Paul S. Anderson
For some time in pharmacology courses and review classes I have mentioned the potential for tendinopathy and other related and unrelated pathologies following the use of the fluoroquinolone drug class. The seemingly obvious mechanism is probably too simplistic, but appears to be supported by the recent review paper quoted below:
“The exact pathophysiology of FQ-induced tendinopathy remains elusive; however, some concepts have been suggested. FQs are synthetic antibiotics that act by inhibiting bacterial DNA gyrase (topoisomerase II). DNA gyrase is directly involved in DNA replication and cell division. Theoretically, FQs should not exert a negative effect on human cell lines because the affected bacterial enzymes have little homology with mammalian DNA gyrase. However, it is possible that FQs have a direct cytotoxic effect on enzymes found in mammalian musculoskeletal tissue.
Because animal studies have shown that FQs may damage juvenile weight-bearing joints, most FQs are contraindicated in children and during pregnancy and lactation.
FQs have chelating properties against several metal ions (e.g., calcium, magnesium, aluminum), and have been known to cause direct toxicity to type 1 collagen synthesis and promote collagen degradation.
Experiments on immature laboratory animals (dogs, rabbits, and rats) have shown that FQs cause cartilage damage by inducing necrosis of chondrocytes (36 hours after treatment), disruption of the extracellular matrix, and formation of vesicles and fissures at the articular surface. In-vitro studies in cultured tendon cells have confirmed the clinical observation that FQs can increase the risk of tendon rupture. Under normal circumstances, the rate of matrix turn-over and tendon fibroblast is low.
Other precipitating factors, such as age and corticosteroid use, do not allow the tendon to repair adequately, resulting in irreversible matrix alteration. It has been theorized that FQs disproportionately affect human tendons that have a limited capacity for repair, such as in older patients or structural compromise (i.e., pre-existing tendinopathy or trauma).” [J Clin Aesthet Dermatol. 2010 April; 3(4): 49–54.]
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This of course all remained a theoretical concern until I began to collect patients with FQ related connective tissue (CT) and other system (almost any system can be affected if one considers that mitochondria run everything) disorders. Treatment needs to be targeted at the restoration, detoxification and repair of the mitochondria while directing support at the osseous system as well.
General and specific notes regarding not only mitochondrial but bone and CT supportive and repair therapies are summarized below. This is NOT an exhaustive list, but represents the factors we have seen most helpful in these cases.
Some cases have taken 1-2 IV treatments a week plus supportive oral therapies for 3-5 months before satisfactory resolution was achieved. Most take much less effort and may begin to resolve in 4-6 weeks.
One can peruse the listing of supportive therapies below and craft a personalized therapy based on level of illness, comorbidity and other factors.
I share this in the hope that it helps any clinician struggling with the very difficult issues associated with FQ toxicity.
Therapies Employed with the Greatest Clinical Success:
Mitochondrial Repair:
This is the largest target along with direct CT nutrient support.
Carnitine, Co-Q 10, MCT’s, Ascorbate, Glutathione (GSH), Iron if deficient and optimal thyroid status. Curcumin is helpful if the patient requires any cellular detoxification (do a search for “curcumin chelating mitochondria” and you will see quite a bit.) Other nutrients and support as mentioned below.
Lipoic-Acid Mineral Complex (LAMC) “PolyMVA”:
LAMC, known in North America as the proprietary formula “Poly-MVA” has and is being researched in the areas of metabolic support and mitochondrial repair. We have found it to be clinically helpful in both the oral and IV dose setting.
[Corduneanu O1, Chiorcea-Paquim AM, Garnett M, Oliveira-Brett AM. Lipoic acid-palladium complex interaction with DNA, voltammetric and AFM characterization. Talanta. 2009 Mar 15;77(5):1843-53. doi: 10.1016/j.talanta.2008.10.046. Epub 2008 Nov 6. PMID: 19159808]
[Ramachandran L1, Krishnan CV, Nair CK. Radioprotection by alpha-lipoic acid palladium complex formulation (POLY-MVA) in mice. Cancer Biother Radiopharm. 2010 Aug;25(4):395-9. doi: 10.1089/cbr.2009.0744. PMID: 20701542]
[Sudheesh NP1, Ajith TA, Janardhanan KK, Krishnan CV. Palladium-α-lipoic acid complex attenuates alloxan-induced hyperglycemia and enhances the declined blood antioxidant status in diabetic rats. J Diabetes. 2011 Dec;3(4):293-300. doi: 10.1111/j.1753-0407.2011.00142.x.PMID: 21679354]
[Antonawich FJ1, Fiore SM, Welicky LM. Regulation of ischemic cell death by the lipoic acid-palladium complex, Poly MVA, in gerbils. Exp Neurol. 2004 Sep;189(1):10-5. PMID: 15296831]
[Ajith TA, Nima N, Veena RK, Janardhanan KK, Antonawich F. Effect of palladium α-lipoic acid complex on energy in the brain mitochondria of aged rats. Altern Ther Health Med. 2014 May-Jun;20(3):27-35. PMID:24755568]
[Sudheesh NP1, Ajith TA, Janardhanan KK, Krishnan CV. Effect of POLY-MVA, a palladium alpha-lipoic acid complex formulation against declined mitochondrial antioxidant status in the myocardium of aged rats. Food Chem Toxicol. 2010 Jul;48(7):1858-62. doi: 10.1016/j.fct.2010.04.022. Epub 2010 Apr 20. PMID: 20412826]
[Sudheesh NP1, Ajith TA, Janardhanan KK, Krishnan CV. Palladium alpha-lipoic acid complex formulation enhances activities of Krebs cycle dehydrogenases and respiratory complexes I-IV in the heart of aged rats. Food Chem Toxicol. 2009 Aug;47(8):2124-8. doi: 10.1016/j.fct.2009.05.032. Epub 2009 Jun 13. PMID: 19500641]
Hyperbaric Oxygen Therapy:
This treatment increases the oxygen delivery gradient from the plasma to the cell and then the mitochondria. In our clinical experience we have found that the combination of appropriately dosed IV nutrients delivered the same day as hyperbaric therapy increases the effect of both therapies on the patients healing. In addition to our clinical experience experts in the field of hyperbaric medicine agree that it can be a significantly helpful addition to the treatment protocol.
