PART
VI:
VASCULAR
DAMAGE
42. THE TWO HEADS OF THE HYDRA
There are two toxic mechanisms of
the fluoroquinolones that explain most of the injuries that they cause:
§
VASCULAR DAMAGE (injury to the small vessels and
extracellular matrix)
§
FAULTY NEUROTRANSMISSION (alteration to the
transmission of nerve signals)
In this chapter we address the
first one, a complex issue that simplifying is called vasculitis.
43. THE VASCULAR-MATRIX CONNECTION
This area of the report is a
hypothesis on the ultimate cause of some of the injuries of the floxing
syndrome. We cannot aim to discover anything of medical importance. But we can
argue about some ideas that correspond well with our experiences, the clinical
symptoms that allow us to favor some habits and avoid others in our daily
lives, with some basic understanding about the why and why not.
Although it is not generally
accepted, we think that one of the main damaging paths used by fluoroquinolones
is vascular. There are many scientific papers that relate vasculitic events
induced by quinolones but they are presented as exceptional or rare happenings.
However, the fluoroquinolones unfailingly provoke a specific sort of vascular
injury(s).
While it is true that all living things are made of
cells, that is only part of the story. Most of the cells in humans are
surrounded by a complex mixture of nonliving material that makes up the
extracellular matrix. In some cases, the extracellular matrix accounts for more
of the organism's bulk than its cells.
Figure 6. You have to pay attention to the attached
figure. This figure has been prepared by a floxed person based in a diagram of
Martin Keymer. The figure shows what you are made of. Arteries (1) supply
nutrients and oxygen by means of the blood (9). The cells (2) of the organs
need that supplies and also to get the toxins away (dark dots). All the
exchanges are done through the capillaries (8) that spread like little worms in
the extracellular matrix (the substance that bathes it all). Blue arrows show
the in-path of oxygen and nutrients, exclusively from the arteries, via the
microvessels and extracellular matrix, to the cells. Black arrows show the
detoxification out-pathway, addressed to the veins (10) and to the lymph
vessels (5), that begin blind in the tissue (let us say the matrix). The veins
remove the wastes (10). When there are toxins, like quinolones, on top of
damaging the cells, degrading the matrix, and injuring the microvessels, they
create deposits of byproducts (4) in the matrix (not necesarily quinolones properly).
All organs are stimulated by nervous cells (3), that are also served by the
microvessels (8) and those nerve cells can get damaged too by the toxicity.
As a general conclusion, take notice that the transfer
of nutrients and oxygen from the arteries to the cell depends on the
extracellular fluid. Nerve supply to the cell is also seen via terminal
autonomic (do not depend on your will) axons with their blind endings in the
extracellular matrix. Cellular waste is carried away from the cell via the extracellular
fluid and transported to capillaries and lymph vessels. This sponge-like matrix
also stores toxins and serves as a buffer to prevent damage to vital tissues. A
heavy onslaught of toxins owerwhelm the body's capacity to clear and evacuate
and can be stored in the matrix and then released at a slow rate later, if the
clearance mechanisms have not been toxically destroyed beyond repair.
The matrix is composed of a mesh of high-polymer
sugar-protein complexes, mostly proteoglycans and structural glycoproteins like
collagen and elastin. You can consult many medical articles describing how
quinolones are specially active at destroying proteoglycans for example.
The extracellular matrix and all its microvessels can
be damaged by toxins from multiple origins and by fluoroquinolones that is the
subject that we are treating. The primary mechanism of the damage is free
radical oxidation and chronic inflammation. The tissues become impregnated with
the quinolones and the products originated by the oxidating reactions they
provoke and finnally the organs become damaged and cellular metabolic processes
become altered.
Once the extracellular matrix is compromised, the
transmission of intercellular information is impaired. The accumulation of
toxins (quinolones, remains of quinolones half metabolized, and toxic
byproducts of the intoxication) within the extracellular matrix creates
multiple problems.
In other words, between the cells of the body and the
capillaries that serve them there is a sort of broth that is called
extracellular matrix, because is the substance that is outside the cells, and
bathes it all, allowing the exchanging of debris and nutritionals between the
vessels and the cells. This matrix has to be in perfect state to do its vital
functions. Many many dysfunctions of the body take place when this
extracellular matrix is degraded by agressive factors.
