PART
XI:
SPECIFIC
INJURIES
The quinolones cause many
injuries in the whole body. More evident are those inflicted on the intestines,
kidneys, liver, pancreas, heart and brain.
In this section, there are some
references to them. For a quite exhaustive relation of medical reports of
quinolone damages on all organs, visit www.fqresearch.org.
73.CENTRAL NERVOUS SYSTEM EFFECTS
Although much about the
pathophysiology of fluoroquinolone-related CENTRAL NERVOUS SYSTEM effects
remains ill defined, one hypothesis suggests that drug interactions with the
g-aminobutyric acid receptor (GABA), an inhibitory neurotransmitter, may
explain CENTRAL NERVOUS SYSTEM-stimulating effects. Ciprofloxacin, enoxacin,
and norfloxacin demonstrate high-affinity binding to GABA and interfere with
GABA binding to its receptor. (See previous chapters for an understanding of
the role of GABA nerve receptors)
Furthermore, some NSAIDs (non
steriod anti-inflammatory drugs) have been shown to enhance binding of
fluoroquinolones to GABA receptors. Co administration of fenbufen and a
fluoroquinolone can induce convulsive seizures.
Fluoroquinolones can also induce
excitatory effects through direct activation of N-methyl-D-aspartate (NMDA) and
adenosine-receptor mechanisms. Thus, it may be that it is only under specific
conditions of sufficient CENTRAL NERVOUS SYSTEM penetration, coupled with
threshold antagonism of inhibitory pathways (GABA) and stimulation of
excitatory pathways (NMDA, adenosine), that observable CENTRAL NERVOUS SYSTEM
symptoms are manifested.
74.
EYE AND VISION ISSUES
Fig. 16
It has already stated that vision damage is so
disturbing and debilitating that just on the grounds
of vision injuries, quinolones should be restricted only for special high-risk
therapies.
This picture number
16 (courtesy of a collaborator) shows some of the main injuries and lesions that
quinolones cause to the eye. Chemically insulted, the optic nerve no longer
sends proper signals to the brain. Within the vitreous gelly substance, many
floaters may develop, and normally remain forever. The retina and its
attachment to the bottom of the eye ball gets damaged and originates flashes of
light that seem to move across the vitreous when in fact they are confined to the
retina itself. The lens may become opaque in certain areas. The muscles that
elongate and compress the lens become injured and painful, so focusing becomes
difficult. Sometimes the neurologic deficit of these muscles that deform the
lens is a sort of inestability (twitching) that takes form as an overscanning
that impedes focusing a single spot for long. Other times the coordination
between the nerves of both eyes is impaired, and therefore, double vision and
lack of precission focusing occurs.
On top of all
these debilitating symptoms, do not forget that your eye cannot recover from
illness or surgery as a normal eye, and that pain and photofobia-phototoxicity
are common and long lasting. The residues of quinolones that are present in the
eye for a long time after taking the drug, react with the ultraviolet radiation
and cause very serious damage, and also skin cancer.
Many of the injuries caused by fluoroquinolones affect
the optic nerves and the retina. Fluoroquinolone induced retinopathies are
suspected to be caused by disruption to the blood flow to the retina, either by
blockage or breakdown of the various vessels, being a common cause a drug
toxicity (and diabetes or hypertension, for instance). This can lead to
bleeding (hemorrhage) and fluids, cells, and proteins leaking into the area
(exudates). There can be a lack of oxygen to surrounding tissues (hypoxia) or
decreased blood flow (ischemia). This damage caused by quinolones is reversible
in some cases.
Some of the pathologies caused by fluoroquinolones are the following:
Floaters: The mechanism of damage may be
a toxic-vascular injury that in turn may cause a small amount of bleeding
inside the eye (vitreous gel), which may appear as a group of floaters. They
could also be caused by
crystal-like deposits that form in the vitreous, and we have not still gathered
a conclusive causative factor. In severe reactions floaters show up some months
after exposure to the quinolone (the reverse does not apply, that is to say, if
you develop floaters some months after exposure it does not mean neccesarily
that you have a severe reaction). Floaters may sometimes interfere with clear
vision, often when one is reading. If a floater appears directly in your line
of vision, moving your eye around will cause the vitreous to swirl around and
will move the floater out of the way. Looking up and down rather than back and
forth will cause different currents inside
the eye and may be more effective in getting the floater out of the way.