[Dave KR, Prado R, Busto R, Raval AP, Bradley WG, Torbati D, Pérez-Pinzón MA. Hyperbaric oxygen therapy protects against mitochondrial dysfunction and delays onset of motor neuron disease in Wobbler mice. Neuroscience. 2003;120(1):113-20. PMID: 12849745]
[http://www.hbot.com/blog/edward-lucarini/hyperbaric-oxygen-treatment-mitrochondrial-cytopathies]
Testosterone:
It is noted in literature that testosterone levels and tendinopathies have a likely relationship. Clinically we do see faster repair in prolotherapy procedures aimed at tendinopathy with the addition of small testosterone doses. At the least a male or female with low testosterone will, based on our clinical observations, have faster resolution of these type issues with adequate testosterone repletion.
Minerals and Trace elements etc:
Ca, Mg, Zn, Mn, Cu …
When one considers the chelating effect mentioned above of the FQ class the importance of repletion of not only Ca/Mg but also the critical trace elements for CT function as well as for GSH recycling. These we also used as IV additives, but oral support is important as well.
[Dimitrov NV, MacDonald D, Malovrh MM. Bioavailability of micronutrients in humans. J Appl Nutr 1997; 49:56-65.]
[Leach RM. Role of manganese in mucopolysaccharide metabolism. Fed Proc 1971; 30:991.]
[Milne DB. Assessment of zinc and copper nutritional status in man. Nutr MD 1987; 13:1-2.]
Other nutrients:
Optimal B-Vitamin status as well as correction of any methyl cycle defects is an underlying support necessity. Oft ignored Vitamin K has a great deal to do with the proper movement of minerals in and out of repairing bone and CT. Additionally the repletion of Vitamin A and D status is required.
Glutathione:
We use IV glutathione in all cases, but oral GSH support (ALA, NAC etc) can be of aid as well.
Some data suggesting a regulatory role in CT development detoxification / protection and maintenance via proper GSH activity. At the least it is helpful in restoring antioxidant balance.
[Nishida T, Emura K, Kubota S, Lyons KM, Takigawa M. CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP). J Bone Miner Res. 2011 Feb;26(2):351-63. doi: 10.1002/jbmr.222.]
[Lieshout et. Al. Localization of glutathione S-transferases a and p in human embryonic tissues at 8 weeks gestational age. Human Reproduction vol.13 no.5 pp.1380–1386, 1998]
Ascorbate:
- Ascorbic acid (Ascorbate) has a major influence on connective tissue metabolism and has been widely studied.
- Ascorbic acid (AA) is a cofactor for many of the enzymatic reactions in synthetic processes.
- Degradation of collagen outpaces synthesis; new collagen cannot replace losses and results in disease (scurvy).
- In connective tissue, Ascorbate is involved in several metabolic reactions.
- Iron is necessary for a variety of enzymatic reactions, and AA protects iron from oxidation. AA preserves the enzyme-iron complex that catalyzes the reaction for intracellular assembly of collagen.
- Underhydroxylated collagen is unable to fold into a stable triple-helix and therefore is subject to increased intracellular degradation. The turnover rate of collagen is then in negative balance and degradation outpaces the rate of synthesis.
[Fisher E, McLennan SV, Tada H, et al. Interaction of ascorbic acid and glucose on production of collagen and proteoglycan by fibroblasts. Diabetes 1991; 40:371-376.]
[Berg RA, Kerr JS. Nutritional aspects of collagen metabolism. Annu Rev Nutr 1992; 369-390.]
[Russell JE, Manske PR. Ascorbic acid requirement for optimal flexor tendon repair in vitro. J Orthop Res, 1991; 9:714-719.]
Amino Acids:
Proline, lysine, carnitine, taurine and a number of other substrates are required.
Vitamin K:
Bone Mineralization / CT Support:
- Osteocalcin – (Increases bone mineralization)
- Matrix GLA Protein – (Decreases soft tissue calcification AND increases normal bone growth and development)
- Protein S – (Believed to increase bone density)
[Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr. 1995;15:399-417.]
[Booth SL. Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore. Nutr Rev. 1997;55(7):282-284.]
For more information register and see the CE webinar on this topic here:
https://www.consultdranderson.com/product/fluoroquinolone-toxicity/