dose was administered to act against the systemic and local
collagenases involved in active disease process. Local application of the SDD would not act against bacteria and would be
minimally effective against the local enzymes.
Question: Devapratim Mohanty
Hi that was a wonderful editorial, as the topic was
on CMT, I have a few doubts and queries regarding them: They are as follows, What are the latest numbers of CMTs? What purpose
the ten or so CMT serve other than being landmarks in the search for the perfect CMT? Is it the osteblast which starts the
bone resorption by secreting collagenase or is it the osteoclast which secrets the collagenase.
There are 10 CMT's available for research purposes.
However chemical modifications of the original structure have been made resulting in dozens of CMT's.
The purpose of the CMT's was: A) to search for the
one which had the maximum half life in serum, so that it reduced the number of times the drug would be administered in a day,
consequently improving the patient compliance. B) To search for the least toxic and the most potent of the group in suppressing
the collagenases. C) To identify the location of chemical side chain on the tetracycline molecule responsible for anticollagenase
activity of the drug, this helps to design more potent and safer drugs. D) In fact one CMT has been selected from the bunch
which is called CMT-3, also known as COL-3, also know as Incyclinide, this drug is the only CMT tested in humans and in high
doses has shown efficacy in Kaposi Sarcoma as anti-angiogenesis drug and in low doses the same drug has shown efficacy in
dermatologic disease, for example, Rosacea.
The osteoblast and osteoclast both secrete collagenases.
The osteoblast initially secretes the collagenases, which degrades the superficial osteoid layer, there by making the underlying
bone accessible to osteoclast to act upon by subsequently secreting collagenases.
Question:
Dr. Anurag Jain
Hello
friends, It was very interesting to read the guest editorial on Collagenase, CMTs and HMT. I wanted to put forward my doubts
– 1. What are the important physiologic roles of MMPs apart from - tissue remodeling, helping in migration of Neutrophils
through tissues etc. 2. Whenever we use HMT, how do we take care of inhibition of physiologic roles of the molecule we are
targeting? For example, if we are using SDD it will also inhibit the physiologic functions of MMPs apart from inhibiting its
pathological functions. Does this inhibition of physiologic functions has potential to produce side effects on long term basis.
MMPs have physiological functions including (but not
limited to) the processing of growth factors and protective endogenous proteinase inhibitors (e.g. SLIP) (Overall and Lopez-Otin,
2002; owen et al, 2004). Physiologic levels of MMP-8 have recently been shown to exhibit anti- inflammatory properties (Owen
et al, 2004)
Batimastat is a broad spectrum MMPI capable of inhibiting multiple MMPs including MMP
-8,-9, and -13 which are the major host derived collagenases (MMP-8 & -13) and gelatinases (MMP-9) belived to mediate
connective tissue ( including bone) breakdown during the progression of periodontitis in the rat model ( Golub et.al, 1994)
and in humans ( Ingman et al,1996; Golub et al, 1997). Recently Bjornsson et al described the effect of Batimastat, on periodontal
destruction in Sprague -Dawley rats. Surprisingly, instead of reducing the severity of experimental periodontitis, as expected,
Batimastat actually enhanced alveolar bone destruction (Bjornsson et al, 2004).
Leaky MMPI, such as the tetracycline-based MMPIs,
may be safe and effective because they only reduce pathologically-excessive MMPs, but do not reduce MMP levels/activity below
those required for physiological functions, whereas Batimastat excessively reduces these MMPs, below the basal levels required
for normal function, resulting in clinically-significant side effects (Overall and Lopez-Otin, 2002)
[From:
Is the excessively inhibition of matrix metalloproteinases (MMPs) by potent synthetic MMP inhibitors (MMPIs) desirable in
periodontitis and other inflammatory diseases? that is 'Leaky' MMPIs vs excessively efficient drugs; T Sorsa, L M Golub: Oral
Diseases (2005) 11, 1-2, In Press.]