JEREMY NORMINGTON, DPT, DIRECTOR OF
PHYSICAL MEDICINE AND REHABILITATION AT
A recent histological exam was aimed at
understanding the direct pathologic mechanism underlying
fluoroquinolone-induced tendinopathies. Williams et al. suggests that
fluoroquinolones alter fibroblast metabolism. The study examined the effects of
one type of fluoroquinolone ciprofloxacin on the fibroblast metabolism of
canine Achilles tendons, paratenons and shoulder capsules.
Researchers looked at fibroblast
metabolism from three standpoints: cell proliferation, matrix synthesis
(collagen and proteoglycan) and matrix degrading activity. The study revealed
the following: a 66 percent to 68 percent decrease in fibroblast proliferation;
a 36 percent to 48 percent decrease in collagen synthesis; and a 14 percent to
60 percent decrease in proteoglycan synthesis, compared to control groups.
Ciprofloxacin also induced a significant increase in matrix degrading activity
over 72 hours.
Descending to the detail, we have to point out that
along this report, when we say that probably fluoroquinolones act injurying the
microvessels we are implying that fluoroquinolones damage the microvessels and
also the extracellular matrix that is the interface between the cells and the
vessels, disorganizing many critical functions.
The role of extracellular matrix is extremely
important. For instance, wound healing involves close interaction between
several different cell types, extracellular matrix components and growth
factors. In hard-to-heal wounds, like all the injuries caused by quinolones,
the healing processes are disrupted by cellular and biochemical imbalances that
compromise the repair processes. All these afirmations have been extracted by
us from medical papers.
The degradation of the extracellular matrix is caused
by the toxicity of quinolones, directly and/or by means of stimulating a large
family of enzymes that degrade the extracellular matrix, called matrix
metalloproteinases.
Matrix metalloproteinases have been implicated in
cancer metastasis, bone remodeling, embryogenesis, angiogenesis, arthritis, and
periodontal disease. Matrix metalloproteinases are put to work by quinolones in
the whole body. Doctors call this phenomenom "expression of matrix metalloproteinases" that means
induction of production of metalloproteinases, that cause matrix degradation.
The following paper manifests this effect of quinolones on the eyes, but could
be extrapolated to any other area of the body:
EFFECT
OF TOPICAL FLUOROQUINOLONES ON THE EXPRESSION OF MATRIX METALLOPROTEINASES IN
THE CORNEA
Victor
E Reviglio, The Wilmer Eye Institute, Johns
Matrix
metalloproteinases play an important role in extracellular matrix deposition
and degradation. Based on previous clinical observations of corneal
perforations during topical fluoroquinolone treatment, we decided to
evaluate the comparative effects of various fluoroquinolone eye drops on the
expression of matrix metalloproteinases in cornea. Methods: Eighty female Lewis
rats were divided into two experimental groups: intact and wounded corneal
epithelium. Uniform corneal epithelial defects were created in the right eye
with application of 75% alcohol in the center of the tissue for 6 seconds. The
treatment groups were tested as follows: 1) Tear drops: carboxymethylcellulose
sodium 0.5 % (Refresh, Allergan); 2) Ciprofloxacin 0.3% (Ciloxan, Alcon); 3)
Ofloxacin 0.3%(Ocuflox, Allergan); 4) Levofloxacin 0.5%(Quixin, Santen). Eye
drops were administered 6 times a day for 48 hours. Results: matrix
metalloproteinases MMP-1, MMP-2, MMP-8 and MMP-9 expression were detected at 48
hrs in undebrided corneal epithelium
roups treated with the topical fluoroquinolones. No statistical
difference was observed in quantitative expression of matrix metalloproteinases
among ciprofloxacin .3%, ofloxacin 0.3%,
levofloxacin 0.5%. When the artificial tear group and the fluoroquinolone
groups with corneal epithelial defect were compared, increased expression of matrix
metalloproteinases was observed as a result of the wound healing process.
However, the fluoroquinolone treated group exhibited high statistically
significantly levels of matrix metalloproteinases expression.
Conclusions: Our study provides preliminary evidence
that topical application of
fluoroquinolone drugs can induce the expression of matrix metalloproteinases
MMP-1, MMP- , MMP-8 and MMP-
The above article shows what we already knew due to
our physical experiences. Fluoroquinolones induce the expression of matrix
metalloproteinase, that means that the interface between cells and vessels is
degraded (destroyed) causing unpredictable and potentially serious injuries all
over the body, that in the case of eyes take the form of corneal perforations,
impaired healing and overall degradation. So simple, so unknown, so ignored.
