ADAM17 inhibiittorit kehittelyssä (2018)

https://www.researchgate.net/publication/320828392_Recent_Advances_in_ADAM17_Research_A_Promising_Target_for_Cancer_and_Inflammation Marcia Moss:
Abstract
Since its discovery, ADAM17, also known as TNF α converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme. ADAM17 inhibitors have broad therapeutic potential, with properties ranging from tumor immunosurveillance and overcoming drug and radiation resistance in cancer, as treatments for cardiac hypertrophy and inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. This review focuses on substrates and inhibitors identified more recently for ADAM17 and their role in cancer and inflammation.

cGAS- cGAMP- STING signaalitiestä ja sen merkityksestä dsDNA materian sensorina

http://jem.rupress.org/content/215/5/1287



 http://jem.rupress.org/content/jem/215/5/1287/F2.medium.jpg
 

Antisheddaasi strategia esim ADAM10/ADAM17 inhibiittorit ?

Cancer Biol Ther. 2016 Aug; 17(8): 870–880.

Published online 2016 Apr 26. doi: 10.1080/15384047.2016.1177684

PMCID: PMC5004698

PMID: 27115328

The ADAMs family of proteases as targets for the treatment of cancer

Maeve Mullooly,^a,b Patricia M. McGowan,^b,c John Crown,^d and Michael J. Duffy^b,e

Author information Article notes Copyright and License information Disclaimer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004698/

Conclusion

Although several different ADAMs have been implicated in cancer development and evolution, the strongest evidence is found with ADAM17. Indeed, as mentioned above, there is substantial preclinical evidence supporting the involvement of this ADAM in cancer development or metastasis. These findings have encouraged the development of multiple inhibitors against ADAM17 for their potential use in the treatment of cancer. However, because of the multiplicity of actions mediated by ADAM17, it might be expected that long-term blockage of its protease activity would cause toxicity such as depressed immunity and an increased risk of infection. Such toxicity however, did not appear to emerge in the short-term animal model studies reported to date. Furthermore with the only ADAM10/17 inhibitor so far investigated in clinical trials, i.e., INCB7839 in phase I/II trials, no major toxicity was reported.^40,41 Indeed, INCB7839, in contrast to the early MMP inhibitors investigated for potential anti-cancer activity, did not cause musculoskeletal side effects.^35,36 To-date, monoclonal antibodies against ADAM17 do not appear to have undergone studies in clinical trials. These biological inhibitors however, might be expected to exhibit more specific targeting than low molecular weight compounds and thus have less toxicity. The time may now be ready to test ADAM17 monoclonal antibodies in clinical trials.

Semaforiineista ja niiden pilkkoutumisesta. ADAMTS1

Tässä lähdeartikkelissa maintiaan ADAMTS1 pilkkomassa esiin  SEMA3C.stä   N-erminaalista fragmenttia, jota erittyy  ECM.stä ja  joka vaikuttaa  tuumorin migroitumista ja  etäkasvua.  ADAMTS1 on jo aiemmin tunnettu  mm syöpäkakeksiassa ilmenevänä  metalloproteinaasina.
Metalloproteinaaseja,   niiden   valtavaa vaikutusta   ei vielä pystytä hallitsemaan lääkkeellisesti.


https://www.dovepress.com/impact-of-semaphorin-expression-on-prognostic-characteristics-in-breas-peer-reviewed-fulltext-article-BCTT
Ramesh Butti, Totakura VS Kumar, Ramakrishna Nimma, Gopal C Kundu

Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Savitribai Phule Pune University, Pune, India

Abstract: Breast cancer is one of the major causes of cancer-related deaths among women worldwide. Aberrant regulation of various growth factors, cytokines, and other proteins and their receptors in cancer cells drives the activation of various oncogenic signaling pathways that lead to cancer progression. Semaphorins are a class of proteins which are differentially expressed in various types of cancer including breast cancer. Earlier, these proteins were known to have a major function in the nerve cell adhesion, migration, and development of the central nervous system. However, their role in the regulation of several aspects of tumor progression has eventually emerged. There are over 30 genes encoding the semaphorins, which are divided into eight subclasses. It has been reported that some members of semaphorin classes are antiangiogenic and antimetastatic in nature, whereas others act as proangiogenic and prometastatic genes. Because of their differential expression and role in angiogenesis and metastasis, semaphorins emerged as one of the important prognostic factors for appraising breast cancer progression.

Keywords: breast cancer, tumor microenvironment, semaphorins, plexins, neuropilins, cancer stem-like cells, prognostic factor, angiogenesis, metastasis, epithelial to mesenchymal transition, vascular endothelial growth factor

• "....The other members of class 3 semaphorins, such as Sema3C and Sema3E, are overexpressed in breast cancer cells and exhibit tumor-promoting function. Zhu et al have shown that siRNA-mediated knockdown of Sema3C in breast cancer cells abolishes cell proliferation and migration.⁴⁹ Interestingly, the p65-Sema3C fragment that is generated from cleavage of full-length Sema3C by FPPC shows tumor-promoting role. Full-length Sema3C shows inhibitory effect on lymphangiogenesis and metastasis in mice breast tumor xenografts (Figure 2).⁵⁰ Nonetheless, the metalloprotease ADAMTS1 induces Sema3C cleavage from ECM and converts it to a soluble form, so that it diffuses and promotes tumor cell migration.⁵¹ The role of Sema3C in regulation of tumor progression also depends on the type and nature of cancers. For example, Sema3C promotes pancreatic cancer progression through ERK1/2 signaling pathway.⁵² However, the molecular mechanism by which Sema3C promotes breast cancer progression is unclear.

. (Figure 1).²⁶ Semaphorins also harbor other distinctive protein domains such as basic charged C-terminal domain, thrombospondin repeats, and immunoglobulin (Ig)-like domains. Class 3 semaphorins are characterized by a conserved, basic charged domain at the C-terminal region and these are secreted semaphorins (Figure 1).¹⁰ Class 4–7 semaphorins are cell membrane-anchored proteins that are characterized by their distinct structural elements. Thrombospondin repeats are present in case of class 5 semaphorins, whereas a glycophosphatidylinositol anchor is present in class 7 semaphorins (Figure 1). Membrane-anchored semaphorins can be further processed into soluble forms through the proteolytic cleavage at a specific site as in the case of class 4 and 7 semaphorins by ADAMTS1 and furin-like proprotein convertase (FPPC; Figure 1).^27,28

Figure 2 Semaphorin signaling in breast cancer.

Notes: Sema3A interacts with NRP1 receptor to induce PTEN/FOXO 3a-dependent MelCAM expression, which, in turn, inhibits tumor growth and angiogenesis. Sema3B binds to NRP1 and induces apoptosis by inhibiting PI3K/Akt signaling. Full-length Sema3C interacts with NRP2 on the lymphatic endothelial cells in tumor and suppresses lymphangiogenesis and metastasis by inhibiting VEGF-C–dependent ERK1/2 and Akt signaling. Full-length Sema3C undergoes proteolytic cleavage by FPPC to form p65-Sema3C, which promotes cancer cell survival. Sema4D binds to plexin-B1 and activates ErbB2, which, in turn, phosphorylates plexin-B1. Phosphorylated plexin-B1 induces migration by activating RhoA GTPase. Cleaved p61-Sema3E binds to plexin-D1 to promote metastasis through ErbB2-dependent MAPK signaling. Sema3E binds to plexin-D1 to inhibit apoptosis by disrupting the interaction between plexin-D1 and NR4A, which is known to induce caspase-9–mediated apoptosis. Sema7A interacts with integrin β1 on the cancer cells to promote invasion. Tumor-derived Sema7A binds with integrin β1 on the macrophages to promote angiogenesis by producing CXCL2, CXCL1, and MMP-9.

Abbreviations: ERK1/2, extracellular signal-regulated kinases1/2; FPPC, furin-like proprotein convertase; MMP, matrix metalloproteinase; PTEN, phosphatase and tensin homolog; VEGFR, vascular endothelial growth factor receptor.

ADAMTS1 lisätietoa: pilkkoo semaforiinia SEMA3C ja edistää metastasoitumista

https://www.ncbi.nlm.nih.gov/pubmed/?term=ADAMTS1+%2C+semaphorins

J Biol Chem. 2010 Jan 22;285(4):2463-73. doi: 10.1074/jbc.M109.055129. Epub 2009 Nov 13.

The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration.

