With the long-term widespread clinical use of quinolones (QNs), the clinical side effects caused by QNs have gradually manifested, especially the damage to articular cartilage in children has received increasing attention from researchers. In this paper, the relationship between the general properties of quinolones and articular cartilage and some hypotheses of articular cartilage damage caused by quinolones are described as follows.
I. The nature and structure of quinolones
Quinolones (QNs), a class of fully chemically synthesized antibacterial drugs, have a wide antibacterial spectrum, strong antibacterial effect, high bioavailability, good intracellular permeability of tissues, inexpensive, easy to use, and few adverse reactions. This class of drugs is a bactericidal agent, its antibacterial mechanism of action is through the inhibition of bacterial DNA helicase and affect the normal form and function of cellular DNA, so as to achieve the purpose of sterilization. They can be used clinically in patients with acute, chronic, systemic and local bacterial infections, and are particularly effective in the treatment of cystic fibrosis. At present, the representative drugs widely used in clinical practice are ciprofloxacin and ofloxacin.
The chemical structure of quinolones not only determines their antibacterial activity, but also is closely related to their adverse effects, so it is very meaningful to clarify their structure-effect relationship and structure-adverse effect relationship. There are two main parent nuclei structures: quinolone nucleus and 1,8-naphthyridone nucleus (see Figure 1). The fluoroquinolones currently used in clinical practice are developed on the basis of this bicyclic structure. 1-nitrogen is required. Their structures have in common the 3-carboxyl, 4-oxo and 6-fluoro substituents, and different substituents can be attached at other positions.
The substituents on each of the parent nuclei are related to the antibacterial activity of quinolones, their binding to bacterial DNA helicases and their pharmacokinetics. In conclusion, the antimicrobial activity of flovonolone is determined by the quinolone or nalidixone nucleus and the substituents at each position. The substituents usually enhance or decrease the antibacterial activity of the drug and change the pharmacokinetic properties or bioavailability.
II. Basic structure of articular cartilage
Articular cartilage consists of chondrocyte and extracellular matrix, which can be divided into two parts in terms of physical form: one part is solid material, including chondrocytes, collagen, proteoglycans and other glycocalyx; the other part is liquid material, including water and ions. The extracellular matrix accounts for 98%-99% of the total volume and consists mainly of collagen, proteoglycans and water, with small amounts of glycoproteins and other proteins.
Chondrocytes and matrix, the two basic components of articular cartilage, give cartilage its structure, while matrix surrounds the chondrocytes and gives cartilage its elasticity and tension strength.
Third, the effect of quinolones on articular cartilage
Adverse effects of QNs have also been reported more comprehensively in the literature. There are mainly gastrointestinal reactions, central toxicity, cardiotoxicity, skin reactions and phototoxicity, hematotoxicity, hepatotoxicity, nephrotoxicity, etc. All of them are type A adverse reactions, which are related to the dose and can generally recover after stopping the drug.
The toxic effects on cartilage have also been reported more comprehensively. The results of numerous animal experiments in China show that QNs do have a damaging effect on the weight-bearing joints of young animals, and the degree of damage is related to the age of the animals and the concentration of the drug. This part of the scholars believe that there are species differences between humans and animals, and human articular cartilage is not sensitive to QNs, and the clinical treatment dose is much lower than the experimental dose, which advocates clinical use for pediatric treatment
Currently, it is still a controversial issue whether the cartilage toxicity of QNs affects the growth and development of children.
The results of animal tests by Liu Mingliang showed that all the wow nolones are potentially arthrotoxic, but they have a greater risk of inducing arthropathy (especially in weight-bearing joints) in young animals than in adults. Several studies in different species of animals have shown that although the observed clinical signs exhibit reversibility (e.g., altered gait), the histomorphological changes are completely irreversible. It is not known if the early changes in articular cartilage are reversible in animals.
Liu Xiaoyan et al [12] did histological examination of cartilage after quinolone administration and showed that
Light microscopy:Smooth cartilage surface was seen in normal control group with normal arrangement of chondrocytes and their matrix. In the drug administration group, thinning of the cartilage layer, reduction in the number of chondrocytes and their matrix, proliferation of collagen fibers, vascular proliferation, thickening of the cartilage membrane was seen in some cartilages, and calcification of the cartilage capsule was seen after four weeks of discontinuation of the drug.
The above changes were different between different dose groups at the same time of discontinuation, with the high and medium dose groups being more severe and the low dose group being less severe, while there was no significant difference between the same dose groups at different times of discontinuation.
Electron microscopy: The morphology of chondrocytes and their cytoplasm were basically normal in the normal control group. Some of the chondrocytes in the administered group showed nuclear consolidation, loss of chromatin, disintegration of organelles, disappearance of some areas of the cell membrane, and loss of pericellular translucent areas, with only cellular remnants visible.
These changes mentioned above were significantly different between the same dose groups at different discontinuation times, and the lesions were severe when the drug was first discontinued, and were reduced as the discontinuation time increased, and at four weeks of discontinuation, the lesions still had not completely recovered; at the same discontinuation time, there were no significant differences between different dose groups, and the light and electron microscopic results showed that large, medium and small doses could cause damage to chondrocytes.
Also Nagai stated [13] that the characteristic morphological changes of articular cartilage damage caused by QNs are articular cartilage erosion, blister-like degeneration, non-inflammatory exudation and cellular infiltration of the joint cavity; loss of cartilage matrix, formation of cracks and cavities, necrosis, reduction or disappearance of chondrocytes; complete disappearance of non-sulfated chondroitin and decreased type II collagen content; chondrocyte nuclear consolidation, intracellular rough endoplasmic reticulum and mitochondria swelling.
Arthropathy has also been reported regarding clinical application of QNs, but the incidence is low and mostly reversible, usually appearing within days or weeks after administration, with symptoms of joint swelling or manifesting only as pain. For example, Bertino reported that 634 immature patients (mainly with CF disease) treated with ciprofloxacin from 3d to 17a developed reversible arthralgia in 8 cases (1.3%), all women, and all recovered after stopping the drug, but some patients did not develop the same symptoms after re-dosing.
Hampel stated that of 1,795 case reports of 2,030 doses of ciprofloxacin, 31 cases developed joint pain, an incidence of 1.5%. Burkhardt reviewed clinical case reports of 10 minors of 14 to 17a who developed joint pain or swelling with QNs, 7 of which were with pefloxacin, 2 with ciprofloxacin, and 1 with nalidixic acid. In 9 of them, no abnormality was found in cartilage tissue on X-ray examination, and clinical symptoms disappeared after stopping the drug for a period of time. Only one 17-year-old patient with endocarditis and brain abscess developed bilateral knee swelling after 4 weeks of pefloxacin use, and cartilage destruction was found on X-ray examination, followed by bilateral knee arthroplasty and pathological examination of epiphyseal necrosis and synovial and cartilage fibrosis.
In China, according to Qu Fen et al. reported that oral QNs were administered to mid- to late-term pregnant women before induction of labor due to infection, and the fetal cartilage drug concentration was greater than the blood concentration after induction of labor, and the swelling of articular chondrocytes and the expansion of mitochondria and endoplasmic reticulum were found under electron microscopy, which is also good evidence of fetal chondrocyte damage by QNs.
Of course there are some scholars who reported no effect on joints after using quinolones. For example, Martell reported that no adverse effects occurred in 7 young children aged <32 weeks, 2 with ciprofloxacin and 5 with pefloxacin, with no difference in weight, length, or head circumference compared to normal children. In addition, Richard reported [18],108 patients with minor CF disease, using a randomized controlled trial, comparing ciprofloxacin with conventional treatment, there was no statistical difference in the diagnosis of articular cartilage in the 2 groups in terms of MRI and ultrasound before and after treatment.
Therefore, in the face of the controversy over the different results of clinical reports by many scholars, whether quinolone drugs have an effect on articular cartilage remains to be further explored and studied.
Fourth, the hypothesis of the mechanism of the effect of quinolones on articular cartilage
(i) the reduction of free magnesium ions
At present, there are quite a lot of research on this aspect, which may be related to the 3-position carboxyl group and 4-position carbonyl group.
It has been documented since 1950 that in puppies fed a magnesium-deficient diet, gait alterations are very similar to those observed after administration of quinolones as described. In rats, articular cartilage damage observed after 9 days or more of magnesium-deficient diet feeding could not be distinguished from that induced by quinolones [20].QNs are magnesium ion chelators that cause local magnesium ion deficiency, which affects the function of magnesium ion-dependent integrins and impedes signal transduction between integrins and the cellular matrix, leading to degeneration of the cellular matrix and consequent damage to chondrocytes; experiments also found that integrin expression was reduced at the site of injury [21].
It was also found that the use of QNs had a synergistic effect on cartilage damage with a low-magnesium diet, while the addition of magnesium ions to cell cultures partially counteracted the toxicity induced by the administration of QNs in in vitro experiments. Based on these findings, it is hypothesized that the chelation of magnesium in articular cartilage may be important in causing subsequent adverse effects, including the eventual formation of irreversible cartilage damage, due to its blocking of transduction signals for chondrocyte integration at the level of cell surface receptors, which have a role in maintaining the cartilage matrix.
The correlation between the chelating activity of quinolones and their cartilage toxicity is further supported by the fact that quinolone-induced cartilage damage is reduced by magnesium preparations or vitamin E supplementation.
(ii) Production of reactive oxygen species.
Flow cytometry was applied to detect the oxidation of chondrocytes cultured in vitro, and it was found that both ofloxacin and norfloxacin l0 mg・L-1 induced an increase in the production of intracellular reactive oxygen species H2O2, which resulted in the structural destruction of extracellular matrix components (collagen, hyaluronidase) [23].
(iii) Inhibition of DNA topoisomerase.
Chondrocytes are the main target site for the action of QNs, and QNs damage chondrocytes by inhibiting their DNA topoisomerase.
In conclusion, in the face of the increasing number of experimental studies and clinical reports on the adverse effects of quinolones on articular cartilage, there will be great interest in whether these joint complications are actually induced by the toxicity of quinolones. I believe that a large, randomized, double-blind, controlled trial could be conducted in patients with joint symptoms and cystic fibrosis, with short-, medium- and long-term follow-up. A control group was set up to compare in detail the incidence of joint complications between the varenicline group and the other placebo groups. The results obtained will certainly have a positive impact on the determination of whether quinolone has adverse effects on articular cartilage