Another research abstract that treats the influence of
the degradation of the extracellular matrix on the tendons of the human body:
FLUOROQUINOLONES
CAUSE CHANGES IN EXTRACELLULAR MATRIX, SIGNALLING PROTEINS, METALLOPROTEINASES
AND CASPASE-
Sendzik J, et al. Institute of
Clinical Pharmacology and
Antimicrobial
therapy with fluoroquinolones can be associated with tendinitis and other
tendon disorders as an adverse reaction associated with this class of
antimicrobials. Here we investigated aspects of the mechanism of
quinolone-induced tendotoxicity in human tenocytes focussing mainly on the
question whether fluoroquinolones may induce apoptosis. Monolayers of human
tenocytes were incubated with ciprofloxacin or levofloxacin at different
concentrations (0, 3, 10, 30 and 100mg/L medium) for up to 4 days. Ultrastructural
changes were studied by electron microscopy, and alterations in synthesis of
specific proteins were determined using immunoblotting. At concentrations,
which are achievable during quinolone therapy, 3mg ciprofloxacin/L medium
significantly decreased type I collagen; similar changes were observed with 3mg
ciprofloxacin or 10mg levofloxacin/L medium for the beta(1)- integrin
receptors. Effects were intensified at higher concentrations and longer
incubation periods. Cytoskeletal and signalling proteins, such as activated shc
or erk 1/2, were significantly reduced by both fluoroquinolones already at
3mg/L. Furthermore, time- and concentration-dependent increases of matrix
metalloproteinases as well as of the apoptosis marker activated caspase-3 were found.
Apoptotic changes were confirmed by electron microscopy: both fluoroquinolones
caused typical alterations like condensed material in the nucleus, swollen cell
organelles, apoptotic bodies and bleb formation at the cell membrane. Our
results provide evidence that besides changes in receptor and signalling
proteins apoptosis has to be considered as a final event in the pathogenesis of
fluoroquinolone-induced tendopathies.
The explanation of the above report is as follows.
Fluoroquinolones cause reductions of key proteins that help maintaining healthy
tendons. Additionally, quinolones increase matrix metalloproteinases (that
degrade the substance that acts as medium for exchanging metabolites with
cells), quinolones increase the marker that send signals to cells to commit
self-destruction (apoptosis), plus many other damages like condensed material
in the nucleus, swollen cell organelles, apoptotic bodies and bleb formation at
the cell membrane. In summary, fluoroquinolones disorganize the very basic of cell
metabolism. Are there many other antibiotics with this profile? Why then are
quinolones considered benign antibiotics?
After knowing the basics of the two articles above,
you can deduct correctly that the same effect of degradation of the extracellular
matrix and microvessels can take place all over the body, what is coherent with
the extremely vast array of injuries that a fluoroquinolone cause in persons.
Only recently we have found these summary of a medical
report:
JEREMY NORMINGTON, DPT, DIRECTOR OF
PHYSICAL MEDICINE AND REHABILITATION AT
The exact mechanism of
fluoroquinolone-induced tendinopathies is unknown. In 1994, Szarfman et al.
provided an early hypothesis. The disruption of the extracellular matrix or
cartilage and the depletion of collagen in animal models led Szarfman to
hypothesize that similar degradation may occur in humans with tendon ruptures.
In another study, Gillet et al. viewed
three Achilles tendons of symptomatic fluoroquinolone therapy patients with
magnetic resonance imaging. Clinical findings were typical of Achilles
tendonitis in all cases. Two cases showed thickening of the tendon and one case
exhibited prominent peritendinous edema.
44.THE "QUINO-VASCULITIS" IN MORE DETAIL
We can profundize a little more
on the subject. The cellular matrix is the ground material for connective
tissue in which nerve fibers and vasa vasorum (small vessels) are dispersed.
The vasa vasorum exist within the extracellular substance of the end organs
(see figure 5). These vasa vasorum include the capillaries, that are
approximately the size of a red blood cell. The very small vessels that
surround and supply the nerves are called vasa nervorum.