Esselens C¹, Malapeira J, Colomé N, Casal C, Rodríguez-Manzaneque JC, Canals F, Arribas J.Abstract

 

Metastasoituminen on sekventiaalinen prosessi, jossa soluille salliutuu  siirtyminen primäärituumorista muualle ksvamaan. Metalloproteinaaseja on ja kauan pidetty avainkomponenteina metastaattisessa ohjelmoitumisessa, koska niillä on kykyä  pilkkoa monenlaisia 

solunulkoisia signaloivia ja  adhesoituvia molekyylejä. Kuitenkin joidenkin metalloproteinaasien kuten ADAMTS1:n  funktio ei ole  ollut aivan selvä ja se näyttää riippuvan  solumiljööstä ja/tai tuumorin etenemisen  vaiheesta. Tässä artikkelin työssä haluttiin luonnehtia ADAMTS1 metalloproteaasin  funktioita ja suoritettiin kaksi  alternatiivista proteomiin perustuvaa tutkimusta tunnistettaessa  metalloproteinaasin uusia substraatteja. Kummatkin tutkimukset osoittivat, että ADAMTS1:n yli-ilmeneminen johti SEMA3C- semaforiinin  vapautumiseen extrasellulaarisesta  matriksista.  Vaikka tiedetäänkin jo, että semaforiinit ovat  aksonin ohjauksen säätelijöitä, on myös kertyvää näyttöä siitä, että ne osallistunevat myös tuumorin etenemiseen. Tässä työssä osoitettiin, että ADAMTS1:n indusoima semaforiinin SEMA3C  pilkkoutuminen edisti rintasyöpäsolujen migroitumista. Tämä viittaa siihen,  että näiden molekyylien samanaikaisilmenemä tuumoreissa saattaa osaltaan vaikutata  metastaattiseen ohjelmoitumiseen. 

• Metastasis is a sequential process that allows cells to move from the primary tumor and grow elsewhere. Because of their ability to cleave a variety of extracellular signaling and adhesion molecules, metalloproteases have been long considered key components of the metastatic program. However, the function of certain metalloproteases, such as ADAMTS1, is not clear and seems to depend on the cellular environment and/or the stage of tumor progression. To characterize the function of ADAMTS1, we performed two alternative proteomic approaches, difference gel electrophoresis and stable isotope labeling by amino acids in cell culture, to identify novel substrates of the metalloprotease. Both techniques showed that overexpression of ADAMTS1 leads to the release of semaphorin 3C from the extracellular matrix. Although semaphorins are well known regulators of axon guidance, accumulating evidence shows that they may also participate in tumor progression. Here, we show that the cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program.

PMID:

19915008

PMCID:

PMC2807303

DOI:

10.1074/jbc.M109.055129

[Indexed for MEDLINE]

Free PMC Article

Muistiin  26.2. 2019 

Semaphorin perhe, SEMA4D

A different approach to inhibit tumor angiogenesis with anti-Sema4D antibodies was presented by Maurice Zauderer (Vaccinex). Sema4D is a member of the semaphorin family of proteins first identified as mediators in axon guidance. Sema4D is involved in the regulation of several different physiological processes, one of which is endothelial and epithelial cell migration. It also enhances CD40-induced immune and inflammatory cell activation, inhibits neurite extension and axon regeneration, and promotes survival and differentiation of oligodendrocyte precursor cells. As a multifunctional target, Sema4D may be of therapeutic relevance in numerous indications, e.g., cancers, rheumatoid arthritis, multiple sclerosis. Results from mouse models suggest that Sema4D antibodies could indeed have wide applicability. For example, a mouse Sema4D-specific antibody, MAb67, was as efficient as the clinically validated anti-TNF therapy etanercept (Enbrel^®) in haltling disease progression in an established collagen-induced arthritis model. Besides reducing the inflammatory response, the anti-Sema4D antibody also inhibited bone erosion. This may be explained with recent findings that Sema4D mediates osteoclast-osteoblast communication. In addition, Sema4D inhibition was also effective in an EAE model, where the clinical score was reduced by 50% by anti-Sema4D antibody treatment initiated during the onset of the disease.
Due to the abundant Sema4D expression on T cells and to a lesser extent on B cells, monocytes and dendritic cells, Vaccinex chose an IgG4 isotype for their humanized anti-Sema4D antibody VX15/2503 to avoid immune cell depletion. VX15/2503 inhibits membrane-bound human Sema4D, as well as a soluble Sema4D that is generated from the membrane-bound form by ectodomain shedding. VS15/2503 was shown to block Sema4D-induced collapse of the actin cytoskeleton and apoptosis in oligodendrocyte precursor cells in vitro. It also neutralized Sema4D mediated inhibition of oligodendrocyte precursor cell maturation into myelin basic protein-producing cells and reverted the inhibition of remyelation following lysophosphatidyl choline induced injury in postnatal brain slice cultures in vitro, thus indicating possible applications in multiple sclerosis patients.

Cu-metalloproteiinit

https://www.sciencedirect.com/science/article/pii/B9780080453828001805

STING- kohteena semaforiini SEMA4D..Sheddaasin ADAM17 osuus.

http://www.jbc.org/content/early/2018/04/04/jbc.RA118.002175.full.pdf
ADAM17 sheddaasen aktivaatio liittyy STING aktivaatioon (  STING on intgrasellulaarinen  organelli) .
Miten kytkeytyy MMP- perheen aktivoitumiset semaforiineihin, jotka esiintyvät kalvossa ECM.ssä  ja liukoisena extrasellulaaristi?

https://www.researchgate.net/figure/Current-model-of-activation-of-proMMP-2-by-MT1-MMP_fig1_273792275

 http://www.jbc.org/content/293/20/7717.abstract

Activation of stimulator of interferon genes (STING) induces ADAM17-mediated shedding of the immune semaphorin SEMA4D

1. Kou Motani¹ and
2. Hidetaka Kosako

1. From the Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan

1. ↵1 To whom correspondence should be addressed. Tel.: 81-88-634-6411: Fax. 81-88-634-6405; E-mail: motani{at}tokushima-u.ac.jp.

1. Edited by Luke O'Neill
   
   

TIIVISTELMÄN suomennosta. Interferonigeenien stimulaattori STING on endoplasmisessa retikulumissa sijaitseva kalvoproteiini, joka välittää isäntäsolun  solulimassa esiityvää dsDNA:ta kohtaan viriävää  luonnollista immuunivastetta ja tulehduksellista vastetta.
STING aktivoituu  syklisillä dinukleotideilla ja sitten translokoituu Golgin laitteeseen. Tämä tapahtuma triggeröi  STING:in asettumiseen  alavirran TBK1- entsyymin yhteyteen ( TANK-sitovan kinaasi-1). Tästä koostumuksesta aiehutuu IRF3-fosforylaatio ja se taas indusoi  tyypin 1 interferoneja ja kemokiinigeenejä. ( Tämä on tapahtuma jka on yleisimmin kuvattu STING- vasteista)
STING  pystyy välittämään  myös tulehduksellisia vasteita IRF3.sta riippumatta, muta näitä teitä ei ole  laajemmin tutkittu- ( Sytosolisen kartan  valkoinen täplä!  Siinä näyttää piilevan  yhteys voimakkaaseen ja  lääketieteellisesti vielä  kontrolloimattomaan  järjestelmään, jonka muodostavat  erilaiset matrixmetalloproteinaasit ja metallopeptidaasit!)

Tässä työssä tutkijat analysoivat makrofagin sekretomia tunnitaen  proinflamamtorisia tekijöitä, joita  pääsee  vapautumaan extrasellulaariseen väliaineeseen STING- aktivaatiossa- siis solun ulkopuolelle!
Kaiken kaikkiaan tutkijat havaitsivat 1299 protiinia makrofagiviljelmän supernatanteista ja niistä 23  oli merkitsevästi  lisääntynyt, kun STING aktivoitui.  Nämä proteiinit  käsittivät IRF-3,stä  riippuvia sytokiineja ja aimemin tuntemattomia  STING:in vaikutuskohteita kuten imuunisemaforiini SEMA4D/CD100, jolla on proinflammatorisia sytokiinin kaltaisia vaikutuksia. Mutta SEMA4D -geeni ei kutienkaan säätynyt ylös sILLÄ  tavalla kuin kanonisten sytokiinien geenit tässä STING- aktivaatiossa.  Mutta mitä sensijaan  sitten tapahtui?
 STING-aktivaatiosta  tapahtui seuraavaa: Solukalvoon sitoutunut SEMA4D pilkkoutui liukoiseen muotoon ja tämä viittaisi posttranslationaaliseen irroittuskoneistoon. (Shedding,  irtoaminen, irti lehteily, vuotaminen solusta; Sheddaasi  on tekijä joka saa tämän lehteilyn, irtoilun aikaan) . Tässä tapauksessa sheddaasina toimi ADAM17 metallopeptidaasi.  Semaforiinin 4D  irtoilu solusta saatiin  blokeerautumaan sheddaasin ADAM17  estäjällä TMI-1. Sen sijaan TBK-1- estäjällä ei ollut  thän m itään vaikutusta.

