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Monday, December 17, 2018

Dapsone, wonder drug? Not just about killing germs

People have been excited about trying Dapsone for PTLDS.  Horowitz has had good clinical results. Then Zhang did the test tube trials and it was a bust. It’s a sulfa drug and I have not been impressed using sulfa drugs treating Lyme.  Dapsone is used for leprosy, skin conditions including acne and dermatitis herpetiformis – the skin condition associated with celiac disease. With this portfolio I wouldn't have thought Lyme.  Dapsone may be a true wonder drug, one off the radar since it has been around forever (since 1937, predating penicillin, first synthetized in 1908) and there is no money in it for pharmaceutical companies. But what a drug! 

There are many ways the drugs may be repurposed and it is not just about killing germs, at least not directly.
Dapsone has tremendous anti-inflammatory properties with widespread effects on immune function. It positively impacts:  effector cells, cytokines, adhesion molecules, prostaglandins, leukotrienes, interleukins, tumor necrosis factor, leukocyte activation, ROS (reactive oxygen species), folate antagonist (this I knew) and a lot more. 
It is active against bacteria and protozoa, including malaria (Babesia?). 
It is bacteriostatic, not bactericidal and suppresses: strep, staph, pneumococcus, mycobacteria and more. 

I has been successfully used in rheumatoid arthritis with efficacy comparable to more toxic drugs.
It has steroid sparing effects which may make it useful in a wide variety of inflammatory and autoimmune disorders
It prevents UV associated photosensitivity (think doxy during the summer). 
It is well adsorbed into all tissues, including the brain. It may have neuroprotective effects (human stroke study). ?Brain fog in Lyme patients. 
It may have anti-cancer effects, even against brain tumors. 
It might be effective for life extension (works in a worm).  We are not worms.  
It may help kill Lyme through non-antibiotic effects. For example, it improves immune function and generates ROS which have natural antibiotic properties. 
There is much more.
It has potential toxicity and side effects which must be monitored.  

It sounds too good to be true, so I include the reference.

Archives of Dermatology (2014) 306:103-124, Wozel, Blasum (University of Dresden, Germany)
Open access with extensive references.

Saturday, December 15, 2018

Biofilm induced inflammation in mouse model and rapid relapsers

Thank you, Dr. Zhang, for your dedication and hard work.  The latest paper published October 11, 2018 is groundbreaking. 
The latest research has moved from the test tube to the mouse model.  Test tube research cannot be applied directly to human medical care and neither animal model research, but it moves the ball closer to the goal.
Doctor Zhang has both an MD and a PhD. He is highly skilled researcher but also has the bona fides to discus clinical, human disease with credibility. 
He speaks of PTLDS, using the term frequently with words carefully chosen. He states the cause of PTLDS is unknown.  But the hypothesis that persistent infection plays a large role is written between the lines. 
I must thank him first for describing 2 types of PTLDS.  This is something I have long railed about.  In the first type(type 1 PTLDS) a patient receives early treatment and experiences clinical failure. In the second (type 2 PTLDS), the diagnosis is delayed and therefore early treatment is never provided. 
 The 4 NIH sponsored clinical trials examined only type 1 PTLDS.  The most recent trial was performed more than 12 years ago. The trials were limited with small patient numbers and have been controversial since day one.  The meaning and interpretation of the study results has been hotly contested.  Dr. Fallon’s expressed beliefs which contradict those of the IDSA were recently described on these pages. 
The IDSA has recently stated that more funding for Lyme research is unnecessary since all is already known. This is frightening. When is more data, evidence, information and science a bad thing?  I thought suppression of scientific inquiry is something left behind with the middle ages. 
For me one of the clinical mysteries has been the rapidity with which clinical symptoms may relapse when antibiotics are stopped. I think the latest study findings provide clarity here. 
 Lyme bacteria are pleomorphic and exhibit a great degree of phenotypic variability.  In layman’s words “they act like shape shifting aliens” which have widely invaded host bodies. 
The Lyme bacterium is a long, thin, twisted bacteria, a spirochete of the genus Borrelia. There are various species and strains which may cause human disease. 
 Dr. Zhang describes 3-4 variations. The spirochetes may be aggregated in a rapidly growing biomass mathematically referred to as a logarithmic growth phase.  One might think this group with its very high numbers causes the most harm and one would be wrong.  a second group he calls microcolonies (aggregated biofilm like colonies). This is a stationary group showing no active growth.  Individual spirochetes, free swimming are planktonic variants.  In microbiology, planktonic bacteria are distinguished from organisms confined to biofilms.  Most of the planktonic bacteria are round forms. This is not something I have seen described with any other pathogenic bacteria. 
Mice joints are infected (inoculated) with one of the 3 forms.  The biofilm forms caused the greatest joint inflammation in the shortest time.  Planktonic forms came in second place and the least joint inflammation was seen with the large number of actively growing spirochetes.  

The Lyme bacteria which are easily killed do not appear to be the problem. The few do more harm than the many. 
Doctor Zhang suggests that the host may be inoculated with biofilm colonies at the time of the tick bite. I suspect it doesn’t matter that much. There is fluidity.  Round forms and biofilm forms arise quickly irrespective of the inoculum. 
Persister forms express more virulence factors such as decorin binding protein, noted in the paper. 
That brings us back to the question: why do patients relapse quick when antibiotics are withdrawn?

This is what I envision.  The bacteria that cause relapse are dug in and battle hardened and barely kept in check with long term antibiotics. 
Any Star Trek fans? The Starship Enterprise (us) is shooting missiles(antibiotics) at the enemy Klingon ship (Lyme persisters). A force shield is in place and the projectiles can’t penetrate enemy strongholds.   When the Enterprise runs out of ammo the enemy drops it shields and the Klingons open fire. Ouch.