Floaters tend to be a permanent
injury in severe reactions. They lose intensity with time but it is really
improbable that they disappear spontaneously. Typically, a floxing that affects
the eyes causes hundreds of floaters, some of which may be big.
Floaters have many causes but when they are caused by quinolones seems to
be the consequence of vitreous hemorrahge and inflammation, as well as of the
presence of red blood cells, pigment cells and pigment granules detached from
the retinal pigment epithelium.
Flashies: Flashing lights is the
sensation of one or a few lights that start crossing a part of the field of
vision, and then fade off, lasting between less than one second and 3 seconds. As
flashies are also referred thousands of little swirling little lights that
swarm in the whole field of vision and that are difficult to detect unless you
stare at a bright sky and unfocus your sight. Individual flashies tend to occur in only one eye at
a time and persist even when the eye is closed. Some doctors hold the opinion
that the flashes are caused when the vitreous, a clear gel-like substance that
fills the inside of the eye, sometimes pulls or tugs on the retina. This
pulling causes the appearance of flashing lights or lightning streaks, though
there is no flashing light actually present. Given the toxic mechanism of all
the disorders of the floxed persons, other doctors believe that the flashes are
generated in the brain, caused by a spasm of blood vessels, what they call
ophthalmic migraines, normally with a little or no headache but possible eye
pain. These lights last many years in severe reactions and are very sensitive
to foods and supplements, for instance soy and sugar provoke a massive
proliferation of them in severe floxed persons. Unlike floaters, flashies tend
to heal with time. They are rare after the 4 year mark in severe floxed persons
and very rare 5 years after the intoxication.
Flashes of light (photopsias) last seconds, never more than 10 seconds, and
are probably caused by posterior vitreous detachment induced by the fluoroquinolones.
Macular degeneration: At the back of the eye there is a thin layer of
light-sensitive nerve cells and fibres called the retina. We see things because
light entering the eye strikes the retina and is turned into an electric
impulse that the brain understands as an image.
Fig. 17
Near the centre of the retina is a small spot about
the size of a pea called the macula. The macula processes the details in the
central part of the image that the brain receives. The macula needs good light
to work efficiently and works best in daylight. The rest of the retina is
responsible for side, or peripheral, vision. It is especially sensitive to dim
light, which makes night vision possible. If the macula deteriorates for some
reason, the retina becomes like a camera with a spot on the film. The centre of
the field of vision blurs and all detail is lost. This condition is called
macular degeneration. Quinolones tend to damage the retinal blood vessels that
supply the macula. In severe reactions, cut off from its source of nourishment,
the macula is permanently damaged and some blurry central spots appear in one
or both eyes. Ophthalmologists can diagnose these injuries, that are not
accompanied by de-pigmentation. But do not expect that any of them accepts that
the fluoroquinolone is behind your problem, because they prescribe
fluoroquinolone drops continously.
Dry eye: Explained
in other sections of the article. Can be very limiting also. Commonly appears
some months after exposure (6 months on average) and symptoms start to
alleviate after year
Curtains: These are
very long-lasting injuries of the visual field usually called curtains. They
can be seen in the upper part of the vision field and move horizontally around
bright fluorescent lights and brilliant backgrounds. They are like a string of
water drops moving like a curtain from side to side of the upper part of the
vision field.
Eye pain: Eye pressure and pain is
typical. Sometimes eye pressure comes in wave-like bursts. It resolves earlier
than the rest of vision issues. There is also a marked loss of strength on the
muscles that move the eye and especially those that bend the cornea, making it
very difficult for the eyes to focus. By year 2 cornea control starts to
resolve and by year 3 the rest of the muscles of the eye begin to recover, so
the floxed person feels clearly that he regains strength in the muscles of the
eyes.
Complete
transient loss of vision: Some floxed persons, very
severely affected, have lost their vision completely up to 4 times. The loss of
vision comes suddenly, and in a matter of seconds the floxed person can see
only a solid blank field. It can last from 30 seconds to 6 minutes. This
phenomenon is described in the medical literature for ciprofloxacin.
Phototoxicity: Two types
of photosensitivity reactions have been associated with fluoroquinolone
therapy: photoallergic reactions and phototoxic responses. Photoallergic
reactions normally require previous exposure to a drug in the class. In
contrast, phototoxic responses are more common and can develop without previous
exposure to a fluoroquinolone if the dose of the photo-labile drug and exposure
to UVA light (around 350 to 360 nm) are sufficiently high. Photosensitivity
reactions are postulated to occur as a result of fluoroquinolone photodegradation,
as well as the molecule's ability to generate free monovalent oxygen radicals.
In turn, these oxidative radicals may attack cellular lipid membranes,
initiating inflammatory processes, and eventually producing DNA damage.
Evidence for photo-induced oxidative DNA damage is demonstrated by the
development of murine tumors in mice treated with lomefloxacin.
Be aware that there are many
ophthalmic preparations based on quinolones, especially cipro. If you have
suffered a small reaction to any quinolone before, these medications can cause
permanent damage to your vision. Some new formulations have been released for
the pediatric population (older than 6 months) with a mixture of cipro and a
cortico-steroid. It is also very well known and cited in medical researchs that
cipro impedes seriously the healing of any eye wound, like the ones caused
during eye surgery (in fact, quinolones jeopardize all healing processes in the
body).
Some floxed persons have lost their vision completely
for some minutes several times after taking the antibiotic. It is a frightening
experience that can have a dramatic end:
DEAF
AND BLIND DUE TO THE INGESTION OF A FLUOROQUINOLONE. 2002.
Canadian
Adverse Reaction Newsletter. October 2002. Case Presentation - moxifloxacin
(Avelox):
Optic
neuritis developed in a 22-year-old woman with sinusitis while she was
receiving moxifloxacin (Avelox) therapy. After 1 dose she experienced fainting
and somnolence, which resolved 2 days after initiation of therapy. After 4 days
of treatment she lost vision in her left eye. She consulted an ophthalmologist
and continued therapy for 6 days. An MRI scan ruled out multiple sclerosis. The
patient was taking birth control pills concomitantly. It was reported that her
vision would not likely return.
Ciprofloxacin:
suspected association with deafness and reduced hearing Health
We have only seen complete visual loss in severely affected persons, all of
which had taken fluoroquinolones in the past without strong adverse effects,
save the last one, that invariably was of a higher dose. What happened to all
these persons is that their cumulative dose of quinolone was too high, what is
the same as saying that the liver had very impaired its P450 pathway, and then
new and stronger doses of quinolones caused extraordinary high concentrations
of the toxic, acting over tissues and cells that were already abused. Doses of cipro
that caused this on the floxed persons studied by us were 1,500 mg/day up from
1,000 mg/day of previous treatments.
The following report is not
estrictly speaking about quinolones, but about another drug with a similar
structure (that the text includes in the same family as quinolones [?]), but
gives a very important clue towards understanding why quinolones are so harmful for the eyes, and why
they cause so long term damage. The article supports the fact that the drug
remains in the body for 5 and more years after ending the treatment. That could
be the same in the case of fluoroquinolones, but no medical group wants to
investigate it. Why not is what is hard to understand. In our opinion it is not
a coincidence that the researchers do not belong to the western mainstream herd
of doctors shepherded by the manufacturers.
emedicine
AUTHOR: MANOLETTE R ROQUE, MD,
GENERAL MANAGER, OPHTHALMIC CONSULTANTS PHILIPPINES CO, EYE REPUBLIC OPHTHALMOLOGY CLINIC
Background: Chloroquine
and hydroxychloroquine belong to the
quinolone family. They are related drugs with different therapeutic and
toxic doses with similar clinical indications for use and manifestations of retinal toxicity.
Initially, chloroquine was given for
malaria prophylaxis and treatment, and, later, it was used by rheumatologists
for treating rheumatoid arthritis, systemic/discoid lupus erythematosus, and
other connective tissue disorders. Dermatologists use these drugs for cutaneous
lupus. Since it is far less toxic to the retina, hydroxychloroquine has
replaced chloroquine, except for individuals who travel in areas endemic with
malaria.
Expanded use of these drugs for
nonmalarial disease entities has resulted in prolonged duration of therapy and
higher daily dosages leading to cumulative doses greater than those used in
antimalarial therapy. The first reports of retinal toxicity attributed to
chloroquine appeared during the late 1950s. In 1958, Cambiaggi first described
the classic retinal pigment changes in a patient receiving chloroquine for
systemic lupus erythematous (SLE) treatment. In 1959,
Pathophysiology: Chloroquine
has an affinity for pigmented (melanin-containing) structures, which may
explain its toxic properties in the eye [please, note that quinolone
antibiotics also have a big affinity for melaning structures]. Melanin serves
as a free-radical stabilizer and as an agent that can bind toxins. Although it
binds potentially retinotoxic drugs, it is unclear whether the effect is
beneficial or harmful. Chloroquine and its principal metabolite have been found
in the pigmented ocular structures at concentrations much greater than in any
other tissue in the body. With more prolonged exposure, the drug accumulates in
the retina. The drug is retained in the pigmented structures long after its use
is stopped. The kinetics of chloroquine metabolism are complicated, with the
half-life increasing as the dosage is increased. In patients with retinopathy, 5 years or more after discontinuation,
traces of chloroquine have been found in plasma, erythrocytes, and urine.
The
antimalarials chloroquine and hydroxychloroquine exhibit practically identical
toxic profile as fluoroquinolones in many aspects. As those antimalarials have
been more extensively and honestly studied than quinolones, the causes of some
symptoms caused by those antimalarials are known, but that is not the case for
the fluoroquinolones. Knowing some facts about the antimalarials could provide
us with some clues in order to orientate our search for answers to the toxicity
of fluoroquinolones. According to the well stablished medical research,
chloroquine can cause degeneration of the optic nerve. It can also cause a
retinal degeneration which can lead to blind spots in the vision, reduced color
vision, and blurred central vision. The risk of retinal problems may be related
to the total cumulative amount of chloroquine taken over time. Its effects are
cumulative. Taking more than
Nevertheless for the fluoroquinolones, the
laboratories have been keen to hide the ocular toxicity, with a complete
success up to now. For chloroquine and hydroxychloroquine, the retinal toxicity
was discovered when the laboratories pushed for the expanded use of these drugs
for nonmalarial disease entities resulting in prolonged duration of therapy and
higher daily dosages leading to cumulative doses greater than those used in
antimalarial therapy. Until more honest research is done, we theorize that the
eye toxicity of the fluoroquinolones may be similar to the eye toxicity of
chloroquine and hydroxychloroquine.
As the antimalarial chloroquine, fluoroquinolones have
an affinity for pigmented (melanin-containing) structures, which may explain
its toxic properties in the eye. Melanin serves as a free-radical stabilizer
and as an agent that can bind toxins. Although it binds potentially retinotoxic
drugs, it is unclear whether the effect is beneficial or harmful.
Fluoroquinolones have been found in the pigmented ocular structures at big
concentrations. With more prolonged exposure, the drug accumulates in the
retina. The drug is retained in the pigmented structures long after its use is
stopped (in other parts of the report it is explained how quinolones can be
detected in dark hairs months after ingestion). For the antimalarial
chloroquine patients with retinopathy, 5 years or more after discontinuation,
traces of chloroquine have been found in plasma, erythrocytes, and urine.
Probably the same happens with fluoroquinolones, but as far as we know the
essays have not been conducted yet.
Quinolones
cause diplopia (double vision) very frequently. It is unclear, for lack of
research, whether the diplopia is a direct effect or secondary to a
quinolone-induced intracranial hypertension.
This big toxicity to the eye has not gone unnoticed to some researchers,
and for instance, the Department of Optometry, at City University London,
started a project in october 2002 that "concerns
the ocular adverse reactions of certain systemic medications. In particular,
several drugs, e.g. cardiac glycosides, phenothiazines, quinolones, NSAIDs and
chemotherapeutic agents, are associated with significant and selective retinal
toxicity". We have not been able to get a copy of the outcome of this
project.
Retinopathies caused by fluoroquinolones are basically considered as
nonproliferative retinopathies.