Näistä  tuloksista päätellään , että STING aktivoi ADAM17  ja tästä aktivaatiosta tuottuu liukoista proinflammatorista  semaforiinia SEMA4D aivan  itsenäisesti riippumatta STING:n   tunnetusta  vaikutustiestä,   TBK1/IRF3 väkitteisestä transkriptiotiestä.

• Abstract 

• Stimulator of interferon genes (STING) is an endoplasmic reticulum–resident membrane protein that mediates cytosolic pathogen DNA–induced innate immunity and inflammatory responses in host defenses. STING is activated by cyclic di-nucleotides and is then translocated to the Golgi apparatus, an event that triggers STING assembly with the downstream enzyme TANK-binding kinase 1 (TBK1). This assembly leads to the phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3), which in turn induces expression of type-I interferon (IFN) and chemokine genes.
•  STING also mediates inflammatory responses independently of IRF3, but these molecular pathways are largely unexplored. 
• Here, we analyzed the RAW264.7 macrophage secretome to comprehensively identify proinflammatory factors released into the extracellular medium upon STING activation. In total, we identified 1299 proteins in macrophage culture supernatants, of which 23 were significantly increased after STING activation. These proteins included IRF3-dependent cytokines, as well as previously unknown targets of STING, such as the immune semaphorin SEMA4D/CD100, which possesses proinflammatory cytokine-like activities. Unlike for canonical cytokines, the expression of the SEMA4D gene was not up-regulated.

•  Instead, upon STING activation, membrane-bound SEMA4D was cleaved into a soluble form, suggesting the presence of a post-translational shedding machinery. Importantly, the SEMA4D shedding was blocked by TMI-1, an inhibitor of the sheddase ADAM metallopeptidase domain 17 (ADAM17) but not by the TBK1 inhibitor BX795. These results suggest that STING activates ADAM17 and that this activation produces soluble proinflammatory SEMA4D independently of the TBK1/IRF3-mediated transcriptional pathway. 

Muistiin  27.2. 2019 

Fluorokinoneista ja aortasta. Uusi asenne fluorokinoloneihin 2019

 Henkilökohtaisestikin  asia on tärkeä ( Olen käyttänyt ciprofloxacin ja norfloxacin- lääkekuureja vuosien varrella  ja olen näihin asti pitänyt niitä erinomaisina  antibiootteina, myös itselleni,  koska en siedä penisilliiniä tai  laajakirjoisia  penisilliinejä, erytromysiiniäkään  tuskin).


Search results

Items: 13

• Showing results for fluoroquinolones, aorta aneurysm,dissection. Your search for Fluoroquinolones, aorta aneurysma, dissecation retrieved no results.

Select item 305651531.    FQ, LEVOFLOXACIN

What Fluoroquinolones Have the Highest Risk of Aortic Aneurysm? A Case/Non-case Study in VigiBase®.

Sommet A, Bénévent J, Rousseau V, Chebane L, Douros A, Montastruc JL, Montastruc F.

J Gen Intern Med. 2018 Dec 18. doi: 10.1007/s11606-018-4774-2. [Epub ahead of print] No abstract available.

aortic aneurysms; aortic dissection; fluoroquinolones; levofloxacin

PMID:30565153

DOI:10.1007/s11606-018-4774-2

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Select item 304781672.    FQ

Patients at Risk for Aortic Rupture Often Exposed to Fluoroquinolones during Hospitalization.

Frankel WC, Trautner BW, Spiegelman A, Grigoryan L, LeMaire SA.

Antimicrob Agents Chemother. 2019 Jan 29;63(2). pii: e01712-18. doi: 10.1128/AAC.01712-18. Print 2019 Feb.

Several studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection (AAD). Because patients with AAD or Marfan syndrome are at increased risk for aortic rupture, we performed a retrospective cohort study to determine the prevalence of systemic fluoroquinolone exposure and predictors of fluoroquinolone use in these patients. Data were obtained from the advisory board billing and administrative database, which contained information on 22 million adult hospitalizations in the United States for the study period (2009 to 2015). International Classification of Diseases (9/10) and Current Procedural Terminology codes were used to identify patients who had AAD or Marfan syndrome or underwent aortic repair. We identified 136,789 admissions for AAD, which involved 99,818 unique patients, 20% of whom received fluoroquinolone during a hospital admission. Of the 7,045 patients with dissection, 18% were exposed to fluoroquinolone. Of the 27,876 AAD patients who underwent aortic repair, 19% received fluoroquinolone during a hospitalization before the repair. In the AAD patients, having a diagnosis of pneumonia or urinary tract infection increased the likelihood of receiving fluoroquinolone during admission by 46% and 40%, respectively (P < 0.001). Additionally, we identified 2,871 admissions for Marfan syndrome, which involved 1,872 patients, 14% of whom received fluoroquinolone during an admission. In these patients, pneumonia and urinary tract infections also increased the risk of fluoroquinolone exposure. If the deleterious effects of fluoroquinolone on aortic integrity are substantiated, reducing fluoroquinolone use in hospitalized patients with aortic disorders will become an urgent safety issue for antibiotic stewardship programs.

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Select item 303096823.   FQ

Fluoroquinolones and the risk of aortopathy: A systematic review and meta-analysis.

Noman AT, Qazi AH, Alqasrawi M, Ayinde H, Tleyjeh IM, Lindower P, Bin Abdulhak AA.

Int J Cardiol. 2019 Jan 1;274:299-302. doi: 10.1016/j.ijcard.2018.09.067. Epub 2018 Sep 21.

To investigate the association between fluoroquinolones use and development of aortopathy. METHODS: A systematic review and meta-analysis was conducted following PRISMA and MOOSE guidelines for reporting systematic reviews of observational studies. Multiple databases were searched and two authors independently screened studies for eligibility. Newcastle Ottawa scale was used to assessed the quality of included studies. Primary outcome of interest was development of aortic aneurysm or dissection among fluoroquinolones users in comparison to non-users. An inverse variance model meta-analysis was used to pool odds ratio or hazards ratio from included studies to calculate the overall effect estimate. Pre specified subgroups analyses were also conducted to explore sources of heterogeneity. RESULTS: Three observational studies that enrolled 941,639 subjects met the inclusion criteria and were included in the final analysis. All studies were of a good methodological quality. Current use of fluoroquinolones, defined as within 60 days from development of the primary outcome, was associated with significantly elevated risk of developing aortic aneurysm and/or dissection in comparison to controls, (OR = 2.04; 95% CI [1.67, 2.48]). There was only a mild degree of between study heterogeneity, I² = 33%. The association remains robust among all subgroups analyses. CONCLUSION:
Our findings indicate that current fluoroquinolone use was significantly associated with increased risk of aortic aneurysm and dissection. Health care providers need to be aware of this serious association and use fluoroquinolones judiciously in order to minimize the risk of the serious sequela of aortopathy.

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Select item 302907364.    FQ

Risks associated with the use of fluoroquinolones.

DeLaney MC.

Br J Hosp Med (Lond). 2018 Oct 2;79(10):552-555. doi: 10.12968/hmed.2018.79.10.552.

Fluoroquinolones are a widely used class of antibiotic that are effective in treating a wide variety of pathogens. Despite their popularity there is increasing concern regarding the potential complications associated with these agents. Patients who take a fluoroquinolone have an increased risk of developing tendinopathy, peripheral neuropathy, and aortic aneurysm or dissection. Providers should consider the risk of these potential complications before using these medications. PMID:30290736 DOI: 10.12968/hmed.2018.79.10.552

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Select item 302133315.     FQ

Do Fluoroquinolones Increase the Risk of Aortic Aneurysms and Aortic Dissection?

Singh S, Nautiyal A.