Blood has to travel all over the
body in order to supply every cell of the body with nutrients and oxygen, and
to remove the wastes from all the tissues. The blood has to be able to
send its white blood cells into the surrounding tissue of cells to clean it up
and respond to injury.
These functions of blood require
that it can exchange its materials with its surrounding tissues. Arteries
and veins are not designed for exchange but merely for transport. It is in the tissue where the exchange has to
take place. Therefore, the capillaries (microvessels), which lie in the
cellular matrix between arteries and veins, must be the regions for exchange.
The quinolone antibiotics alter
the cellular matrix and also target the vasa vasorum and vasa nervorum, either changing
the capillaries permeability (the microvessels are one cell thick and allow the
exchange of substances through openings), or inducing the deposition of
immunological complexes inside them, or causing a spasm-like narrowing of their
ducts, or simply chemically damaging them. In any case, the result is the same:
muscles, skin, nerves, heart, brain and other organs are deprived of adequate blood
flow (ischemia), and owerwhelmed by toxic intermetiate compounds and they die
or do not work properly. For the sake of simplicity, in this report we call quinolone-vasculitis
the degradation of the extracellular matrix plus an alteration of the
microvessel walls with vascular damage or attendant tissue injury.
What nobody knows and requires
much more research are the factors that determine the duration of disease, the
type of tissues involved and their damage, as well as how to target therapies
at inflammation without interfering with healing. Apparently, part of the
process explained earlier is vehicled through an inmune response of the body.
Immune complexes with certain
immuno-chemical characteristics activate a complementary cascade that induces
neutrophil mediated damage to the vessel wall. The presence of granulocytes is
usually associated with fibrinoid necrosis as would be expected on the basis of
their release of toxic enzymes during inflammation. Necrosis in the vessel wall
is a large contributor to scarring and the delayed sequelae present in some
cases of vasculitis, such as the quinolone-induced vasculitis.
Accumulation of inflammatory
cells in the vessel wall is the common feature of common vasculitis, although
it is not well understood how tissue damage occurs. It is widely admitted that
there is a three-stage process:
initiation of the injury
recruitment of inflammatory cells and tissue
damage
regulation of the immune response.
Quinolone vasculitis is a
systemic vasculitide (so called because of its multi-organ nature).
Inflammation and damage can be transient or more permanent. The alterations in
coagulation and vasomotor tone result from local damage to the endothelium
(inner part of the walls of the ducts of large calibre and is the only layer of
the wall of microvessels) as well as intrinsic components of the cytokines that
are released through the process. Drug toxicities are among the causes and
processes strongly associated with vascular injury.
Normally, quinolone vasculitis
appears some time after exposure, and is a link in the chain of adverse events
that take place for months on end. All of the vasculitides are likely secondary
to some form of inflammatory stimulus, usually infectious or toxic, as in our
case. In quinolone vasculitis the real underlying cause either cannot be
identified (no doctor is willing to admit that quinolones are the direct cause
of vascular disorders) or has long since been cleared by the host, leaving only
a chronic or recurrent inflammation focused on the vasculature.
Toxins as a cause of vasculitis
are increasingly established. Overall, vasculitis secondary to a defined
infection or toxin is clearly the most frequently encountered vasculitis and an
important etiology in peripheral nerve vasculitis. Because quinolone vasculitis
is so varied in its presentation and clinical pace, early identification may be
difficult. In this vasculitis, neuropathies are frequent, occurring in 80%-100%
of patients. Mono-neuropathy multiplex is the most distinctive pattern in
intermediate reactions to quinolones, although nerve alterations of other kinds
are very common as well (twitching, throbbing, pins and needles, numbness,
sensory poly-neuropathies). See the paragraph devoted to neuropathies.
Then, there is the issue of
diagnosis. The diagnosis of vasculitis is fundamentally an invasive process
(biopsy). A critical feature is the identification of inflammatory cells that diminish
the delivery of blood to tissue.
Furthermore, the numerous causes that may result in vasculitis can often
be distinguished only at the cellular level. Histological studies
characterizing injuries on the basis of the infiltrating cells may provide information
on both the mechanisms inducing inflammation and predict the sequelae of the
injuries. There is an urgent need to determine the underlying mechanism for
appropriate treatment.
For most floxed persons the blood
studies may be entirely normal. There is no serological test that confirms or
excludes a vasculitis. Quinolone-vasculitis is: