140. PATHOPHYSIOLOGY OF THE CHEMICAL TOXICITY CAUSED BY FLUOROQUINOLONES

Most connective tissue injuries involve damage to the structural components of the tissue. Metabolic states, such as a floxing, may also affect connective tissue health.

Degradation of the extracellular matrix is also responsible for the pathogenesis of osteoarthritis. Chondrocytes in articular cartilage with osteoarthritis may be unresponsive to local growth factors resulting in decreased synthesis of matrix components. According to several doctors that are treating some floxed persons, the fluoroquinolone reaction activates a cascade of inflammatory events, and chemical degradation of cells and metabolism, that ends up in a given state of osteoarthritis, more or less symptomatic.

PROF. DR. RALF STAHLMAN. CHARITÉ - UNIVERSITÄTSMEDIZIN BERLIN. INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY CBF

Fluoroquinolones can cause tendon disorders as an adverse reaction associated with this class of antimicrobials. We investigated aspects of the pathomechanism of quinolone-induced tendotoxicity in human tenocytes focussing mainly on the question whether fluoroquinolones induce apoptosis. Monolayers of human tenocytes were incubated with ciprofloxacin or levofloxacin at different concentrations (0, 3, 11, 30, 100 mg/L medium) for up to 4 days. Alterations in synthesis of specific proteins were determined using immmunoblotting. At concentrations which are achievable during quinolone therapy, 3 mg ciprofloxacin or 10 mg levofloxacin/L medium significantly decreased type I collagen; similar changes were observed for the 1-chain of the integrin receptor. Effects were intensified at higher concentrations and longer incubation periods. Furthermore, time- and concentration-dependent increases of the apoptosis marker activated caspase-3 were found. Our results provide evidence that apoptosis has to be considered as a final event in the pathogenesis of fluoroquinolone-induced tendopathies. As a follow up to this project we will study the effects of glucocorticoids alone and in combination with fluoroquinolones on human tendon cells. In this part of the project, we hope to provide biochemical evidence for the clinical observation that a treatment with steroids has been recognized as a risk factor for quinolone-induced tendopathies.

Apoptosis means programmed cell death. Cells commit suicide when receive given signals, for example signals emitted by quinolones.

141. REPAIR OF FLOXED CONNECTIVE TISSUE

Injury to connective tissue involves damage to the cells and structural components of the tissue. Several responses are triggered and a sequence of events begins to repair the tissue. The reaction to injury includes vascular, cellular and biochemical responses. (The explanations concerning connective tissue have been obtained from the work of Elzi Volk and others).

Three phases of the repair process can be applied to the general healing of connective tissue. These phases, however, may overlap. These responses prevent the spread of damaging agents to nearby tissues, dispose of damaged cells, and replace damaged tissue with newly synthesized components.

Acute inflammation phase: Immediately after the chemical (floxing) injury, several vascular and cellular reactions initiate the response known as inflammation. The primary purpose of inflammation is to rid the site of damaged tissue cells and set the stage for tissue repair. Many of the events that occur during this time initiate tissue repair. Leukocytes (white blood cells), such as neutrophils and monocytes, accumulate within the damaged tissue along with resident macrophages. Enzymes released from these cells help digest necrotic cells and degrade matrix molecules; neutrophils and macrophages engulf cell debris. Blood platelets release growth factors that stimulate new fiber and matrix molecule synthesis.

Matrix and cellular proliferation phase: Chemical mediators released by inflammatory cells stimulate migration and proliferation of fibroblasts, which participate in the repair process. As you have seen this phase is profoundly impaired by quinolones by means of many mechanisms among which there is fibroblast metabolism impairment. Fibroblasts secrete fibronectin, proteoglycans and small diameter Type III collagen fibers. In addition to these fibers, newly formed capillary channels, clotting proteins, platelets and freshly synthesized matrix molecules form granulation tissue. A floxed person is deprived from this phase, up to an extent that defines the severity of his/her floxing.

Remodeling phase: Remodeling reshapes and strengthens damaged tissue by removing and reforming the matrix and replacing cells. As repair progresses, inflammatory cells disappear, the number of blood vessels and the density of fibroblasts decrease. The proportion of Type I collagen to Type III collagen and the matrix organization increases. Collagen fibers are reoriented in the direction of loading, especially in ligament repair. As you know, there are many medical reports that indicate that quinolones cause a faulty, disoriented remodeling of collagen fibers. Collagen matures and elastin forms; tensile strength increases in normal people but not much in floxed persons, who end up with very weak tendons. The remodeled tissue does not completely resemble the original and thus the mechanical capabilities of that tissue may be altered.

142. THE ANKLES: AN EXAMPLE OF TENDONS SEVERELY HIT BY QUINOLONES

As an example of the implications of a floxing over a joint, in the present edition of this paper, we deal briefly only with the ankle joint and surrounding tissues, although the quinolones also target any other joint in the body.

This picture 26 of the ankle area shows the main tendons that are so commonly damaged by quinolones. It is a class effect, that is to say, a direct injury, irrespective of one's build. The colors mean: Red: achilles tendon; Green: flexor digitorum longus; Blue: posterior tibial tendon; Purple: tibialis anterior.

As stated before, the achilles tendon is not the one most affected by fluoroquinolones. The posterior tibial tendon and the flexors of the toes are much more frequently affected, and more severely, but contrary to the achilles, these tendons do not tend to rupture so easily.

This picture 27 shows a dorsiflexion movement (forcing the toes upwards). This manoeuver stretches the achilles tendon and stresses the posterior tibial tendon and forces the flexor digitorum longus to work.

In severe reactions, this movement performed against resistance on the tip of the toes, can cause extremely incapacitating injuries in the posterior tibial and flexor digitorum group of tendons, that require months to resolve.

This same gesture plus some pronation is done during the contact phase of a normal running activity, which from repetition can cause a devastating damage to the floxed athlete.

According to the studies of the mainstream, industry-prone, researchers, "tendon disorders associated with fluoroquinolones have been estimated to occur at a rate of approximately 15 to 20 per 100,000 patients." The real figures are those stated in table 3 of this paper, that account for 100,000 patients per 100,000 patients if they are given a high, yet approved, therapeutic dose. This is so because of a direct toxic effect.

According to the most widespread manufacturer's version of this problem, out of 100 cases of Achilles disorders, "tendon rupture occurred in 31% and tendinitis in 69%." That is again an incorrect figure because ruptures are much less common than that. They also tell us "the average time between the start of treatment to the onset of symptoms was 13 days, with a range of 1 to 90 days". This means that they have only studied report of ruptures associated with quinolones up to 90 days after the start of treatment, whereas in reality they occur up to many months later.

One of their studies found that 50% of patients with fluoroquinolone-induced tendinitis recovered in 1 month. In another study, 25% of the patients had symptoms that persisted for at least 2 months. So they conclude, "even with early diagnosis and management, discontinuance of the fluoroquinolone, and placement of the tendons at rest, tendinitis heals slowly". We would like to know how slow would they rate the healing of many athletes with unremitting and incapacitating tendinitis after 4, 5 or 7 years of suffering from quinolone toxicity.

There have been reports of patients with fluoroquinolone-associated ruptures of the Achilles tendon in which histopathology was obtained. In one patient who had a rupture, the histopathology showed necrosis along with neovascularization, multiple fissures, and interstitial edema, but no inflammatory cell infiltrate. Histopathology in a second case of ruptured Achilles tendon showed necrosis and cystic changes that are not found in non-drug-associated tendinopathies.

Another patient had pain and swelling of one Achilles tendon 9 months after only a 1-week course of ciprofloxacin (500 mg bid). Biopsy of the tendon was done 4 months after the onset of symptoms. Histologic examination revealed abnormal fiber arrangement and structure with fibrotic areas, hypercellularity with some nuclei being more rounded, neovascularization, and increased glycosaminoglycans in the extracellular matrix. These histologic findings are similar to those in tendon overuse injuries in athletes.

In summary, the damage is extensive and deep on tissues that have very little capacity to regenerate, so the injuries linger on for a long time or become chronic or permanent.