J Am Coll Cardiol. 2018 Sep 18;72(12):1379-1381. doi: 10.1016/j.jacc.2018.07.018. No abstract available.

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Select item 302133306.     FQ

Oral Fluoroquinolone and the Risk of Aortic Dissection.

Lee CC, Lee MG, Hsieh R, Porta L, Lee WC, Lee SH, Chang SS.

J Am Coll Cardiol. 2018 Sep 18;72(12):1369-1378. doi: 10.1016/j.jacc.2018.06.067.

Previous studies raised safety concerns on the association between fluoroquinolone treatment and serious collagen disorders, aortic aneurysm and dissection (AA/AD). OBJECTIVES: This study sought to evaluate this association via a case-crossover analysis in a large national administrative database. METHODS: A case-crossover design was used to compare the distributions of fluoroquinolone exposure for the same patient across a 60-day period before the AA/AD event (hazard period) and 1 randomly selected 60-day period (referent period) between 60 to 180 days before the AA/AD events. In the sensitivity analysis, the authors repeated the main analysis using a 1:5 ratio of hazard period to referent period, to adjust for the effect of time-variant confounders. A disease-risk score-matched time control analysis was performed to investigate the potential time-trend bias. The risks were calculated by a conditional logistic regression model. RESULTS:
A total of 1,213 hospitalized AA/AD patients were identified between 2001 and 2011. In the main case-crossover analysis, exposure to fluoroquinolone was more frequent during the hazard periods than during the referent periods (1.6% vs. 0.6%; odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.14 to 6.46). In the sensitivity analysis, after adjustment for infections and co-medications, the risk remains significant (OR: 2.05; 95% CI: 1.13 to 3.71). An increased risk of AA/AD was observed for prolonged exposure to fluoroquinolones (OR: 2.41 for 3- to 14-day exposure; OR: 2.83 for >14-day exposure). Susceptible period analysis revealed that the use of fluoroquinolone within 60 days was associated with the highest risk of AA/AD. In the case-time-control analysis, there was no evidence that the observed association is due to temporal changes in fluoroquinolone exposure. CONCLUSIONS: Exposure to fluoroquinolone was substantially associated with AA/AD. This risk was modified by the duration of fluoroquinolone use and the length of the hazard period.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. KEYWORDS:

aortic and arterial diseases; aortic aneurysm; aortic dissection; fluoroquinolones

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Select item 300468097. FQ, CIPROFLOXACIN

Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice.

LeMaire SA, Zhang L, Luo W, Ren P, Azares AR, Wang Y, Zhang C, Coselli JS, Shen YH.

JAMA Surg. 2018 Sep 1;153(9):e181804. doi: 10.1001/jamasurg.2018.1804. Epub 2018 Sep 19.

Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD. Objective:
To examine the effect of ciprofloxacin on AAD development in mice. Design, Setting, and Participants: In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells. Results: No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase (MMPs)  levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression.  Conclusions and Relevance:
Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

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Select item 203014248.

Polycystic Kidney Disease, Autosomal Dominant.

Harris PC, Torres VE.

In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2002 Jan 10 [updated 2018 Jul 19].

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Select item 300028129.    FQ

Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder?

Demetrious JS.

Chiropr Man Therap. 2018 Jul 9;26:22. doi: 10.1186/s12998-018-0193-z. eCollection 2018.

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Select item 2951988110.   FQ

Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study.

Pasternak B, Inghammar M, Svanström H.

BMJ. 2018 Mar 8;360:k678. doi: 10.1136/bmj.k678. Abstract OBJECTIVE:

To investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection. DESIGN:
Nationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection. SETTING:
Sweden, July 2006 to December 2013. PARTICIPANTS:
360 088 treatment episodes of fluoroquinolone use (78%ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088). MAIN OUTCOME MEASURES:
Cox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment. RESULTS:

Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection. CONCLUSIONS: In a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. Comment in

• Fluoroquinolones and the aorta. [BMJ. 2018]
  BMJ. 2018 Mar 8;360:k988. doi: 10.1136/bmj.k988. Fluoroquinolones and the aorta.
  Juurlink DN¹. Comment on
  • Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. [BMJ. 2018]

  PMID:

  29519782

  DOI:

  10.1136/bmj.k988

PMID Free PMC Article

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Select item 2873920011.    FQ

Aortic Dissection and Aortic Aneurysms Associated with Fluoroquinolones: A Systematic Review and Meta-Analysis. Singh S, Nautiyal A.

Am J Med. 2017 Dec;130(12):1449-1457.e9. doi: 10.1016/j.amjmed.2017.06.029. Epub 2017 Jul 21. Review. Abstract BACKGROUND: Our objective was to evaluate the association between fluoroquinolone use and aortic dissection or aortic aneurysm in a systematic review and meta-analysis. METHODS: We searched Medline, Embase, and Scopus from inception to February 15, 2017. We selected controlled studies for inclusion if they reported data on aortic dissection and aortic aneurysm associated with fluoroquinolones exposure versus no exposure. Data were extracted by 2 independent reviewers, with disagreements resolved through further discussion. We assessed the quality of studies using the Newcastle-Ottawa Scale for observational studies and the strength of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. The odds ratios (ORs) from observational studies were pooled using the fixed-effect inverse variance method, and statistical heterogeneity was assessed using the I² statistic. RESULTS: After a review of 714 citations, we included 2 observational studies in the meta-analysis. Current use of fluoroquinolones was associated with a statistically significantly increased risk of aortic dissection (OR, 2.79; 95% confidence interval [CI], 2.31-3.37; I² = 0%) and aortic aneurysm (OR, 2.25; 95% CI, 2.03-2.49; I² = 0%) in a fixed-effects meta-analysis. The unadjusted OR estimates and sensitivity analysis using a random-effects model showed similar results. We rated the strength of evidence to be of moderate quality. The number needed to treat to harm for aortic aneurysm for elderly patients aged more than 65 years who were current users of fluoroquinolones was estimated to be 618 (95% CI, 518-749). CONCLUSIONS: Evidence from a small number of studies suggests that exposure to fluoroquinolones is consistently associated with a small but significantly increased risk of aortic dissection and aortic aneurysm. Copyright © 2017 Elsevier Inc. All rights reserved. KEYWORDS: Aortic aneurysm; Aortic dissection; Fluoroquinolones; Meta-analysis; Systematic review

PMID:

28739200

DOI:

10.1016/j.amjmed.2017.06.029

[Indexed for MEDLINE]

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Select item 3073065212.   FQ

Fluoroquinolones: aortic aneurysm and dissection?.

[No authors listed]

Prescrire Int. 2016 Jul;25(173):184. No abstract available.

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Select item 2643652313.

Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone.

Lee CC, Lee MT, Chen YS, Lee SH, Chen YS, Chen SC, Chang SC.

JAMA Intern Med. 2015 Nov;175(11):1839-47. doi: 10.1001/jamainternmed.2015.5389. Abstract IMPORTANCE:

Fluoroquinolones have been associated with collagen degradation, raising safety concerns related to more serious collagen disorders with use of these antibiotics, including aortic aneurysm and dissection. OBJECTIVE:
To examine the relationship between fluoroquinolone therapy and the risk of developing aortic aneurysm and dissection. DESIGN, SETTING, AND PARTICIPANTS:
We conducted a nested case-control analysis of 1477 case patients and 147 700 matched control cases from Taiwan's National Health Insurance Research Database (NHIRD) from among 1 million individuals longitudinally observed from January 2000 through December 2011. Cases patients were defined as those hospitalized for aortic aneurysm or dissection. One hundred control patients were matched for each case based on age and sex. EXPOSURES: Current, past, or any prior-year use of fluoroquinolone. Current use was defined as a filled fluoroquinolone prescription within 60 days of the aortic aneurysm or dissection; past use refers to a filled fluoroquinolone prescription between 61 and 365 days prior to the aortic aneurysm; and any prior-year use refers to having a fluoroquinolone prescription filled for 3 or more days any time during the 1-year period before the aortic aneurysm or dissection. MAIN OUTCOMES AND MEASURES:
Risk of developing aortic aneurysm or dissection. RESULTS:
A total of 1477 individuals who experienced aortic aneurysm or dissection were matched to 147 700 controls. After propensity score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio [RR], 2.43; 95% CI, 1.83-3.22), as was past use, although this risk was attenuated (RR, 1.48; 95% CI, 1.18-1.86). Sensitivity analysis focusing on aortic aneurysm and dissection requiring surgery also demonstrated an increased risk associated with current fluoroquinolone use, but the increase was not statistically significant (propensity score-adjusted RR, 2.15; 95% CI, 0.97-4.60). CONCLUSIONS AND RELEVANCE: Use of fluoroquinolones was associated with an increased risk of aortic aneurysm and dissection. While these were rare events, physicians should be aware of this possible drug safety risk associated with fluoroquinolone therapy.