But again, for the industry and their well paid or brainwashed doctors, our group of 42 floxed persons, mostly young healthy athletes with zero previous health problems, is a group of people with special risk factors prone to rupture their tendons. Read what they always add to any report on side effects of quinolones: "....................effects such as tendon ruptures, which may occur in the absence of any medication, particularly since the reported cases frequently had coexisting risk factors. However, clinical reports, histopathologic findings, and an experimental model support a causal relationship between fluoroquinolone use and tendon ruptures". ../.. "Since it is often difficult to establish causality for individual cases, efforts to quantify the risk of tendon ruptures should be viewed as only estimates. There may be a bias in over reporting an association between tendon rupture and fluoroquinolone use, involving cases that might have spontaneously occurred without the medication. On the other hand, the association may be unrecognized, and therefore some cases may be underreported". This sort of disqualification of every study makes doctors not pay attention to ADVERSE EFFECTS at all.

Some researchers are more independent from industry: A case report described an individual who had 9 months of symptoms after a 1-week course of fluoroquinolones: "The histopathology in this patient is particularly noteworthy. Abnormal biopsy findings, consistent with a reactive healing process, were found at 4 months, suggesting these medications may have prolonged effects on tendons. The presence of a cystic change in another patient suggests the pathophysiologic changes associated with fluoroquinolones may not be completely reversible, at least in some cases. The prolonged symptoms associated with increased glycosaminoglycans of the tendon in one patient who had only a 1-week course of antibiotics and the cystic changes in another patient support mechanisms for ruptures to occur long after the antibiotic therapy has been discontinued. An abnormal reactive healing response, or cystic degeneration, may be responsible for our case of the rupture that occurred 6 months after ciprofloxacin therapy was discontinued".

It follows: "Our cases add to the anecdotal evidence suggesting a causal relationship between fluoroquinolones and tendon rupture. Additionally, these cases highlight the broad nature of tendon ruptures that may be associated with this class of medications. Tendons other than the Achilles may be affected by the use of fluoroquinolones. Furthermore, a considerable delay may exist between the administration of a fluoroquinolone and the spontaneous rupture of a tendon. In one of our cases, the delay was 6 months after completion of a course of ciprofloxacin. However, evidence from previous reports suggests that such a delay is possible. The rat model shows that fluoroquinolones may produce inflammation of the tendon within 1 day after their administration. An abnormal healing response to fluoroquinolone-associated inflammation, or cystic degeneration may produce effects months after completion of even a short course of a fluoroquinolone".

The conclusions were: "Fluoroquinolone-associated tendon disruption, including rupture, is well described in the literature. Although the Achilles tendon is the most susceptible site, other tendons may be affected. Typically, spontaneous tendon rupture occurs during or shortly after a course of therapy, but symptoms may occur months after taking fluoroquinolones. Whether fluoroquinolones should be used in patients with a history of tendon problems or with risk factors for the development of tendon ruptures depends on the seriousness of the infection and the alternatives available. Awareness of the association between tendon disorders and fluoroquinolones may lead to enhanced surveillance, which should be extended to sites beyond the Achilles tendon and to periods of months after a course of these antibiotics".

Other problems diagnosed by means of MRI's to the floxed persons that participated in the creation of this flox paper include (for the ankle):

tendinitis of the achilles

tendinitis of the posterior tibial tendon, flexor digitorum and tibialis anterior

tenosynovitis with inflammation of the tendons sheath

synovial infiltrate on tendons

stenosing tenosynovitis in one or more major tendons

partial ruptures of one or more of the major tendons

tendon cysts

Figure 28 (with permission; sorry for the low quality of the file received). Look what "mild" tendinitis and tenosynovitis look like in a young healthy athlete three years and three months after unnecesary exposure to quinolones for a minor suspected bladder infection. Here, you (or your doctor) can see some fluid accumulation and paratendon engorssment in the posterior tibialis tendon and flexor digitorum longus. It is a cross section of the ankle, with the achilles tendon in the lower right side of the picture.

And in the following sequence of a MRI plane of a knee, you can see the irreversible injury caused by ciprofloxacin to a young and previously healthy young man.

This is a cross section (figure 29) (with permission) of the knee of a floxed athlete 41 years old, that have never had any problem before, completely attributable to ciprofloxacin. He also has a MRI taken one year before the intoxication with quinolones, taken as a volunteer for a rutinary study for leg alignments and gait analysis. So there is proof that no problem existed before.

In this image, the central dark item is the femur close to the knee. The upper oval shape is the patella. The two white stripes that appear in the contact between the patella and the femur are the cartilages of both bones. The signal of the cartilage of the patella is engrossed and diffuse, indicating that a first grade osteoarthritis has developed.