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Hälyttävääkin tietoa fluorokinoloneista ja niiden sivuvaikutuksista extrasellulaarimatriksiin.

Ruotsin lääkärilehti  #6,2019  antaa varoituksia ja tarkennuskehoituksia fluorokinonien liian  anteliaaseen käyttöön.
Katson mitä PubMed sanoo  fluorokinoneista ja MMP-entsyymeistä.  Suoran assosiaation vastauksia en saa, mutta katson mitä jäi seulaani.

 https://www.ncbi.nlm.nih.gov/pubmed/?term=Fluorokinolones+%3B+MMPs
Showing results for fluoroquinolones mmps. Your search for Fluorokinolones ; MMPs retrieved no results.
 

Select item 269698711.  ENROFLOXACIN , MARBOFLOXACIN

Two fluoroquinolones and their combinations with hyaluronan: comparison of effects on canine chondrocyte culture.

Siengdee P, Euppayo T, Buddhachat K, Chomdej S, Nganvongpanit K.

J Vet Pharmacol Ther. 2016 Oct;39(5):439-51. doi: 10.1111/jvp.12305. Epub 2016 Mar 11.Abstract

Fluoroquinolones (FQs) are frequently used for septic arthritis. Increased antibacterial activity has been associated with mammalian cell cytotoxicity that may increase the risk of developing osteoarthritis. This study compared the direct effects of two different FQs, enrofloxacin (Enro) and marbofloxacin (Mar), on normal primary canine chondrocytes and inflammatory-stimulated chondrocytes, in addition to their administration in combination with hyaluronan (HA). Cell viability, cell apoptosis, s-GAG production, and expression patterns of inflammatory, extracellular matrix (ECM) component and protease genes were measured. Enro co-culturing with HA could modify s-GAG synthesis compared with the negative control group. Co-treatment with both FQs and HA significantly decreased cell viability and induced more total apoptotic cell death compared with the negative control and pre-IL-1β-stimulated group. Enro regulated IL-1β-stimulated cells to overexpress IL-1β, TNF, and MMP3, whereas Mar induced upregulation of PTGS2 and NFKB1 and enhanced the expression of ECM component genes HAS1, COL2A1, and ACAN as well as TIMP1 and MMP9. Simultaneous use of HA with Enro can effectively reduce the expression of IL-1β, TNF, and MMP3 in pre-IL-1β-stimulated chondrocytes. These results suggest the beneficial effects of HA in reducing the adverse effects of Enro treatment at the transcriptional level.

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Select item 253806572.   LEVOFLOXACIN

Toxic effects of levofloxacin on rat annulus fibrosus cells: an in-vitro study.

Bai ZL, Chen Q, Yang SD, Zhang F, Wang HY, Yang DL, Ding WY.

Med Sci Monit. 2014 Nov 8;20:2205-12. doi: 10.12659/MSM.892610. Abstract BACKGROUND:

Fluoroquinolones are in wide clinical use as safe and effective antibiotics. Articular cartilage, tendons, and epiphyseal growth plates have been recognized as targets of fluoroquinolone-induced connective tissue toxicity. However, the effects of fluoroquinolones on annulus fibrosus (AF) cells are still unknown. MATERIAL/METHODS: The main objective of this study was to investigate the effects of levofloxacin, a typical fluoroquinolone antibiotic drug, on rat AF cells in vitro. Rat annulus fibrosus (RAF) cells were treated with levofloxacin at different concentrations (0, 10, 20, 30, 40, 60, 80, and 90 μg/ml) and were assessed to determine the possible cytotoxic effects of levofloxacin. Inverted phase-contrast microscopy was used to accomplish the morphological observation of apoptosis of treated cells. Western blot and real-time quantitative RT-PCR (qPCR) was used to explore the expression of active caspase-3 and MMP-3. Flow cytometry was used to measure the apoptotic incidences. RESULTS:
Our study showed that levofloxacin, with concentrations at 30, 60, and 90 μg/ml, induced dose-dependent RAF cell apoptosis and higher expression of caspase-3 and MMP-3. More apoptotic cells were observed by inverted phase-contrast microscopy. Moreover, levofloxacin increased the activity of caspase-3, and it also reduced cell viability with different concentrations ranging from 10 to 80 μg/ml.CONCLUSIONS:
Our study results suggest that levofloxacin has cytotoxic effects on RAF cells, characterized by enhancing apoptosis and reducing cell viability, and indicate a potential toxic effect of fluoroquinolones on RAF cells.

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Select item 251434903. FLEROXACIN

Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study.

Fox AJ, Schär MO, Wanivenhaus F, Chen T, Attia E, Binder NB, Otero M, Gilbert SL, Nguyen JT, Chaudhury S, Warren RF, Rodeo SA.

Am J Sports Med. 2014 Dec;42(12):2851-9. doi: 10.1177/0363546514545858. Epub 2014 Aug 20.

Abstract BACKGROUND: Recent studies suggest that fluoroquinolone antibiotics predispose tendons to tendinopathy and/or rupture. However, no investigations on the reparative capacity of tendons exposed to fluoroquinolones have been conducted. HYPOTHESIS: Fluoroquinolone-treated animals will have inferior biochemical, histological, and biomechanical properties at the healing tendon-bone enthesis compared with controls. STUDY DESIGN: Controlled laboratory study. METHODS:  Ninety-two rats underwent rotator cuff repair and were randomly assigned to 1 of 4 groups: (1) preoperative (Preop), whereby animals received fleroxacin for 1 week preoperatively; (2) pre- and postoperative (Pre/Postop), whereby animals received fleroxacin for 1 week preoperatively and for 2 weeks postoperatively; (3) postoperative (Postop), whereby animals received fleroxacin for 2 weeks postoperatively; and (4) control, whereby animals received vehicle for 1 week preoperatively and for 2 weeks postoperatively. Rats were euthanized at 2 weeks postoperatively for biochemical, histological, and biomechanical analysis. All data were expressed as mean ± standard error of the mean (SEM). Statistical comparisons were performed using either 1-way or 2-way ANOVA, with P < .05 considered significant. RESULTS:

Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) analysis revealed a 30-fold increase in expression of matrix metalloproteinase (MMP)-3, a 7-fold increase in MMP-13, and a 4-fold increase in tissue inhibitor of metalloproteinases (TIMP)-1 in the Pre/Postop group compared with the other groups. The appearance of the healing enthesis in all treated animals was qualitatively different than that in controls. The tendons were friable and atrophic. All 3 treated groups showed significantly less fibrocartilage and poorly organized collagen at the healing enthesis compared with control animals. There was a significant difference in the mode of failure, with treated animals demonstrating an intrasubstance failure of the supraspinatus tendon during testing. In contrast, only 1 of 10 control samples failed within the tendon substance. The healing enthesis of the Pre/Postop group displayed significantly reduced ultimate load to failure compared with the Preop, Postop, and control groups. There was no significant difference in load to failure in the Preop group compared with the Postop group. Pre/Postop animals demonstrated significantly reduced cross-sectional area compared with the Postop and control groups. There was also a significant reduction in area between the Preop and control groups. CONCLUSION:
In this preliminary study, fluoroquinolone treatment negatively influenced tendon healing. CLINICAL RELEVANCE:

These findings indicate that there was an active but inadequate repair response that has potential clinical implications for patients who are exposed to fluoroquinolones before tendon repair surgery. © 2014 The Author(s). KEYWORDS:

fleroxacin; fluoroquinolone; rotator cuff repair; tendinopathy; tendon healing

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Select item 248905934.   MOXIFLOXACIN   and antimycobacterial drugs  (TBC)

Antimycobacterial drugs modulate immunopathogenic matrix metalloproteinases in a cellular model of pulmonary tuberculosis.

Singh S, Kubler A, Singh UK, Singh A, Gardiner H, Prasad R, Elkington PT, Friedland JS.

Antimicrob Agents Chemother. 2014 Aug;58(8):4657-65. doi: 10.1128/AAC.02141-13. Epub 2014 Jun 2. Abstract

Tuberculosis is characterized by extensive destruction and remodelling of the pulmonary extracellular matrix (ECM). Stromal cell-derived matrix metalloproteinases (MMPs) are implicated in this process and may be a target for adjunctive immunotherapy. We hypothesized that MMPs are elevated in bronchoalveolar lavage fluid of tuberculosis patients and that antimycobacterial agents may have a modulatory effect on MMP secretion.
Concentrations of MMP-1, -2, -3, -7, -8, and -9 were elevated in the bronchoalveolar lavage fluid from tuberculosis patients compared to those in bronchoalveolar lavage fluid from patients with other pulmonary conditions.
There was a positive correlation between MMP-3, MMP-7, and MMP-8 and a chest radiological score of cavitation and parenchymal damage.
Respiratory epithelial cell-derived MMP-3 was suppressed by moxifloxacin, rifampicin, and azithromycin in a dose-dependent manner. Respiratory epithelial cell-derived MMP-1 was suppressed by moxifloxacin and azithromycin, whereas MMP-9 secretion was only decreased by moxifloxacin. In contrast, moxifloxacin and azithromycin both increased MMP-1 and -3 secretion from MRC-5 fibroblasts, demonstrating that the effects of these drugs are cell specific. Isoniazid (INH)  did not affect MMP secretion. In conclusion, MMPs are elevated in bronchoalveolar lavage fluid from tuberculosis patients and correlate with parameters of tissue destruction. Antimycobacterial agents have a hitherto-undescribed immunomodulatory effect on MMP release by stromal cells.
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Select item 247769055. CIPROFLOXACIN , radioactive exposure, radiation combined  ijury

Ciprofloxacin increases survival after ionizing irradiation combined injury: γ-H2AX formation, cytokine/chemokine, and red blood cells.

Kiang JG, Fukumoto R.

Health Phys. 2014 Jun;106(6):720-6. doi: 10.1097/HP.0000000000000108.

Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury (radiation combined injury, CI) is a crucial life-threatening factor in nuclear and radiological accidents. It is well documented that RI and CI occur at the molecular, cellular, tissue, and system levels. However, their mechanisms remain largely unclear. It has been observed in dogs, pigs, rats, guinea pigs, and mice that radiation exposure combined with burns, wounds, or bacterial infection results in greater mortality than radiation exposure alone. In this laboratory, the authors found that B6D2F1/J female mice exposed to 9.75 Gy ⁶⁰Co-γ photon radiation followed by 15% total body surface area wounds experienced 50% higher mortality (over a 30-d observation period) compared to irradiation alone. CI enhanced DNA damages, amplified iNOS activation, induced massive release of pro-inflammatory cytokines, overexpressed MMPs and TLRs, and aggravated sepsis that led to cell death. In the present study, B6D2F1/J mice that received CI were treated with ciprofloxacin (CIP, 90 mg/kg p.o., q.d. within 2 h after CI through day 21). At day 1, CIP treatment reduced CI-induced γ-H2AX formation significantly. At day 10, CIP treatment not only reduced cytokine/chemokine concentrations significantly, including IL-6 and KC (i.e., IL-8 in humans), but also enhanced IL-3 production compared to vehicle-treated controls. CIP also elevated red blood cell counts, hemoglobin levels, and hematocrits. At day 30, CIP treatment increased 45% survival after CI (i.e., 2.3-fold increase over vehicle treatment). The results suggest that CIP may prove to be an effective therapeutic drug for CI.

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Select item 247709666.

Suppression of stent-induced tissue hyperplasia in rats by using small interfering RNA to target matrix metalloproteinase-9.

Kim EY, Shin JH, Song HY, Kim JH, Lee EW, Kim WJ, Shin DH, Lee H.

Endoscopy. 2014 Jun;46(6):507-12. doi: 10.1055/s-0034-1365495. Epub 2014 Apr 25.

We evaluated the efficacy of small interfering RNA (siRNA) in targeting matrix metalloproteinase (MMP-9) to suppress stent-induced tissue hyperplasia in a rat esophageal model. METHODS:
The silencing effect of the candidate siRNA (termed (MMP-9 siRNA) was evaluated in 9 L rat glial cells. Four groups of rats (n = 10, each group) were used: Eso-S, stent insertion only, comparison; Eso-R, stent insertion plus treatment with MMP-9 siRNA complexed with Chol-R9 for delivery, experimental; Eso-P, stent insertion plus treatment with pCMV-luc complexed with Chol-R9, for confirmation of Chol-R9 delivery effect; and Eso-N, no stent insertion and no treatment, controls. All rats were sacrificed at 3 weeks. The therapeutic efficacy of the MMP-9 siRNA/Chol-R9 complex was assessed. RESULTS:
The most potent MMP-9 siRNA was selected. Compared with the Eso-S group, the Eso-R group showed significantly less tissue hyperplasia with a lower percentage of granulation tissue and smaller granulation tissue area, and also significantly lower MMP-9 level. CONCLUSIONS:
MMP-9 siRNA/Chol-R9 is effective for inhibiting stent-induced tissue hyperplasia in a rat esophageal model.

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Select item 238139467. QUINOLONES, LEVOFLOXACIN

Cytotoxic effects of the quinolone levofloxacin on rabbit meniscus cells.

Wang L, Wu Y, Tan Y, Fei X, Deng Y, Cao H, Chen B, Wang H, Magdalou J, Chen L.

J Appl Toxicol. 2014 Aug;34(8):870-7. doi: 10.1002/jat.2903. Epub 2013 Jul 1.

Quinolones have been reported to induce adverse effects on articular cartilage, tendons and ligaments. However, the effects of quinolones on menisci have not been revealed. The present study was to test the effects of levofloxacin on meniscus cells in vitro. Rabbit meniscus cells were administrated with different concentrations of levofloxacin (0, 14, 28, 56, 112 and 224 µm) for 24 or 48 h, and cell viability and apoptosis were measured. The mRNA expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-3, Col1a1, Bcl-2, caspase-3 and inducible nitric oxide were analyzed by real-time polymerase chain reaction. Active caspase-3 was detected by immunocytochemical assay, while protein expression levels of MMP-3 and MMP-13 were measured by Western blotting assay. After treatment with levofloxacin for 48 h, cell viability was decreased from dose of 28 to 224 µm in a concentration-dependent manner. An increase of apoptotic cells was observed by flow cytometry. Active caspase-3 protein expression level was also increased. The mRNA level of Bcl-2 was decreased and levels of MMP-1, MMP-3 and MMP-13 in experimental groups were higher than those of controls. The protein levels of MMP-3 and MMP-13 were increased. Moreover, the mRNA levels of TIMP-3 and col1a1 were decreased. A dose-dependent increase of inducible nitric oxide mRNA expression level was also observed. Our results suggested the cytotoxic effects of levofloxacin on meniscus cells through induction of apoptosis and unbalanced MMPs/TIMPs expression. These side effects might result in meniscus extracellular matrix degradation and meniscal lesion. Thus, quinolones should be used cautiously on patients who perform athletic activities or undergo surgical meniscus repair.

Copyright © 2013 John Wiley & Sons, Ltd. KEYWORDS:

apoptosis; extracellular matrix degradation; levofloxacin; matrix metalloproteinases; meniscus cell

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Select item 232014418.   OFLOXACIN (OFLOX)

Effect of body-weight loading onto the articular cartilage on the occurrence of quinolone-induced chondrotoxicity in juvenile rats.

Goto K, Imaoka M, Goto M, Kikuchi I, Suzuki T, Jindo T, Takasaki W.

Toxicol Lett. 2013 Feb 4;216(2-3):124-9. doi: 10.1016/j.toxlet.2012.11.017. Epub 2012 Nov 29.

The effect of body-weight loading onto the articular cartilage on the occurrence of chondrotoxicity was investigated in male juvenile Sprague-Dawley rats given ofloxacin (OFLX) orally once at 900 mg/kg. Just after dosing of OFLX, hindlimb unloading was performed for 0, 2, 4, or 8 h by a tail-suspension method. Animals were sacrificed at 8h post-dose, and then the distal femoral articular cartilage was subjected to a histological examination and an investigation for gene expression of tumor necrosis factor receptor superfamily, member 12a (Tnfrsf12a); prostaglandin-endoperoxide synthase 2 (Ptgs2); plasminogen activator (PA), urokinase receptor (Plaur); and matrix metalloproteinase 3 (Mmp3) by qRT-PCR analysis. As a result, cartilage lesions and up-regulations of these 4 genes that were seen in rats without the tail suspension were not observed in rats with the 8-h tail suspension, and a tendency to decrease in the incidence of the cartilage lesions and the gene expression was noted in a tail-suspension time dependent manner. Our results clearly indicate that body-weight loading onto the cartilage is necessary to induce cartilage lesions and gene expression of Tnfrsf12a, Ptgs2, Plaur, and Mmp3 in juvenile rats treated with OFLX.

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Select item 230677229.  LEVOFLOXACIN

The effects of levofloxacin on rabbit fibroblast-like synoviocytes in vitro.

Tan Y, Lu K, Deng Y, Cao H, Chen B, Wang H, Magdalou J, Chen L.

Toxicol Appl Pharmacol. 2012 Dec 1;265(2):175-80. doi: 10.1016/j.taap.2012.10.003. Epub 2012 Oct 12.

It is widely accepted that tendon and cartilage are adversely affected with the toxic effects of quinolones. However, the effects of quinolones on synovium have not been deciphered completely. In this study, our main objective was to investigate the effects of levofloxacin, a typical quinolone antibiotic drug, on fibroblast-like synoviocytes (FLSs) in vitro. FLSs of rabbits were treated with levofloxacin at different concentrations (0, 14, 28, 56, 112 and 224 μM). The possible cytotoxic effects of levofloxacin on FLS were determined. Levofloxacin significantly reduced the cell viabilities, gene expression of hyaluronan synthase-2 (HAS-2), and the level of hyaluronan in FLSs. Moreover, levofloxacin-induced concentration-dependent increases of apoptosis and active caspase-3 were determined in this study. Ultrastructural damages of FLSs were observed by electron microscopy. The mRNA expression levels of matrix metalloproteinase (MMP)-3 and MMP-13 were increased in FLSs treated with levofloxacin. In addition, levofloxacin played a role in suppressing the expression of interleukin (IL)-1 and IL-6. Our data suggest that the cytotoxic effects of levofloxacin on FLS were shown to be able to affect cell viability and HA synthesis capacity. The potential mechanisms of the cytotoxic effects may be attributed to the apoptosis and increased expression of MMPs.

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Select item 2304176510. CIPROFLOXACIN ,  Systemic sclerosis, Lungfibrosis

Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1.

Bujor AM, Haines P, Padilla C, Christmann RB, Junie M, Sampaio-Barros PD, Lafyatis R, Trojanowska M.

Int J Mol Med. 2012 Dec;30(6):1473-80. doi: 10.3892/ijmm.2012.1150. Epub 2012 Oct 5.

Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. The present study was undertaken to examine the effects of ciprofloxacin, a fluoroquinolone antibiotic implicated in matrix remodeling, on dermal and lung fibroblasts obtained from SSc patients. Dermal and lung fibroblasts from SSc patients and healthy subjects were treated with ciprofloxacin. Western blotting was used to analyze protein levels and RT-PCR was used to measure mRNA expression. The pharmacologic inhibitor UO126 was used to block Erk1/2 signaling. SSc dermal fibroblasts demonstrated a significant decrease in collagen type I mRNA and protein levels after antibiotic treatment, while healthy dermal fibroblasts were less sensitive to ciprofloxacin, downregulating collagen only at the protein levels. Connective tissue growth factor (CCN2) gene expression was significantly reduced and matrix metalloproteinase 1 (MMP1) levels were enhanced after ciprofloxacin treatment to a similar extent in healthy and SSc fibroblasts. Ciprofloxacin induced Erk1/2 phosphorylation, and Erk1/2 blockade completely prevented MMP1 upregulation. However, Smad1 and Smad3 activation in response to TGFβ was not affected. The expression of friend leukemia integration factor 1 (Fli1), a transcriptional repressor of collagen, was increased after treatment with ciprofloxacin only in SSc fibroblasts, and this was accompanied by a decrease in the levels of DNA methyltransferase 1 (Dnmt1). Similar effects were observed in SSc-interstitial lung disease (ILD) lung fibroblasts. In summary, our study demonstrates that ciprofloxacin has antifibrotic actions in SSc dermal and lung fibroblasts via the downregulation of Dnmt1, the upregulation of Fli1 and induction of MMP1 gene expression via an Erk1/2-dependent mechanism. Thus, our data suggest that ciprofloxacin may be an attractive therapy for SSc skin and lung fibrosis.

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Select item 2222098711. NADIFLOXACIN

Nadifloxacin downregulates the production of matrix metalloproteinases in the human epidermal keratinocyte cell line HaCaT.

Hosoda S, Komine M, Karakawa M, Tsuda H, Ohtsuki M.

J Dermatol. 2012 Oct;39(10):855-7. doi: 10.1111/j.1346-8138.2011.01466.x. Epub 2012 Jan 4. No abstract available.

PMID:

22220987

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Select item 2105893612.  NORFLOXACIN, CIPROFLOXACIN, LOMEFLOXACIN, SPARFLOXACIN, GATIFLOXACIN, MOXIFLOXACIN

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats.

Sharma C, Velpandian T, Baskar Singh S, Ranjan Biswas N, Bihari Vajpayee R, Ghose S.

Toxicol Mech Methods. 2011 Jan;21(1):6-12. doi: 10.3109/15376516.2010.529183. Epub 2010 Nov 9.

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n = 6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48 h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.

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Select item 2060246413. CIPROFLOXACIN,  Achilles tendon

Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen.

Tsai WC, Hsu CC, Chen CP, Chang HN, Wong AM, Lin MS, Pang JH.

J Orthop Res. 2011 Jan;29(1):67-73. doi: 10.1002/jor.21196.

Ciprofloxacin-induced tendinopathy and tendon rupture have been previously described, principally affecting the Achilles tendon. This study was designed to investigate the effect of ciprofloxacin on expressions of matrix metalloproteinases (MMP)-2 and -9, tissue inhibitors of metalloproteinase (TIMP)-1 and -2 as well as type I collagen in tendon cells. Tendon cells intrinsic to rat Achilles tendon were treated with ciprofloxacin and then underwent MTT (tetrazolium) assay. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis were used, respectively, to evaluate the gene and protein expressions of type I collagen, and MMP-2. Gelatin zymography was used to evaluate the enzymatic activities of MMP-2 and -9. Reverse zymography was used to evaluate TIMP-1 and -2. Immunohistochemical staining for MMP-2 in ciprofloxacin-treated tendon explants was performed. Collagen degradation was evaluated by incubation of conditioned medium with collagen. The results revealed that ciprofloxacin up-regulated the expression of MMP-2 in tendon cells at the mRNA and protein levels. Immunohistochemistry also confirmed the increased expressions of MMP-2 in ciprofloxacin-treated tendon explants. The enzymatic activity of MMP-2 was up-regulated whereas that of MMP-9, TIMP-1 or TIMP-2 was unchanged. The amount of secreted type I collagen in the conditioned medium decreased and type I collagen was degraded after ciprofloxacin treatment. In conclusion, ciprofloxacin up-regulates the expressions of MMP-2 in tendon cells and thus degraded type I collagen. These findings suggest a possible mechanism of ciprofloxacin-associated tendinopathy.

Copyright © 2010 Orthopaedic Research Society.

Free Article

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Select item 1614802014. CIPROFLOXACIN, NORFLOXACIN, OFLOXACIN,  non-fluorinated quinolone nalidixic acid

Contrasting effects of fluoroquinolone antibiotics on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, in human tendon-derived cells.

Corps AN, Harrall RL, Curry VA, Hazleman BL, Riley GP.

Rheumatology (Oxford). 2005 Dec;44(12):1514-7. Epub 2005 Sep 7.

Fluoroquinolone antibiotics may cause tendon pain and rupture. We reported previously that the fluoroquinolone ciprofloxacin potentiated interleukin (IL)-1beta-stimulated expression of matrix metalloproteinases (MMP)-3 and MMP-1 in human tendon-derived cells. We have now tested additional fluoroquinolones and investigated whether they have a similar effect on expression of MMP-13. METHODS: Tendon cells were incubated for two periods of 48 h with or without fluoroquinolones and IL-1beta. Total ribonucleic acid (RNA) was assayed for MMP messenger RNA by relative quantitative reverse transcriptase polymerase chain reaction, with normalization for glyceraldehyde-3-phosphate dehydrogenase mRNA. Samples of supernatant medium were assayed for MMP output by activity assays. RESULTS: MMP-13 was expressed by tendon cells at lower levels than MMP-1, and was stimulated typically 10- to 100-fold by IL-1beta. Ciprofloxacin, norfloxacin and ofloxacin each reduced both basal and stimulated expression of MMP-13 mRNA. In contrast, ciprofloxacin and norfloxacin increased basal and IL-1beta-stimulated MMP-1 mRNA expression. Both the inhibition of MMP-13 and the potentiation of MMP-1 expression by fluoroquinolones were accompanied by corresponding changes in IL-1beta-stimulated MMP output. The non-fluorinated quinolone nalidixic acid had lesser or no effects. CONCLUSIONS:
Fluoroquinolones (FQs)  show contrasting effects on the expression of the two collagenases MMP-1 and MMP-13, indicating specific effects on MMP gene regulation.

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Select item 1589044115. CIPROFLOXACIN, LEVOFLOXACIN

Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells.

Sendzik J, Shakibaei M, Schäfer-Korting M, Stahlmann R.

Toxicology. 2005 Aug 15;212(1):24-36.

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.

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Select item 1452957416.CIPROFLOXACIN  (Ciloxan, Alcon), OFLOXACIN ( Ocuflox, Allergan), LEVOFLOXACIN  (Quixin, Santen)

Effect of topical fluoroquinolones on the expression of matrix metalloproteinases in the cornea.

Reviglio VE, Hakim MA, Song JK, O'Brien TP.

BMC Ophthalmol. 2003 Oct 6;3:10.

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 (MMPs) 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. Rats were sacrificed at 48 hours. Immunohistochemical analysis and zymography were conducted using antibodies specific to MMPs-1, 2, 8 and 9. RESULTS: MMP-1, MMP-2, MMP-8 and MMP-9 expression were detected at 48 hrs in undebrided corneal epithelium groups treated with the topical fluoroquinolones. No statistical difference was observed in quantitative expression of MMPs among ciprofloxacin 0.3%, ofloxacin 0.3%, levofloxacin 0.5%. When the artificial tear group and the fluoroquinolone groups with corneal epithelial defect were compared, increased expression of MMPs was observed as a result of the wound healing process. However, the fluoroquinolone treated group exhibited high statistically significantly levels of MMPs expression. CONCLUSIONS:
Our study provides preliminary evidence that topical application of fluoroquinolone drugs can induce the expression of MMP-1, MMP-2, MMP-8 and MMP-9 in the undebrided corneal epithelium compared to artificial tear eye drops.

Free PMC Article

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Select item 1242824717. CIPROFLOXACIN,

Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Corps AN, Harrall RL, Curry VA, Fenwick SA, Hazleman BL, Riley GP.

Arthritis Rheum. 2002 Nov;46(11):3034-40.

To determine whether the fluoroquinolone antibiotic ciprofloxacin, which can cause tendon pain and rupture in a proportion of treated patients, affects the expression of matrix metalloproteinases (MMPs) in human tendon-derived cells in culture.  METHODS:
Cell cultures were derived from 6 separate tendon explants, and were incubated in 6-well culture plates for 2 periods of 48 hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1beta (IL-1beta), alone and in combination. Samples of supernatant medium from the second 48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was extracted from the cells and assayed for MMP messenger RNA (mRNA) by semiquantitative reverse transcription-polymerase chain reaction, with normalization for GAPDH mRNA. RESULTS:
Unstimulated tendon cells expressed low or undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1beta induced a substantial output of both MMP-1 and MMP-3 into cell supernatants, reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1beta-stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1beta-stimulated MMP-1 mRNA expression, but did not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA expression or output. CONCLUSION:
Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.

Free Article

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Select item 1121202018. ENROFLOXACIN

Effects of enrofloxacin and magnesium deficiency on matrix metabolism in equine articular cartilage.

Davenport CL, Boston RC, Richardson DW.

Am J Vet Res. 2001 Feb;62(2):160-6.

To investigate the effects of enrofloxacin and magnesium deficiency on explants of equine articular cartilage. SAMPLE POPULATION:
Articular cartilage explants and cultured chondrocytes obtained from adult and neonatal horses. PROCEDURE: Full-thickness explants and cultured chondrocytes were incubated in complete or magnesium-deficient media containing enrofloxacin at concentrations of 0, 1, 5, 25, 100, and 500 microg/ml. Incorporation and release of sulfate 35S over 24 hours were used to assess glycosaminoglycan (GAG) synthesis and degradation. An assay that measured binding of dimethylmethylene blue dye was used to compare total GAG content between groups. Northern blots of RNA from cultured chondrocytes were probed with equine cDNA of aggrecan, type-II collagen, biglycan, decorin, link protein, matrix metalloproteinases 1, 3, and 13, and tissue inhibitor of metalloproteinase 1. RESULTS:
A dose-dependent suppression of 35S incorporation was observed. In cartilage of neonates, 35S incorporation was substantially decreased at enrofloxacin concentrations of 25 mg/ml. In cartilage of adult horses, 35S incorporation was decreased only at enrofloxacin concentrations of > or =100 microg/ml. Magnesium deficiency caused suppression of 35S incorporation. Enrofloxacin or magnesium deficiency did not affect GAG degradation or endogenous GAG content. Specific effects of enrofloxacin on steady-state mRNA for the various genes were not observed. CONCLUSION AND CLINICAL RELEVANCE:
Enrofloxacin may have a detrimental effect on cartilage metabolism in horses, especially in neonates.

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• OBS:  ( Varmuuden vuoksi katson ettei rustotoksista antibioottia liitetä  näihin luun korvikkeisiin)

Bone void  filler  substitutes   with antibiotics? Are there even FQ???

 https://www.ncbi.nlm.nih.gov/pubmed/?term=Fluoroquinolone+in+antibiotic-loaded+Bone+substitute
Löytyi levofloxacin mainittuna.

Orthopade. 2010 Apr;39(4):437-43. doi: 10.1007/s00132-009-1528-1.[Collagen hydroxyapatite (Healos) saturated with gentamicin or levofloxacin. In vitro antimicrobial effectiveness - a pilot study].[Article in German]

Fürstenberg CH¹, Wiedenhöfer B, Putz C, Burckhardt I, Gantz S, Kleinschmidt K, Schröder K. Abstract BACKGROUND:

The functions of synthetic bone graft substitutes include not only structural support to provide bone healing and osseous ingrowth but also the ability to serve as a local antibiotic delivery system to prevent or treat infections of the spine. MATERIAL AND METHODS:
The impregnation and antibiotic efficiency of gentamicin and levofloxacin with Healos was investigated in vitro and compared with Healos without an antibiotic additive. These antibiotic-loaded bone graft substitutes were examined without dilution and with 10-fold and 100-fold dilution for activity against spondylodiscitis-causing bacteria on different agar plates using an agar diffusion method. RESULTS:
All hydroxyapatite (HA)/collagen-saturated diluted antibiotics showed elliptical inhibition zones on the corresponding agar plates. For both antibiotics, there was a linear correlation between dilution and area of the inhibition zone. CONCLUSION:
The analysis showed that the antimicrobial activity of HA/collagen-saturated antibiotics corresponded to the antimicrobial dilutions. These results should be further analyzed using in vivo studies to determine the remaining antibiotic efficiency after implantation of bone graft substitutes. PMID: 19784617 DOI: 10.1007/s00132-009-1528-1

• Tarkistan Ceramentin  antibiootit.

https://www.ncbi.nlm.nih.gov/pubmed/21622638 Abstract

Several nonbiodegradable and biodegradable antibiotic cement delivery systems are available for the delivery of antibiotics for adjunctive therapy in the management of osteomyelitis. A major nonbiodegradable delivery system is polymethylmethacrylate beads. Antibiotics that can be incorporated into this delivery system are limited to the heat-stable antibiotics vancomycin and aminoglycosides, tobramycin being the most popular. Calcium sulfate and hydroxyapatite (Cerament Bone Void Filler) is a unique biocompatible and biodegradable ceramic bone void filler that can successfully deliver heat-stable and heat-unstable antibiotics in musculoskeletal infections. The use of Cerament as antibiotic beads has not been previously reported. An off-label case of diabetic foot osteomyelitis successfully managed with surgical bone resection and vancomycin Cerament antibiotic beads is presented. Subsequent surgery for the bone infection and staged removal of the antibiotic beads was not necessary.