Talk:Adverse effects of fluoroquinolones

Mortality

We need better evidence for the mortality section. These are not association and we should use the exact wording of the FDA. We also need to contrast it with other meds for perspective.--Doc James (talk · contribs · email) 03:56, 1 March 2009 (UTC)

The mortality section has been edited to address your concerns and additional information added regarding the FDA's policy of NOT verifying these reports. Also edited to note that the exact number of fatalities cannot be determined at this time, as well as that the article is ONLY drawing attention to the fact that fatalities have been reported with this class and that the article is NOT attempting to either estimate or determine how many such fatalities have actually taken place. Balance is achieved by making note that fatalities have also been reported with other drugs.Davidtfull (talk) 04:13, 1 March 2009 (UTC)

Appreciate your reminder to provide the proper context when referring to a citation or qouting directly from it. Review of the math showed an additional 600+ fatalities that were not included in the totals. Adjusted the numbers accordingly. Also provided context in the intro regarding the claims made regarding safety profile as compared to other antibiotics and frequency of such events. Put qoute marks around the exact text found within the citation used, and made reference to the year the opinion was rendered and who had actually rendered it. Though Ball was affliated with Bayer at the time he made his statement, I saw no pressing need to include that information at this time, unless you feel it to be prudent to let the reader know of this association as this is a known COI regarding Ball's opinions, not only in the citation used, but other articles he had written regarding this class over the years.Davidtfull (talk) 04:55, 1 March 2009 (UTC)

Reviews used conflict of interest

Ambrose address given in this paper is Bristol–Myers Squibb, Plainsboro, NJ 08536, USA. So he works for the manufacturer. This is crazy, could you imagine if a climate researcher gave his address as Exxon Mobil?

Owens reports having received research funding from Elan, Bayer, Ortho-McNeil, and Pfizer.

Lipsky has received fees for speaking at symposia organized on behalf of Merck & Co., Inc., and Pharmacia, and has also received funds for research from Merck & Co., Inc., Pharmacia and Wyeth-Ayerst and has worked for cubist pharmaceuticals. B. Lipsky’s pharmaceutical contacts (research support, advisory board, honoraria) include Pfizer, Ortho-McNeil, Wyeth-Ayerst, Cubist, Merck, F. Hoffmann-La Roche Ltd and Bristol-Myers-Squibb.

Mandell, also has conflicts of interest. Lionel Mandell: recent research funding from Bayer, GlaxoSmithKline, Pfizer, and Wyeth; consultant for AstraZeneca, Aventis, Bayer, Genesoft, GlaxoSmithKline, Pfizer, and Wyeth; speakers’ bureau for Aventis, Bayer, GlaxoSmithKline, Pfizer, and Wyeth.

Mandell also has received research funding from Ortho-McNeil

Tillotson consults for Bayer, BMS, Chiron, GeneSoft, Replidyne and Roche.

Niki is a consultant for Pfizer Japan who manufactured of trovafloxacin.

What is very interesting is in most full text articles I looked at these people didn't declare conflict of interest even though they were promoting fluoroquinolones. Not only did one of the reviewers have a conflict of interest but it appears all or almost all were reviewing the literature on the product that their employers manufactured!--Literaturegeek | T@1k? 07:58, 1 March 2009 (UTC)

Literaturegeek, I'd just like to say thanks for your contributions. Yes, I too agree that articles from pharmaceutical companies are innately biased. The problem is that most of these reviews are written by them. JamesLockson (talk) 12:29, 1 March 2009 (UTC)

They can used in a very limited fashion, but I think it inappropriate that they be used to support things that are disputed. It has been suggested a number of times that such reviews are to be considered the best evidence available. But when reviewing the definition of evidence based medicine I find the exact opposite, to wit:

• Level I: Evidence obtained from at least one properly designed randomized controlled trial.
• Level II-1: Evidence obtained from well-designed controlled trials without randomization.
• Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
• Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
• Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Randomized clinical trials is considered to be the gold standard, followed by well designed controlled trials. Third on this list is analytical studies, which are not the gold standard as some have suggested thus far. As such I would suggest that items in dispute be cited to Levels I and II-1,2,3. Level III is considered to be the poorest evidence available, that being a opinion. Which is what we find in such reviews authored by the drug companies for the most part. Therefore they should not be used to ajudicate such disputes, as they are considered to be of little to no value using the above scheme.Davidtfull (talk) 01:03, 3 March 2009 (UTC)

More conflicts

David tracked down these conflicts of interest and I found some myself mentioned above. I have copied and pasted here.

Treating acute bacterial exacerbations of chronic bronchitis in patients unresponsive to previous therapy : Sparfloxacin versus clarithromycin Auteur(s) / Author(s) LIPSKY B. A. (1) ; UNOWSKY J. (2) ; HAO ZHANG (2) ; TOWNSEND L. (2) ; TALBOT G. H. (2) Author(s) Affiliation(s) (1) University of Washington School of Medicine, and Medical Service, VA Puget Sound Health Care System, Seattle, Washington, ETATS-UNIS (2) Rhône-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pennsylvania, ETATS-UNIS

Sparfloxacin versus ciprofloxacin for the treatment of community-acquired, complicated skin and skin-structure infections MDBenjamin A. Lipsky1, , MDBruce Miller2, MDRobert Schwartz3, MDDan C. Henry4, MDThomas Nolan5, BSAnn McCabe6, *, MSDavid J. Magner6, † and MDGeorge H. Talbot6 1University of Washington and VA Puget Sound Health Care System, Seattle, Washington, USA 2Oregon Medical Research Center, Portland, Oregon, USA 3Associates in Research, Fort Myers, Florida, USA 4Foothill Family Clinic, Salt Lake City, Utah,USA 5Baptist Health Center, Columbiana, Alabama, USA 6Rhone-Poulenc Rorer, Collegeville, Pennsylvania, USA

OFLOXACIN VERSUS CEPHALEXIN FOR TREATING SKIN AND SOFT TISSUE INFECTIONS BENJAMIN A. LIPSKY, M.D. 1 , DABNEY R. YARBROUGH III, M.D. 1 , FREDERIC B. WALKER IV, M.D. 1 , ROBERT D. POWERS, M.D. 1 , MANUEL R. MORMAN, M.D., PH.D. 1 * 1 Seattle VA Medical Center, University of Washington School of Medicine, Seattle, Washington, the Department of Surgery, Medical University of South Carolina College of Medicine, Charleston, South Carolina, the Departments of Internal Medicine, and Emergency Medical Services, University of Virginia School of Medicine, Charlottesville, Virginia *private practice. Address for correspondence: Benjamin A. Lipsky, M.D., General Internal Medicine Clinic, Seattle VA Medical Center (111M), 1660 S. Columbian Way, Seattle, WA 98108. Supported by an educational grant from the Robert Wood Johnson Pharmaceutical Research Institute.

Treating Foot Infections in Diabetic Patients: A Randomized, Multicenter, Open-Label Trial of Linezolid versus Ampicillin-Sulbactam/Amoxicillin-Clavulanate Benjamin A. Lipsky,1 Kamal Itani,2 Carl Norden,3 and the Linezolid Diabetic Foot Infections Study Groupa 1Antibiotic Research Clinic, Veterans' Affairs Puget Sound Health Care System, and Department of Medicine, University of Washington, Seattle, Washington; 2Department of General Surgery, Veterans’ Affairs Medical Center, Houston, Texas; and 3Pfizer, Peapack, New Jersey

Financial disclosure: B.A.L. { Benjamin A. Lipsky }and K.I. { Kamal Itani }have received research support from, served as advisors to, and served as speakers for Pharmacia (now Pfizer). C.N. { Carl Norden } is an employee of Pfizer (formerly Pharmacia).

Peter Ball M.D. / Tillotson G. Comparative Tolerability of the Newer Fluoroquinolone Antibacterials Authors: Ball P.1; Mandell L.2; Niki Y.3; Tillotson G.4 Source: Drug Safety, Volume 21, Number 5, November 1999 , pp. 407-421(15) Publisher: Adis International Affiliations: 1: School of Biomedical Sciences, University of St Andrews, St Andrews, Fife, Scotland 2: McMaster University, Division of Infectious Disease, Henderson General Hospital, Hamilton, Ontario, Canada 3: Department of Medicine, Kawasaki Medical School, Kurashiki-City, Okayama, Japan 4: Bayer Corporation, West Haven, Connecticut, USA *

Oscient Pharmaceuticals' FACTIVE Tablets Subject of Poster Presentations at European Congress of Clinical Microbiology and Infectious Diseases; Leading European Conference Draws Key Scientific and Pharmaceutical Decision Makers Posted on: Tuesday, 4 April 2006, 09:00 CDT Presentation Schedule Tuesday, April 4, 2006

P 1578: "Clinical Outcome of Community-Acquired Pneumonia Infections Treated with Gemifloxacin: The Effect of Patient Risk Factors," J. Garau, T. File, P. Ball, H. Lode, G. Tillotson, I. Morrissey

P 1576: "Dual Action of Gemifloxacin in Acute Bacterial Sinusitis in Patients with Allergic Rhinitis: Antibacterial and Immunomodulatory Effects," H. Lode, J. Garau, T. File, P. Ball, G. Tillotson, I. Morrissey

FACTIVE is currently approved by the U.S. FDA for the treatment of mild to moderate community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis. FACTIVE is not approved by the FDA for the treatment of acute bacterial sinusitis.

Safety profile of oral and intravenous moxifloxacin: Cumulative data from clinical trials and postmarketing studies Peter Ball MDa, Ralf Stahlmann MD, b, , , Rolf Kubin MDc, Shurjeel Choudhri MDd and Robert Owens PharmDe a University of St. Andrews, Fife, Scotland b Benjamin Franklin Institut für Klinische Pharmakologie und Toxikologie, Fachbereich Humanmedizin der Freien Universität, Berlin, Germany c Bayer HealthCare, Wuppertal, Germany d Bayer Corporation, West Haven, Connecticut, USA e Antimicrobial Stewardship Program, Maine Medical Center, Portland, Maine, USA Accepted 18 March 2004. Available online 25 August 2004.

Peter Ball, Mandell L., Tillotson G., B A. Lipsky, H. Lode, Ralf Stahlmann, and Robert Owens have written just about all the fluoroquinolone articles. And they all have strong ties to the various manufacturers. They collaborate on each other’s papers, often times citing to and plagiarizing each other’s work. And all these papers say pretty much the same thing no matter what drug is being discussed. Ball and Tillotson in my opinion are to be considered frauds in white, whores if you will. They are Bayer’s head henchmen in Bayer’s office of misinformation. They all have conflicts of interest, as they are the academic spokespersons for the various drugs companies. Thought you would be interested in some of their statements:

Attachment EE

Quotes from Dr. Peter Ball and Glen Tillotson:

Comparative tolerability of the newer fluoroquinolone antibacterials Ball P, Mandell L, Niki Y, Tillotson G Drug Saf 1999 Nov;21(5):407-21

“…However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin…. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid… rare but serious hepatotoxicity has been reported with other fluoroquinolones…. Prolongation of the QTc interval is also a class effect,… Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones,…

3: Semin Respir Infect 2001 Sep;16(3):215-24 Future of the quinolones. Ball P. School of Biomedical Sciences, University of St. Andrews, St. Andrews, Fife, Scotland.

” New fluoroquinolones and fluoronaphthyridones continue to provide the mainstay of antibiotic development, despite recent events associated with unexpected or uncharacteristically severe adverse drug reactions. These have included hepatotoxicity caused by trovafloxacin (suspended), cardiotoxicity associated with grepafloxacin, and phototoxicity caused by clinafloxacin (both withdrawn). Prolongation of the QT interval appears to be an emergent class effect, the implications of which are not yet fully understood. However, the second-generation agents ciprofloxacin and, latterly, levofloxacin have excellent safety profiles… and to be remarkably free of clinically significant adverse effects.

9th European Congress of Clinical Microbiology and Infectious Diseases Berlin, Germany / March 21-24, 1999

"Ten years ago I would have been howled down for including fluoroquinolones in a list of agents for the management of community-acquired pneumonia," remarked Dr. Peter Ball, Senior Lecturer at the Department of Bio-Medical Sciences, University of St. Andrews, St. Andrews, Scotland. "Nowadays," he said, "the IDSA guidelines have endorsed their use in almost every classification (P. Ball)

"Why should we use these new fluoroquinolones?" Dr. Ball asked. The advantages, he answered, include excellent activity against both typical and atypical respiratory pathogens, very high penetration into tissues and fluids where the infections are centered, activity with once-daily intravenous or oral administration and excellent tolerability”

“Dr. Ball believes, too, that the incidence of dizziness and lightheadedness sometimes attributed to trovafloxacin is not entirely justified”

“"The more than 400,000 patients from post- marketing surveillance studies I have reviewed reveal this to be a very, very small problem," he said. On the other hand, Dr. Ball noted that 97% of patients taking grepafloxacin think that the drug affected their sense of taste and many of them have refused to continue taking the compound for that reason”

Trovafloxacin (Trovan) withdrawn due to severe liver damage Dr. Ball “excellent tolerability”

Grepafloxacin Voluntarily withdrawn because of the possibility of torsades de pointes occurring with its use.

Safety of the Fluoroquinolone Antibiotics: Focus on Molecular Structure CME Stacy J. Childs, MD, University of Colorado Health Sciences Center, Denver [Infect Urol 13(1):3-10, 2000. © 2000 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.] “…] The pathophysiology of adverse hepatic events (trovafloxacin) and hypoglycemia (trovafloxacin and temafloxacin) remains unknown. It has been suggested that the addition of 2,4-difluorophenyl moieties at C1 may be the culprit for the toxic effects associated with both these agents, although there is no definitive evidence. A proposed mechanism is that this component may be metabolically cleaved off and act as a hapten, triggering an array of unusual immunologic sequelae, including hepatic eosinophilia (Peter Ball, MD, University of St Andrews, Scotland, personal communication, 1999). “

Safety Profile of Moxifloxacin Professor Lionel Mandell (Departments of Medicine and Infectious Diseases, McMaster University, Canada) reviewed safety issues with the fluoroquinolones as a class.

Dr Peter Ball (Department of Medical Science, University of St Andrews, Scotland) provided an update on the safety of moxifloxacin.

“Although their use in hundreds of millions of patients worldwide has demonstrated that the fluoroquinolones are generally well tolerated,”

“Most adverse effects with the fluoroquinolones are mild, transient and rarely result in discontinuation of therapy.”

“. The overall incidence of quinolone-related adverse events is similar for moxifloxacin and comparator drugs, discontinuation rates are also similar and serious adverse events are extremely rare”

Other quotes of interest from various articles:

“. A small number of patients receiving fluoroquinolones developed visual disturbances including color distortion and diplopia (Ball, 1989).”

“…the development of severe neuropsychiatric problems including hallucinations and psychosis were reported. The reactions occurred predominantly in the elderly and may have involved predisposing factors (Ball, 1989; Jungst & Mohr, 1988). “

“. Abdominal pain, dyspepsia, anorexia, vomiting, and nausea have been reported with therapeutic use of these agents (Boerema et al, 1985; Holmes et al, 1985; Ball, 1989; Rahm & Schacht, 1989; Prod Info Trovan(R), 1997; Prod Info Raxar(R), 1997). “

“PSEUDOMEMBRANOUS COLITIS has been reported on rare occasions with both OFLOXACIN and CIPROFLOXACIN (Ball, 1989; Rahm & Schacht, 1989; Jungst & Mohr, 1988).”

“- At therapeutic doses hematuria, crystalluria, and interstitial nephritis have been associated with CIPROFLOXACIN therapy in humans. No permanent renal impairment has resulted from ciprofloxacin therapy (Ball, 1989; Hootkins et al, 1989; Garlando et al, 1985). “

“A small number of patients receiving fluoroquinolones developed visual disturbances including color distortion and diplopia (Ball, 1989).”

“Headache, nervousness, anxiety, lightheadedness, and dizziness have been observed during therapeutic use of these agents (Boerema et al, 1985; Holmes et al, 1985; Ball, 1989; Rahm & Schacht, 1989; Prod Info Raxar(R), 1997; Prod Info Trovan(R), 1997; Gajjar et al, 2000)”

“PSEUDOMEMBRANOUS COLITIS has been reported on rare occasions with both OFLOXACIN and CIPROFLOXACIN (Ball, 1989; Rahm & Schacht, 1989; Jungst & Mohr, 1988). “

“At therapeutic doses hematuria, crystalluria, and interstitial nephritis have been associated with CIPROFLOXACIN therapy in humans. No permanent renal impairment has resulted from ciprofloxacin therapy (Ball, 1989; Hootkins et al, 1989; Garlando et al, 1985). “

Safety of the new fluoroquinolones compared with ciprofloxacin. Ball P. “Ciprofloxacin is well tolerated; the incidence of adverse events is low and serious adverse events are rare.”

Tolerability of fluoroquinolone antibiotics. Past, present and future. Ball P, Tillotson G. Infectious Diseases Unit, Victoria Hospital, Kirkcaldy, Fife, Scotland. “The new fluoroquinolones are essentially a well tolerated group of antibacterials”

The following have been removed from clinical practice, approval denied or their use severely restricted by the FDA.

Trovafloxacin (Trovan) withdrawn due to severe liver damage

Grepafloxacin Voluntarily withdrawn because of the possibility of torsades de pointes occurring with its use.

Clinafloxacin Removed from clinical use due to severe toxicity (i.e.: severe phototoxicity and hypoglycemia)

Enoxacin (Penetrex) Removed from clinical use by the manufacturer due to severe toxicity concerns

Gemifloxacin (Factive) Glaxo SmithKline received a non-approval letter from the FDA for the treatment of respiratory tract infections.

Sparfloxacin ( Zagam) Removed from clinical use due to severe toxicity (i.e.: qt time)

Temafloxacin (Omniflox) Removed from clinical use due to severe toxicity (i.e.: haemolytic hepatic reactions)

Almost fifty percent of the fluoroquinolones introduced since 1973 have been sidelined due to severe toxicity issues.--Literaturegeek | T@1k? 08:38, 1 March 2009 (UTC)

suggested edits

The opening statement makes reference to some of the drugs found in this class being withdrawn. There are additional drugs that have been withdrawn that are not included in that statement:

gatifloxacin in 2006

grepafloxacin in 2003

temafloxacin in 1992

here are some references for the removal of trovafloxacin in 1999.

Additionally other drugs in this class have been restricted regarding their use due to either safety concerns or lack of efficacy:

sparfloxacin in 1995

norfloxacin in 2008

moxifloxcacin in 2008.

I did not add this content as LG is working on cleaning up the loose ends here and did not wish to hinder his efforts. But this is something that should be added some time down the road.Davidtfull (talk) 23:37, 1 March 2009 (UTC)

I added the updated information David. Thanks. I knew that part was only partially complete and needed finishing.--Literaturegeek | T@1k? 10:08, 2 March 2009 (UTC)

Yes, a good start to tidying up the introduction would be that a number of members of this class have been withdrawn and a tie to a general report in the scientific literature of this nature. Later on in the article, possibly not the lead paragraph, but still the lead section, since this article is specifically about adverse affects, this point could be elaborated upon. --KP Botany (talk) 00:12, 2 March 2009 (UTC)

Thank you for the feedback Botany. I have added about other quinolones suspended or restricted due to safety concerns. That might be an idea to add as you suggested info in another section of why they were withdrawn. --Literaturegeek | T@1k? 10:08, 2 March 2009 (UTC)

Such info can be added under the proper adr heading associated with the reason for removal. i.e. Raxar was removed due to cardiac problems so we can mention this under the adr section dealing with cardiac. But I would suggest we let LG finish cleaning up the article before we add any new content. He has been working his butt off on this and no sense making this job harder than it is by adding more content while he is removing bad content. We can simply make suggestions here in the meantime and add it in once he is done.Davidtfull (talk) 06:52, 3 March 2009 (UTC)

The section that needs the most work I think is the DNA section. Have any papers linked interferance with DNA replication as playing a role in any of the fluoroquinolone adverse effects such as tendon toxicity or arthralgia in growing joints for example or other toxicities?--Literaturegeek | T@1k? 11:17, 3 March 2009 (UTC)

There is very little research regarding this. Not something that anybody has bothered to look into. I have a few articles that touch on this but they involve the phototoxic issues such as the disfiguring rash we find with factive that the FDA advisory panel found to be so hilarious. A few articles involving the use of eye drops do the same.

There are a lot of articles that talk about the tendon damage resulting from celluar changes, but none so bold as to suggest that changes to DNA may be involved. They just state that this is a "mystery" they do not understand the mechanics of. All of the signs are there, but I don't think anybody has actually paid any attention to them and then wrote a paper about it as of yet. But will look through my files and see what I have. A quick search shows the following:

“Ciprofloxacin-treated chondrosarcoma cultures and tissue samples showed changes in cartilage matrix composition. Ultrastructural analysis demonstrated clumped glycogen, dilation of endoplasmic reticulum, numerous abnormal lysosomes containing degeneration products, and a decreased proteoglycan deposit surrounding the tumor cells. Treated chondrosarcoma cells and tissue specimens did not proliferate, and apoptosis was induced.” Fluoroquinolone's effect on growth of human chondrocytes and chondrosarcomas. In vitro and in vivo correlation. Multhaupt HA, Alvarez JC, Rafferty PA, Warhol MJ, Lackman RD. Division of Biomedical Sciences, Imperial College of Science Technology and Medicine, Sir Alexander Fleming Building, Exhibition Hall, London SW7 2AZ, England. http://fqresearch.org/causation_4.htm

“These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.” In vitro method for prediction of the phototoxic potentials of fluoroquinolones. Yamamoto T, Tsurumaki Y, Takei M, Hosaka M, Oomori Y. Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi-Mitarai, Shimotsuga-gun, 329-0114, Tochigi, Japan. fvbb0984@mb.infoweb.ne.jp J Bone Joint Surg Am 2001;83-A Suppl 2(Pt 1):56-61 http://fqresearch.org/causation_3.htm

The following pretty much sums up what I think is taking place regarding the toxicity of this class:

Date: Sun Mar 19 12:10:32 2000 Posted By: Kenneth Mitton, Post-doc/Fellow, Molecular Development Retina, Cataract, Dept Ophthalmology / U. Mich Area of science: Cell Biology ID: 951760497.Cb Necrosis, is simply a cell dying, all of its coordinated activities going wrong and things shut down. Necrosis is best understood if you compare it to another way cells shut down called apoptosis: Cells these days, are seen by biologists as dying in two major ways: necrosis or apoptosis. Cells can undergo programmed cell-death or "apoptosis", where the cell triggers special metabolic, signal transduction and gene regulation pathways or "programs" that systematically shut down and disassemble the cells components. Apoptosis is not death the way necrosis is. If a cell gets too much heat, or is poisoned by a toxic substance or exposed to chemicals that damage its proteins and membranes or radiation that breaks its DNA molecules, that cell can just stop functioning. In necrosis, the cell dies as damage leads to loss of control of ion gradients between the outside and the inside of the cell, and also loss of the proton gradient across the membranes of mitochondria (where alot of our ATP is made for energy). A toxic insult that damages a cell and causes it to loose energy (ATP levels fall down), and to loose control of ion gradients (Na+ and Ca++, which are low in the cell, rush into the cell and rise in levels), are causing necrosis. In Apoptosis, cells chop up their DNA, disassemble their organelles (mitochondria, ER, golgi) and break themselves up into little peices of cells. But in programmed cell death, apoptosis, this is meant to happen and is under control of the cell...the cell breaks down its proteins and DNA and membranes to eventually be recycled. During apoptosis, in contrast to necrosis, the cell and eventually the fragments of the cell all maintain their ion-gradients and energy levels. In other words, ATP levels are high, and Na+ and Ca++ levels remain low in the cell fragments because the membrane ion pumps are still working (they need ATP for energy). So cells can recycle(die) on purpose by using the apoptosis systems, eventually they fragment into small fragments of cell remains that are phagocytosed (eaten up) by neighboring cells. When tadpoles lose their tails, the tail seems to shrink day after day, that is because the cells are being recycled. Leaves fall from trees in the autumn, because apoptosis shuts the leaves down where they connect to the branch. These are programed cell deaths, and they are good for the organism to develope as it should. In the womb, our hands start off as paddles, and the skin separates into fingers, as the paddles are remodeled by apoptosis. Some cells go away, and new ones are made somewhere else. In necrosis, damage from toxic compounds or oxidation damage often harms the mitochondria or membrane ion pumps and causes the energy levels in the cells to drop. ATP levels fall and this also means that cell glutathione levels drop (important antioxidant in cells), and a vicious cycle of damage starts. Lower glutathione levels make the mitochondria even sicker and less able to make ATP and on and on. When mitochondria are damaged in the cell electron transport does not work well, and more oxygen reacts at the wrong place in the chain, leading to formation of superoxide. (a very reactive free radical) The cell and mitochondria have superoxide dismutase, to quickly convert this into H2O2 (hydrogen peroxide) which is less reactive (toxic). However, lots of H2O2 can build up, and react with metal ions to create hyroxy radicals .OH that react and damage proteins and membranes. Catalase gets rid of H2O2 to make water, but it can become overwhelmed. If the cell is in a state of lower energy too, it also cannot make more of these proteins to protect itself either. Therefore when cells are undergoing a necrotic type of cell death from some toxic insult, they often show increased oxidation damage etc in the tissue where this is happening. Ken Mitton, Eye Research Netork Research Fellow, Kellogg Eye Center, University of Michigan. http://fqresearch.org/causation_13.htm http://www.madsci.org/posts/archives/mar2000/953489856.Cb.r.html

Also found this regarding eye drops and floxin being more toxic.

“Relative effects of aminoglycosides and fluoroquinolones on stromal keratocytes appear to be different: netilmicin was shown to be significantly less toxic than ofloxacin” In vitro effects of fluoroquinolone and aminoglycoside antibiotics on human keratocytes. Leonardi A, Papa V, Fregona I, Russo P, De Franchis G, Milazzo G. Department of Neuroscience, Ophthalmology Unit, University of Padova, Italy. http://fqresearch.org/causation_38.htmDavidtfull (talk) 14:47, 3 March 2009 (UTC)

Thank you for these. It will take several days for me to finish reviewing the literature on the DNA and see where it leads and whether it is relevant to the article or not. I have read a few interesting things on the DNA fluoroquinolone interaction.--Literaturegeek | T@1k? 18:59, 5 March 2009 (UTC)

Another review of FQ

This article http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2267830 seems to do a good comparison of antibiotics. Here is part of it:

Comparisons of safety

Adverse events

The rate of adverse events did not differ significantly between patients given a respiratory fluoroquinolone and those who received a β-lactam (random-effects model for 6 trials with a total of 2732 patients, OR 1.17, 95% CI 0.86–1.59) (Figure 5). The same was true for patients given any fluoroquinolone relative to those given a β-lactam (random-effects model for 9 trials with a total of 5018 patients, OR 1.16, 95% CI 0.95–1.40) (Figure 5). The specific types of adverse events reported for patients treated with any fluoroquinolone and with β-lactams were total gastrointestinal adverse events (4 trials, 2828 patients, incremental rate 10.2% v. 9.8%), diarrhea (8 trials, 4650 patients, 3.8% v. 7.2%), nausea (7 trials, 4379 patients, 5.9% v. 3.1%), adverse events affecting the body as a whole (4 trials, 3053 patients, 5.9% v. 5.5%), abdominal pain (5 trials, 2672 patients, 2.7% v. 2.4%), vaginitis (5 trials, 1990 female patients, 1.7% v. 4.6%) and adverse events affecting the nervous system (3 trials, 2454 patients, 2.7% v. 0.9%). In blinded randomized controlled trials, significantly more adverse events were associated with the use of respiratory fluoroquinolones than with β-lactam antibiotics (fixed-effects model for 2 trials with a total of 1030 patients, OR 1.54, 95% CI 1.19–2.00). The same was true for patients given any fluoroquinolone rather than a β-lactam antibiotic (fixed-effects model for 4 trials with a total of 1905 patients, OR 1.33, 95% CI 1.09–1.63).

Severe adverse events

Significantly fewer adverse events were assessed as severe among patients who received respiratory fluoroquinolones than among those who received β-lactams (fixed-effects model for 6 trials with a total of 2503 patients, OR 0.53, 95% CI 0.30–0.95). The same was true for patients given any fluoroquinolone rather than a β-lactam antibiotic (fixed-effects model for 7 trials with a total of 3004 patients, OR 0.53, 95% CI 0.30–0.93).--Doc James (talk · contribs · email) 23:26, 3 March 2009 (UTC)

It also states: Thus, the use of respiratory fluoroquinolones as first-line therapy in the vast majority of patients with bacterial sinusitis, in whom the condition often has a benign clinical course, is not supported by the available evidence. --Doc James (talk · contribs · email) 23:31, 3 March 2009 (UTC)

Just another propaganda piece promoting the use of the quinolones Doc.

Once again you are presenting a bias study as three of the authors have a direct link to Abbott Laboratories and all of the studies selected, except one, have either financial support received from associated pharmaceutical companies or some of the authors were affiliated with such companies.

This is yet another propaganda piece and useless for our purpose. Try and find an independent study, where NOBODY has ties to the drug companies to support your point of view. It is a given that the drug companies are going to support what ever is in their best interest. And properly reporting adverse events is anything but.

This is why I am insisting you do so. Papers written by folks such as Tillotson, who spent his entire career working for the drug companies, cannot possibly be writing papers that are anything BUT bias:

Glenn S. Tillotson, Ph.D., FRSM, FCCP, has joined ViroPharma as head of medical affairs where he will be responsible to lead the medical affairs team providing medical leadership to disease-specific strategy to support optimal positioning of marketed and development products. Prior to joining ViroPharma, Dr. Tillotson was most recently Executive Director of Scientific Affairs at Replidyne. Dr. Tillotson brings to ViroPharma over 20 years pharmaceutical industry experience in numerous areas including clinical research, marketing, scientific communications, strategic development and global launch programs. From 2003 to 2006, Dr. Tillotson worked for Oscient Pharmaceuticals as vice president, scientific and medical relations. After training in medical microbiology and infectious diseases in the United Kingdom he subsequently spent 13 years at Bayer AG in the UK, US and Germany where he was instrumental in the development of ciprofloxacin and moxifloxacin as well as other drugs in the Bayer AG portfolio. Dr. Tillotson has published over 100 peer-reviewed manuscripts, presented more than 250 scientific posters and is on several journal Editorial Advisory Boards including the Lancet Infectious Diseases. He holds a Bachelors of Science in Microbiology and Biochemistry from Liverpool Polytechnic, a Master of Science in Medicine from University of Manchester Medical School, and Ph.D. from Richmond University in London, UK.

http://people.forbes.com/profile/glenn-s-tillotson-frsm/122118

This would be compared to Ford Motor Company financing a study to show how safe the Pinto was, and then only using reports that they had previously financed to do so. It has already been stated that these types of reviews or studies cannot be used to support anything that is in dispute. We will only use neutral studies or reviews that the drug manufacturers did not finance, or those beholding to the drug companies did not author for such a purpose. This review fails on both counts.

The article also stated that "The absence of these adverse events could be partly attributed to the exclusion from clinical trials of patients who are prone to experience a serious adverse event associated with the study drugs. In fact, in 4 of the 11 trials included in this meta-analysis, patients were excluded if they had a history of seizure disorder, fluoroquinolone-related tendinopathy or a prolonged QRS interval." And in all but one study the patients were given a much higher dose of compactor, which of course would result in a higher adr rate for the compactor. In one case almost four times as much. So you are far from comparing apples to apples here. It is a bias review, using bias studies that were designed to make the quinolones look as good as the compactors by greatly increasing the doses of the compactors, hence the adr rates for the compactors to they would then be on par with the quinolones. And then excluding any patient who was more than likely to experience the severe adrs to the quinolones, skewing the results even more. I swear, do you even check this data out before presenting it? Or do you just take it at face value?Davidtfull (talk) 05:19, 4 March 2009 (UTC)

I found a good review paper but want to sort out the DNA damage section first. I am going to rename it "dna effects" in the meantime for neutrality until I can confirm or deny whether quinolones at therapeutic doses can actually damage DNA. Much of what I have read suggests only at very very high doses.--Literaturegeek | T@1k? 13:35, 4 March 2009 (UTC)

I agree that we should just draw attention to that fact, (high doses) and leave it at that for the moment and make the changes you suggest. The only reason I even included it in the first place was the fact that the drug companies insisted that the quinolones had NO effect on healthy DNA whatsoever but only on bacterial DNA. Which simply is not the case as those studies have shown. But we should not fail to let the readers know that this was shown at high levels and not therapuetic levels if we wish to include this. We can always come back and change that if we can find studies that show this taking place at therapuetic levels. But we may also wish to just leave the DNA section out completely until we have more to work with instead. I would have no objections to either option.Davidtfull (talk) 15:05, 4 March 2009 (UTC)

David I agree that there can be lots of bias in industry sponsored studies. Are there any published reviews that you would accept as none biased? If you look at SSRIs for example the recent reviews show that they have no clinical benefit for mild, moderate, and severe depression even though most of the studies are sponsored by the pharma industry. They pharma industry often tries to withhold result and tries to spin the data but to get published in a well repected journal people look to make sure that this has not taken place to too great an extent.--Doc James (talk · contribs · email) 17:31, 4 March 2009 (UTC)

Doc, not trying to bust your chops here. The New England Journal of Medicine used to have a policy for its review articles and editorials, where it did not even consider manuscripts written by authors with conflicts related to the topic. But abandoned it when they felt they could not find enough experts without ties to industry—a sad commentary indeed. It is illogical to think that disclosing biases somehow sanitizes the content, or that readers will then be able to take the authors’ financial relationships into consideration when reading the article. This is naïve and misguided. Biased information is biased information. And our goal as responsible editors here is to eliminate as much bias within the article as possible.

Would you rather read a review article about the safety profile of a drug written by someone with ties to the manufacturer, or by an independent expert? Which would you find to be most reliable? Simply noting the authors’ close financial ties to the topic simply does not provide us with enough safeguards.

The discussion we are having here centers around your attempts to add content that is a falsehood. These statements are not truefull:

"Fluoroquinolones are synthetic broad-spectrum antibiotics that are generally well tolerated with an incidence of side effects occurring in 5-8% of patients."

"These common side effects are generally mild to moderate and self limiting"

"Nausea and vomiting is the most common side effect of the fluoroquinolones"

"They are for most patients mild and reversible"

A falsehood repeated a thousand times over fifteen years or more within hundreds of medical journals, still remains a falsehood. The repition of such statements do not make them facts.

"Joint pain and swelling occurs in approximately 1% of people who take fluoroquinolones and usually remits within days of stopping treatment"

"Any CNS side effect occurs with an incidence of 1 - 2 %"

"Peripheral neuropathy has been rarely reported"

No doubt you can cite to any number of reviews where such statements may be found. But this does not make them true. They may have been correct when the original statement was made, and they very well have applied to the drugs being studied at that time. But the majority of these statements were made by people employed by the drug manufacturers to make them. And they were based upon very selective studies. Things have changed dramatically since then. This is 2009, not 1995. The majority of these drugs that were studied and used to support such statements have been removed from clincal use, due to an unsafe safety profile. Newer drugs have taken their place and are not included in these older studies. So they have not been reviewed. Far too much relevant data is missing. In fact the newest data clearly refutes these statements.

More than half of these drugs have been removed. You do not find such statistics with the compactors. All of these drugs now have black box warnings. Again you do not see this with the compactors. New information concerning their safety profile has also emerged. Serious ADRS are associated with this class. Adrs that are not associated with compactors. You see a very strong lobby that is pursuing reform regarding product labeling. You do not see this with the compactors. You see websites and forums that have been online for over a decade now discussing such issues. Again, something we do not see with the compactors. As such it would not be ethical for us to cite to older studies, or inadequate studies to support statements that are not, today, truefull. We cannot plead ignorance, as we have all these facts set before us. Nobody here can, with a straight face, assert that this class is comparitive, in regards to incident and severity of adverse reactions, to the other antibiotics in use, while relying upon antiquated data to support such a contention. Or that any of above statements even apply today.

Within the NDAs for this drug we do not find side effects occurring in 5-8% of patients. We find side effects occurring in about 40% of the patients. And we find this wittled down by the investigators, who work for the drug companies, to around 25% or so. Logic would dictate that the manufacturers submitted THE BEST STUDIES they had. So to claim a rate of 5-8% is a proven falsehood. Irregardless of what the reviews may state.

To state that these common side effects are generally mild to moderate and self limiting is all well and good if we are talking about side effects, and apply this statement to side effects. But we are NOT addressing side effects in this article. We are addressing adverse reactions. Which are NOT one and the same. And since we lack long term studies, how then do we know for certain that such side effects do not return at a later date, far more severe? Again this is a statement that cannot be supported with a review.

Nausea and vomiting is the most common side effect of the fluoroquinolones. Again discussing side effects. With this appearing in about 14% of those who suffer a side effect, logic would dictate that 86% suffered something else. So nausea and vomiting, looking at it from this perspective, would not be the most common. Other side effects would. As they as a group reflect 86% of the side effects.

Joint pain and swelling occurs in approximately 1% of people who take fluoroquinolones and usually remits within days of stopping treatment. I have already posted about a dozen clinical trials that refute this statement completely. Joint pain is at the top of the post marketing survelliance list. So we know this is not true. But we state it anyhow based upon an antiqated review.

Any CNS side effect occurs with an incidence of 1 - 2 % and this statement is immedately followed by "Adverse event reporting found 12.2% of adverse reaction reports involved the CNS versus 3.6% for other antibiotics". Hence it is already refuted without even adding a reference. The newer quinolones have a far greater incident of CNS effects compared to the older drugs. But we are stating something we know not to be true.

Peripheral neuropathy has been rarely reported. Technically true, but false non the less. The FDA uses about forty different terms to describe what we would cal PN. If you combine all of the various terms used by the FDA for PN, then you would find it has been reported frequently.

So after this long winded discourse I will finally answer your question. I would find acceptable a review, clinical study, or other such data that is current, reveals all financial ties, COIs and beholdings to the various manufacturers, encompasses the drugs we currently employ and states what we all here know to be the truth. That being the statements contained in the antiquated data, based upon what we now know about this class, has proven to be false.

What I continue to find unacceptable, is the use of antiquated reviews, or those unduly influenced by the drug companies, that supports a falsehood. No matter how many times the falsehood is repeated and published, if the current data does NOT support it, then it would be unethical and morally wrong for us to use it. The cardinal rule of wiki appears to be verifiable. This does not mean verifiable in 1982, 1986, 1995, 1999, etc. It means verifiable TODAY, using what is known and proven to be true today, not what was assumed to be true in the past, for our purposes here within this article.

Find me something today that is a good match to the facts that we are aware of and I will not dispute its use, whether it supports your position as the physician, or my position as the patient. If it is factual and verifiable then it meets our demands. If it is not, then it does not, and we should not use it in any capacity. This is our job here from what I can gather. Find the facts, verify the facts, and present the facts. Nothing more, nothing less. It is asburd and a waste of our time and effort to find one review that is refuted by another and then post both. This is a cop out and you know this. The truth lies somewhere in the middle and we need to find such nuetral reviews if we wish to do our job here correctly. And I have no preference as to who actually authors such a review. If it is up to date, fair, factual and accurate, is to be considered worthy of our attention. If it is written by a spin doctor and out of date, we will use it to wrap our garbage in. Fair enough?Davidtfull (talk)

David, is it Wikipedia policy to refuse references to published results because of alleged bias? Isn't it enough, from a editing point of view, to acknowledge the ties between the author of a paper and the pharma company in question, then let the reader decide who to believe? I don't think I agree with you that any article published by anyone connected to a drug company is automatically biased. Science is science; if it is performed properly, with careful controls and honest reporting of data, then it shouldn't matter who the scientist is. To use a common analogy, I would say the same thing about climate science published by a researcher who works for Exxon Mobile. And yes, if Ford did a study on the safety of the Pinto, we should cite that too--as long as everyone knows that the study was done by Ford. If the research is fully documented then people ought to have a chance to consider it. Science isn't about opinions, bias, or arguments from authority--it is about experiments and data. Experiments should mean the same thing no matter who performs them. That is the essence of the scientific method. It seems that this rejection of citations to industry studies has more to do with your personal opinion than with any legitimate Wikipedia standards. This is just my two cents as a science teacher. It bugs me that people treat science as if it were a matter of opinion that automatically gets infected by bias the moment someone has any prior work with the subject that they're researching, as if the numbers and the data would change based on the mere inclinations of the scientist.0nullbinary0 — Preceding unsigned comment added by 27.55.5.180 (talk) 07:14, 22 October 2012 (UTC)

If we eliminate talk of side effects from this article and start talking about adverse reactions causing long term damage then we are going to get the percent lowered down to decimal point states like 1 in four thousand (PNS damage) or 4 in 100,000 (tendon damage) etc. I don't see how eliminating side effect stats from the article is going to do you any favours. The stats for CNS, joint and muscle adverse effects are probably much higher but there are no long term studies assessing this. The thing about percent of side effects is lots and lots of drugs have high percents of side effects if you include all side effects. Erythromycin, for causing nausea alone is probably 15 - 30% experiencing nausea alone, nevermind diarrhea, headache and other side effects. I suggest that you suggest which review you believe is least bias and is not connected to the drug companies. A lot of your complaints above have already been addressed by the creation of the controversy section by the way.--Literaturegeek | T@1k? 19:23, 5 March 2009 (UTC)

I am still baffled as to what difference it could possibly make presenting percentages. Either the reaction is associated with the drug or it is not. This is a black and white issue. Doesn't make any difference whether it is one in ten or one in a thousand or even one in a million to the patient experiencing it, or the physician faced with treating it. I was not complaining, I was commenting in response to doc's post and my position was that the statements found within the older studies are not to be considered valid today. I realize that the controversy section addresses this and was not rehashing old dirt. I just think that there is no justification to present things we know to be false beforehand is all. But you do as you see fit and add the percentages in what ever manner you choose. To me they are meaningless, irrelevant and unsupported for the most part due to the lack of long term studies, inherent bias of the reviewers, and lack of post marketing surviellance. My preference would be, if we must present percentiles, that we cite to the original studies found with the drugs NDAs for the most part regarding the common reactions, and the latest independent studies concerning those that showed up down the road. Nor did I suggest we eliminate side effects, my comment was:

:"To state that these common side effects are generally mild to moderate and self limiting is all well and good if we are talking about side effects, and apply this statement to side effects."

I believe the major emphasis of the article should be placed upon adverse reactions, as we have done with LG's recent edits. I have no problem with including side effects, but undue emphasis should not be place upon them, as for the most part indeed they are mild, of limited duration, and resolve once the drug is stopped with no lingering after effects. Hence a non issue in my mind, entitled to perhaps a sentence or two at most to describe them as anything more distracts from the issues at hand. I realize that the current revisions have removed the prior emphasis on common reactions. LG has done a great job so far and I am not complaining a whit. He deserves a medal. I am just concerned that when we reintroduce these percentiles that the focus will once again return to common side effects or such percentiles used in a manner to minimize the adverse reactions and we will return to square one here. The article in my opinion is thus far fair, balanced, and for the most part factual. There are few sections that we may wish to expand upon once LG finishes. But all in all I have no complaints to make at this point and do not wish to do anything that would interfere with LG's efforts. I am raising but two issues for future discussion. I am suggesting that we not even make any reference to percentiles, or if we must, urging great caution when we do so and I am asking that we not include something that we know to be false, no matter how many times it had been cited to in the past, regardless of which side of the fence it may fall upon. These are the only two remaining issues that I believe bears a bit of further discussion here and they need not be addressed at this very moment. LG has enough to deal with at the moment so lets put these two items on the back burner for now. Davidtfull (talk) 00:11, 6 March 2009 (UTC)

I think once I have finished the DNA section that we can start looking at different reviews and discuss any further tweaking of the structure of the article but I am just going to do a little editing here and there most days to the article and keep an eye on the talk page for disagreements or suggestions by you or the doc or other editors. As I think that the major issues have been dealt with I feel that I or we can take a more relaxed approach to the article and slowly improve it over the next few weeks.--Literaturegeek | T@1k? 16:15, 10 March 2009 (UTC)

vision and hearing damage

Why has all the information regarding vision and hearing damage been replaced with citations in support of the use of quinolone eye and ear drops?Davidtfull (talk) 05:37, 5 March 2009 (UTC)

A user called Serrin did this. I would probably revert it if I were you, he just deleted all the previous references.

1. (cur) (prev) 11:40, 4 March 2009 Serrin (talk | contribs) (74,673 bytes) (→Hearing damage) (undo)
2. (cur) (prev) 11:32, 4 March 2009 Serrin (talk | contribs) (74,622 bytes) (→Hearing damage: Removed flagrant plagiarism; also animal studies and case reports makes not good evidence) (undo)

Can someone please revert his edits?

116.48.73.241 (talk) 09:59, 5 March 2009 (UTC)

The vision damage information is still there. I could find no information on pubmed or papers on your site which stated that quinolones are ototoxic, infact all the in vivo articles I read state that they are not ototoxic at all. All that I could find was isolated case reports, which are mentioned in the article. All of the case reports involved oral or iv therapy. Not even one case report saying ear drops can be ototoxic. Even the in vitro study which found some ototoxic potential found that they were safer and less toxic than the aminoglycosides in terms of ototoxicity. I cannot find even an in vivo primary source study let alone a review article which states that quinolone ear drops are ototoxic. If you can find one cite it.--Literaturegeek | T@1k? 11:40, 5 March 2009 (UTC)

I had done no real research into eye and ear drops. I had focused strictly on oral and iv use and the vision and hearing damage associated with oral and iv use. As such this aspect was not even considered to be relevant as topical use has nothing to do with oral or iv use. If we are to include eye and ear drops then let us make a subheading for them and not confuse the two, as one is for topical use and the other is not. I will submit a rewrite to the talk page for discussion once I accumulate the evidence and we can take it from there. There have been studies involving the treatment of otis media that may prove to be helpfull.

As to reverting this I continue to limit my editing of the article to making sugggestions that others can either incorporate or reject. I do not wish to start an editing war while FG is still working on the article. I just thought it odd that this section would suddenly focus on eye and ear drops when that aspect had not even been discussed, let alone researched to any degree. And the information concerning oral and iv use minimized to where it is not even noticable anymore. Furthermore what was place there did not even address any adrs, simply stated that ear drops were not found to be otoxic. Promoting its use while not even addressing the associated adrs. Text promoting the use of a drug should not be included in an article addressing its adverse reactions, in my opinion. Furthermore you cannot compare the use of a topical application to oral and iv use. They are not even close to being one and the same.

There is only one sentence, "There have also been isolated reports of reversible vision loss and irreversible blindness associated with oral fluoroquinolone therapy" within both sections that addresses the known adrs associated with oral and iv use. There is no mention of tinititus, permanent and partial hearing loss, permanent double vision, etc and this needs to be addressed.Davidtfull (talk) 13:52, 5 March 2009 (UTC)

I did have a look in the British National Formulary and "hearing disturbances" is listed as a possible side effect but it is impossible to glean from that what they meant by hearing disturbances. The section as it is I think is fairly clear that it is talking about ear drops. I am not sure if there is enough data in that section to split it into two seperate sections. There is little information on ototoxic events of fluoroquinolones to address it other than case reports and a mention of "hearing disturbances" in the British National Formulary. I am tempted to just delete the section to be honest. I am not sure that there even needs to be an ototoxic section, just because of a 1 in a million adverse reaction, perhaps 1 in 10 million adr who knows. If you have any additional data this would be most helpful, particularly anything in review articles discussing hearing disturbances or damage. Ototoxicity though I do think from what I have read is a very very rare complication of fluoroquinolones but I can be persuaded if I see more info on it. I also don't think that things like deafness would be overlooked to a major extent like other quinolone ADRs. If someone gets muscle pain, PNS symptoms, fatigue, anxiety or insomnia a doctor could easily overlook or dismiss those symptoms as "in the imagination" or as "CFS", "fibromyalgia", "mental health" and so forth but deafness, the first thing a doctor will do and even a patient who goes from healthy hearing to deafness is to blame the drug they took. Things like liver damage, going deaf for no reason etc are not commonly misdiagnosed to a massive extent. So I do believe ototoxicity from quinolones is literally 1 in several million. Things like tinnitus and alterations in hearing tone etc happen but that can be due to CNS effects eg alteration of or damage to the GABA system leading to sensory hypersensitivity which is not the same as ototoxicity. Show me more evidence and I might change my mind. I think that visual damage appears to be more common from the quinolones than hearing damage. I added though about irreversible and irreversible deafness.--Literaturegeek | T@1k? 19:44, 5 March 2009 (UTC)

I have no citations on permanent double vision.--Literaturegeek | T@1k? 19:44, 5 March 2009 (UTC)

Guess that makes me, and numerous others, one in several million then as I have both permanent double vision, vision loss, chronic tinititus and hearing loss. Doctors refused to associate my sudden loss of vision and hearing loss with the drugs. Just about everyone on the forums have complained about both vision and hearing problems, particulary loss of high freqeuncies as well as floaters, which is several thousand people. But like I said I will gather the evidence and present it here for your review and we will take it from there.

On a side note all of the package inserts here in the States make note of all of this being an associated reaction, and it has been reported numerous times to the FDA via the AERS system. And within my original draft of this article I did not present the best possible evidence. I just presented the bare minimum evidence that this had either been reported, or associated with the drugs. I was not writing a peer review article meant to be published in a medical journal. I was writing a brief article touching briefly on these issues in hopes that others would provide the strongest documentation and expand the article accordingly.

If had I known it was expected of me to write a journal class article, citing to the strongest possible evidence to every statement made, I would have taken the six months to a year required to gather such documentation before even attempting to do so. And would have never put that original article on wikipedia beforehand. Rather naive of me in hindsight to think that others would have help support what was stated in the original article. Never crossed my mind for a second that they would be hell bent on destroying it, or disputing and refuting every statement made instead. Seems so far that you (LG) are the only one here doing what I had expected, trying to support the article rather than dismantle it. But lessons learned the hard way are lessons not soon forgotten. But I am having serious regrets regarding ever getting involved in this in the first place. But once I start something I tend to stick to it till the end. Since I am ultimately responsible for this mess, really not cool of me to walk away from it now is it? Now that I know what is expected of me I will go to work diligantly to provide it.Davidtfull (talk) 22:38, 5 March 2009 (UTC)

I only said about hearing loss. Maybe that is what the British National Formulary means about "hearing disturbances". I was talking more about deafness. How many people in all honesty do you know who are completely deaf because of quinolones? Anyway, alteration or loss of tones or hearing quality are significant adverse reactions and if you have the data please do cite it. I was just thinking we should concentrate on the main ADRs and those which are well documented and accepted. Then we can if necessary add a small section called "other adverse effects" and quote something like the British National Formulary and list other possible side effects and adverse effects without writing big paragraphs about them. That way a reader of the page can see all the major adverse effects. I do not deny hearing disturbances, that is listed in the British National Formulary, I was thinking of deafness due to quinolones. The main thing I think that you should want is an article from your perspective that explains the adverse effects to the reader (patient and health provider) so if these adverse effects are happening to someone they or the doctor will be able to identify them as quinolone related and discontinue it. We already have a controversy section dealing with controversy over misdiagnosis and drug companies playing down adverse effects etc. We can try to find an independent review article if you like but they are all going to say most people don't get serious adverse reactions. I actually don't think serious adverse reactions are common in the sense of 1 in 20 people are ending up in mental hospitals or with muscle and CNS toxicity, I really don't believe that. I am sorry but I do think that serious ADRs happen only occasionally. However, if you look at vioxx the rate of death compared to the number of peopple prescribed it would make its serious ADR as "occasional" but because the ADR was so serious it was judged to be a dangerous drug. Aminoglycosides only occasionally or perhaps rarely cause ototoxic but there are strict safety measures in place due to its severe nature and severe consequences for someone who would suffer ototoxicity when overdosed on (accidently or in renal failure) or in people who are genetically susceptible to it (middle eastern people are more likely to get ototoxicity from aminoglycosides). If you look at the numbers of people getting liver failure from the quinolones or QT interval problems or whatever which lead to death or serious injury, it wasn't 1 in 10 or 1 in a hundred or even 1 in a thousand, it was relatively rare but because the consequences were death it was pulled from the market even though it was a rare ADR. You were talking a very small minority of people but because of the severity of the toxicity it was pulled, so worrying about the article saying most people tolerate the drug shouldn't matter. What we need is an article which reflects the facts accurately, not downplaying the severe nature and in some cases life destroying adverse effects of some of the adverse reactions from quinolones but also at the same time not trying to mislead the reader that people are dropping like flies on every street corner from tendon and CNS damage or whatever from quinolones. Actually here's a question that has popped into my head. I read on your site that quinolones are used in poultry. If poultry take quinolones throughout their life, surely they would all go psychotic, have muscle degradation, stop eating, their ligaments and muscles would blow out and wouldn't be able to walk and farmers wouldn't be able to sell them. Could it be possible that a minority of people are susceptible to severe toxicity of quinolones due to some biological or genetic sensitivity similar to how some people are more genetically sensitive to aminoglycoside ototoxicity?--Literaturegeek | T@1k? 23:44, 5 March 2009 (UTC)

"Could it be possible that a minority of people are susceptible to severe toxicity of quinolones due to some biological or genetic sensitivity similar to how some people are more genetically sensitive to aminoglycoside ototoxicity?" I would agree that this is indeed possible. But this had been researched to a certain degree and no common denominator found. Possible problems with the person's liver that results in excessive serum levels is one theory. But I think it is a matter of constant exposure more than anything. You reach a certain level of exposure and the party's over. You do well with nine different courses of the drug over your life span and number ten trashes you. You had reactions all along but never put two and two together. And they resolved over a period of time and were forgotten about. But with the last exposure you reach the point where recovery is no longer possible. I really don't know why some people do just fine and others are crippled for life. To this question I do not have any answer that makes the least amount of sense. But the FDA had banned the use of quinolones in any farm animal about five years ago, and severely restricts the levels of quinolones found in any imported foods. But we have found quinolone residue in the entire food chain and groundwater as well. So perhaps this is even a factor. People being inadvertently exposed to the drug every time they eat a big mac or fried chicken. It continues to accumulate in the body over time for some people so they reach a toxic level when therapy is started, as a result of this residue. Others do not have such residue floating about so they do not, they are getting just the standard dose.Davidtfull (talk) 04:02, 6 March 2009 (UTC)

I see your personal story User_talk:Davidtfull#Adverse_effects_of_fluoroquinolones_.2F_Fluoroquinolone_toxicity fits the profile of someone who went beyond their toxic threshold. I know with parkinson's disease you need to pass a threshold of 80% loss of dopamine before symptoms materialise so makes sense the theory of a threshold before symptoms emerge and or become chronic. Your story was of someone who had you or your physician known even the basics of fluoroquinolones would have stopped treatment and you wouldn't have suffered long term damage.--Literaturegeek | T@1k? 16:36, 10 March 2009 (UTC)

I am glad that you think that I don't want to destroy the article, I am hoping development will be near completion soon. I don't think anyone wants to destroy the article per se. It just needs to be reliably cited and it is for the most part reliably cited. Just some ongoing disputes which can I think be resolved fairly soon. What I want is that the toxicities/adverse effects are accurately documented, number 1. Number 2 it needs to be accurate, for starters if it isn't accurate it will be unbelievable and no health provider will even take it seriously if it distorts data, so must be cited.. Number 3, if data isn't verifiable the article will constantly be under dispute and I don't have the time or patience to be constantly working on an article. I just want the article to get reliably cited and balanced, using independent reviews if possible. Number 4 I want the article to educate the reader about the recommendations to discontinue therapy if toxicities appear according to FDA and CSM guidelines etc eg CNS toxicity, tendon or nerve symptoms etc and also about interactions with nsaids, corticosteroids and so forth and high risk groups like elderly and children and so forth. I think that the article is close to doing that and we should be nearing completion. I want to sort the DNA section out, then use an independent review article and then simply move on from this article. Life is too short.--Literaturegeek | T@1k? 23:52, 5 March 2009 (UTC)

I think we have made tremendous progress from our messed up beginnings. We are on the same page here. I do not wish for the data to be exagerated either and your goals and mine are one and the same. As far as the chickens go they don't live long enough for this to be an issue. The are slaughtered and then fed to the public quinolone residue and all. My problem, which I readily admit to, is the constant denial from the medical community regarding these reactions I have had to deal with for almost half of my life. As such I feel threatened by anyone who attempts to deny this reality. Unfortunately, and much to my own self destruction at times while working on this project, this presents itself at the worse possible moments. I appreciate your never ending patience dealing with this throughout this whole effort. The good thing here is that when this is done you can move on and be proud of what you have accomplished. Rightly so I might add. The bad thing here is I can never escape this constant dread and fear of once again being told "It cannot be the drugs" when in fact it was the drugs. A horrible thing to live with my friend. Horrible to be constantly denied medical care due to such ignorance and have to fight tooth and nail with every doctor you come in contact with. And have them roll thier eyes at you if you dare to even suggest the drugs may be responsible. Makes a person unreasonably aggresive in defense of themselves. For this I apologize. But for the most part I am helpless to prevent it from happening. Just another gift from Johnson and Johnson, Bayer and Ortho McNeil I will have to spend the rest of my life living with. But that is my problem, and again I am truly sorry that I ended up making it yours and Doc's for this short amount of time we have spent together here.Davidtfull (talk) 03:42, 6 March 2009 (UTC)

Not to worry, I think that we have achieved or will achieve an article which is balanced but at the same time acknowledging the potential for serious and sometimes long term or permanent harm to a small group of patients and the controversy over them being misused for minor infections or as first line drugs by doctors and also patients demanding antibiotics. I think that the article at present provides enough information where a physician or patient should be able to recognise the adverse effects of fluoroquinolones and respond accordingly.--Literaturegeek | T@1k? 16:36, 10 March 2009 (UTC)

partial results concerning vision damage

I am continuing to research this particular adverse reaction, which may take another week or more, but this is what I have so far. Where applicable I included a link to the papers found on my site for review, and if we choose to use these citations we can find other sources to link to rather than the reseach site:

Oral and I.V. use of the fluoroquinolones are associated with a significant number of serious visual disturbances. Such disturbances include blurred and dim vision, disturbed vision, diplopia (double vision), and changes in color perception, flashing lights, decreased visual acuity as well as cataracts.(22) There have also been spontaneous reports of rare cases of permanent double vision(diplopia), as well as reports of floaters that never resolved in some patients.(8)

Chloroquine is also a member of the quinolone family and has been linked to manifestations of retinal toxicity. In 1958, Cambiaggi first described the classic retinal pigment changes in a patient receiving chloroquine for systemic lupus erythematous (SLE) treatment. In 1959, Hobbs established a definite link between long-term use of chloroquine and subsequent development of retinal pathology. In the US despite the variability of the statistics the incidence of retinopathy increased with both the dose and the duration of treatment. Bernstein estimated an incidence of 10% in unmonitored patients taking 250 mg/d of chloroquine. (1)

It is well known that the older quinolones, such as nalidixic acid, may affect the eye as a potential target organ (2). In this connection alteration of the lens or melanin-containing eye tissues (retina, iris, ciliary body) have been reported from human medicine. There have also been isolated reports of reversible vision loss and irreversible blindness associated with oral fluoroquinolone therapy. (3)(4) Retinal degeneration has also been observed in animals. (5)(6) These reports, while uncommon, include blindness, temporary blindness, partial blindness, and mydriasis. (7) There have been a significant number of spontaneous reports involving serious vision disturbances in patients undergoing fluoroquinolone therapy involving decreased visions, double vision, floaters, and other vision problems. While for some patients the symptoms resolve relatively soon after discontinuing the fluoroquinolone antibiotic, other patients reported vision problems that persisted for months or even years after discontinuation of fluoroquinolones. In some cases this was permanent in nature. (8) There have also been three reports of serious macular detachment of the neuro-epithelium involving flumequine. (9) An in vitro study assessing the ocular toxicity potential of antibiotics compared a fluoroquinolone against an aminoglycoside antibiotic and found that the fluoroquinolone ofloxacin was significantly more toxic to stromal human keratocytes. (10)

RPE cells are critical to the functioning of the eye and are involved in many eye diseases. In one study DNA damage to RPE cells was observed with sparfloxacin. (11) Fluoroquinolones displayed the potential to be cytotoxic to human corneal keratocytes and endothelial cells, depending on drug concentration and duration of exposure. The potential for cytotoxicity may differ among fluoroquinolones. (12) There have also been a significant number of reports concerning corneal deposits after administration of topical fluoroquinolones. (13-18) Gatifloxacin, a fourth-generation fluoroquinolone, can cause intrastromal macroscopic crystalline deposits through a compromised corneal epithelium, similar to what has been described for ciprofloxacin, a second-generation fluoroquinolone. (19)

In regards to eye drops the relative effects of Ofloxacin on stromal keratocytes had also shown Ofloxacin to be more toxic than netilmicin. (20) Brown et al stated, again in reference to eye drops, that “serious complications such as corneal perforation, evisceration, or enucleation of the affected eye occurred in 16.7% of patients receiving fluoroquinolone, compared with only 2.4% of patients receiving fortified antibiotic therapy.” The authors of that review estimated those patients taking fluoroquinolones had an 8.9-fold increased risk of serious complications. (21)

References

(1) eMedicine Journal, May 25 2001, Volume 2, Number 5 Authored by Manolette Rangel Roque, MD, Chief of Service, Immunology and Uveitis Service, Consulting Staff, Cornea and Refractive Surgery Service, Q.C. Eye Center, Cavite Eye and ENT Center, Makati Eye Laser Center Coauthored by C Stephen Foster, MD, FACS, Director of Immunology and Uveitis Service, Professor, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School http://fqresearch.org/vision_2.htm

(2) Takayama S, Hirohashi M, Kato M, Shimada H: Toxicity of quinolone antimicrobial agents. Journal of Toxicology and Environmental Health, 45: 1-45, 1995.

(3) Reversible visual loss in a patient receiving high-dose ciprofloxacin hydrochloride (Cipro) Vrabec TR, Sergott RC, Jaeger EA, Savino PJ, Bosley TM. Neuro-Ophthalmology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA 19107. http://fqresearch.org/vision_8.htm

(4) "Case Presentation - Moxifloxacin (Avelox)". written at Canada (PDF). Canadian Adverse Drug Reaction Newsletter. October 2002. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v12n4-eng.pdf. Retrieved on 30 January 2009.

(5) Enrofloxacin-associated retinal degeneration in cats. Gelatt KN, van der Woerdt A, Ketring KL, Andrew SE, Brooks DE, Biros DJ, Denis HM, Cutler TJ. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Box 100126, University of Florida, Gainesville, FL, USA. Gelattk@mail.vetmed.ufl.edu http://fqresearch.org/vision_9.htm

(6) Bayer Agriculture Division Animal Health July 6, 2000 Dear Doctor Letter, Baytril® (enrofloxacin) http://fqresearch.org/vision_15.htm

(7) Shimoda K, Okawara S, Kato M.Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice. Arch Toxicol. 2001 Sep;75(7):395-9. PMID 11693179 [PubMed - indexed for MEDLINE]

(8) vision report http://fqresearch.org/vision_report.htm

(9) Sirbat D, Saudax E, Hurault de Ligny B, Hachet E, Raspiller A.[Serous macular detachment of the neuro-epithelium and flumequine] J Fr Ophtalmol. 1983;6(10):829-36. French. PMID 6672059 [PubMed - indexed for MEDLINE]

(10) Leonardi A, Papa V, Fregona I, Russo P, De Franchis G, Milazzo G (January 2006). "In vitro effects of fluoroquinolone and aminoglycoside antibiotics on human keratocytes". Cornea 25 (1): 85–90. doi:10.1097/01.ico.0000164782.10667.ed. PMID 16331047.

(11) Cell Biol Toxicol. 2000;16(5):303-12. Related Articles, Links UVA-induced oxidative damage in retinal pigment epithelial cells after H2O2 or sparfloxacin exposure. Verna LK, Holman SA, Lee VC, Hoh J. Division of Biomedical Sciences, University of California Riverside, 92521, USA. http://fqresearch.org/vision_25.htm

(12) Curr Med Res Opin. 2008 Feb;24(2):419-24. Links Intrinsic cytotoxic effects of fluoroquinolones on human corneal keratocytes and endothelial cells. Bezwada P, Clark LA, Schneider S. Santen Incorporated, Napa, CA 94558, USA. pbezwada@santeninc.com http://fqresearch.org/text_documents/9.doc

(13) Cornea. 2006 Aug;25(7):855-7. Links Severe corneal toxicity after topical fluoroquinolone therapy: report of two cases. Walter K, Tyler ME. From Wake Forest University Eye Center, Winston-Salem, NC. http://fqresearch.org/vision_38.htm

(14) Corneal deposits and topical ofloxacin-the effect of polypharmacy in the management of microbial keratitis. Mitra A, Tsesmetzoglou E, McElvanney A. 1Department of Ophthalmology, Epsom and St Helier University Hospitals NHS Trust, Sutton Hospital, Sutton, UK. http://fqresearch.org/vision_35.htm

(15) Sparfloxacin corneal deposits Nikhil S Gokhale, MD Correspondence to Dr. Nikhil S. Gokhale, Gokhale Eye Hospital and Eyebank, Anant building, Gokhale road (S), Dadar West, Mumbai 400 028. E-mail: <gokhlay@vsnl.com>

(16) Castillo A, Benitez Del Castillo JM, Toledano N, Diaz-Valle D, Sayagues O, Garcia-Sanchez J. Deposits of topical norfloxacin in the treatment of bacterial keratitis. Cornea 1997;16:420-23.

(17) Eiferman RA, Snyder JP, Nordquist RE. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg 2001;27:1701-2.

(18) Claerhout I, Kestelyn Ph, Meire F, Remon JP, Decaestecker T, Van Bocxlaer J. Corneal deposits after the topical use of ofloxacin in two children with vernal keratoconjunctivitis. Br J Ophthalmol 2003;87:646.

(19) Corneal Intrastromal Gatifloxacin Crystal Deposits After Penetrating Keratoplasty. Eye & Contact Lens: Science & Clinical Practice. 30(3):169-172, July 2004. Awwad, Shady T. M.D; Haddad, Walid M.D; Wang, Ming X. M.D., Ph.D; Parmar, Dipak M.B.B.S., B.Sc.(Hons.), F.R.C.Ophth; Conger, Darrel C.R.A; Cavanagh, H Dwight M.D., Ph.D http://fqresearch.org/vision_24.htm

(20) In vitro effects of fluoroquinolone and aminoglycoside antibiotics on human keratocytes. Leonardi A, Papa V, Fregona I, Russo P, De Franchis G, Milazzo G. Department of Neuroscience, Ophthalmology Unit, University of Padova, Italy. http://fqresearch.org/causation_38.htm

(21) Br J Ophthalmol 2000;84:378-384. Fluoroquinolone Effective In Treating Corneal Ulcer But Should Be Used With Caution May 4, 2000

(22)The antimicrobial drugs By Eric Michael Scholar, William B. Pratt Edition: 2, illustrated Published by Oxford University Press US, 2000 ISBN 0195125290, 9780195125290 607 pages citing to page 271 and reference [160], to wit: W. Christ and B. Esch, Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994;3 (Suppl 3). S168-S176 http://books.google.com/books?id=gACeB8XCnpgC&pg=PA271&lpg=PA271&dq=%22diplopia%22+%22quinolone%22&source=bl&ots=5Mcj9Hc-jm&sig=eZXYD15q5LPQ8EpFtsZgLeDrRMA&hl=en&ei=PTe0SbvYLIGCtwfZvpmtCQ&sa=X&oi=book_result&resnum=9&ct=resultDavidtfull (talk) 18:38, 10 March 2009 (UTC)

As there had been no comment or discussions regarding the above proposed changes to the vision section of this article I have gone ahead and changed the article accordingly with a few minor changes in the text and additional references.Davidtfull (talk) 18:38, 10 March 2009 (UTC)

I will continue to work on the hearing adverse reactions, and will post the results here on the talk page when completed for comments or discussions prior to adding any content regarding this.Davidtfull (talk) 18:54, 10 March 2009 (UTC)

I have been quiet because I have been working on a few other articles. I came across major bias carried out by David J. Hanson who lobbies in the USA for the alcohol industry. He had turned the long term effects of alcohol into an article on the wonder cures of alcohol. I have finished the DNA section. Might add a review article to the DNA section to finish it off but this quinolone article is not on my top priorities at the moment but I will periodically tweak this article over the next couple of weeks.--Literaturegeek | T@1k? 02:32, 15 March 2009 (UTC)

Not a problem in the least. You have spent a tremendous amount of time working on this, which is greatly appreciated. I'm sure that there were other articles you were working on that this took a lot of time away from. But I do believe we are in pretty good shape now and other than minor maintenance as the need arrives nothing more needs to be done here. Job well done FG.Davidtfull (talk) 21:28, 15 March 2009 (UTC)

hearing loss, etc.

Suggested edit to this section as follows,

Oral and IV use

Hearing loss appears to be a very rare event, while fluoroquinolone induced tinnitus appears to be far more common. Oral and IV use of the fluoroquinolones have been reported to cause hearing loss, decreased hearing acuity, hypoacusis and tinnitus. [1-2] The package inserts for the majority of the fluoroquinolones in use today[3] all list tinnitus as post marketing events. Specific fluoroquinolones[4] list the loss of hearing as reported events. Within the AERS maintained by the FDA, hearing loss, tinnitus, decreased hearing acuity, and hypoacusis have all been reported with the fluoroquinolone class.[5] There have also been isolated case reports of ototoxicity leading to reversible and irreversible deafness as a result of oral or IV therapy.[6] There have been spontaneous reports of fluoroquinlone induced tinnitus being permanent in nature, together with the loss of hearing in the higher frequencies.

Otic use (ear drops)

There have been studies showing some in vitro ototoxicity potential in fluoroquinolones.[7] Within a 1992 animal study involving Long Evan rats, nalidixic acid showed partial loss of the outer hair cells of the organ of Corti in the cochlea, suggesting that nalidixic acid had slight ototoxicity.[8] The package insert for Ofloxacin otic solution list the loss of hearing as reported events. There has also been a case report associating the use of Ciprofloxacin ear drops and seizures.[9] Nevertheless, the fluoroquinolone eardrop solutions are believed to be non-ototoxic and are preferred over the known ototoxic aminoglycoside antibiotics, in the topical treatment of ear infections.[10]

1. See package inserts

2. Tinnitus and ciprofloxacin. Paul J, Brown NM. Public Health Laboratory, John Radcliffe Hospital, Oxford. PMID 7627041 [PubMed - indexed for MEDLINE] PMC 2550285

3. Moxifloxacin (Avelox), Ciprofloxacin (Cipro), Ofloxacin (Floxin), Levofloxacin (Levaquin), Norfloxacin, Proquin XR, Sparfloxacin (Zagam), Cinoxacin (Cinobac) and Equin package inserts

4. Ciprofloxacin (Cipro), Ofloxacin otic solution, Norfloxacin and Proquin XR package inserts

5. http://www.fdable.com/aers/query/b931629ae5f4 (ciprofloxacin) http://www.fdable.com/aers/query/d69c84a9bc25 (moxifloxacin) http://www.fdable.com/aers/query/8754a794bbbc (ofloxacin) http://www.fdable.com/aers/query/5d7b35b12b8a (levofloxacin) http://www.fdable.com/aers/query/a5041b448bd6 (norfloxacin) http://www.fdable.com/aers/query/d7bb3200ff5e (cinoxacin)

6. ^ "Ciprofloxacin: suspected association with deafness and reduced hearing" (PDF). Canadian Adverse Reaction Newsletter (Health Canada) 14 (1). January 2004. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v14n1-eng.pdf. Retrieved on 18 February 2009.

7. ^ Russell PT, Church CA, Jinn TH, Kim DJ, John EO, Jung TT (January 2001). "Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells". Acta Otolaryngol. 121 (2): 135–9. doi:10.1080/000164801300043208. PMID 11349764.

8. Ophthalmotoxicity and ototoxicity of the new quinolone antibacterial agent levofloxacin in Long Evans rats. Nomura M, Yamada M, Yamamura H, Kajimura T, Takayama S. Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.

9. MJA Vol 178 7 April 2003 343 The Medical Journal of Australia ISSN: 0025-729X 7 April 2003 178 7 343-343 Eardrop attacks: seizures triggered by ciprofloxacin eardrops.

10. ^ Coats H (April 2008). "Ear drops and ototoxicity". Australian Prescriber 31 (2): 40–1. http://www.australianprescriber.com/magazine/31/2/40/1/. Davidtfull (talk) 00:16, 16 March 2009 (UTC)

As there was no discussion or disputes I had added these revisions to the article.Davidtfull (talk) 23:19, 20 March 2009 (UTC)

I have read over the refs, not in indepth detail as I am involved in drama believe it or not. I reverted some vandalism and am now being harrassed by sockpuppets. Anyhow, my first suggestion would be to replace the package insert links with an online source. I would recommend webmd. See this link for an example.[1]. Other sources could be rxlist or drug.com or similar.--Literaturegeek | T@1k? 20:10, 21 March 2009 (UTC)

I made the changes you suggested linking the package inserts to the latest releases available on the FDA site. The information found on Webmd and Rxlist can be outdated and reference older inserts at times. The inserts undergo rapid changes regarding new warnings and these sites at times fail to keep up with that information. For example rxlist is using the July 2008 package insert for cipro, even though it was updated March of 2009. And for Levaquin they are using August of 2008, though it was updated on March 2009 as well. Webmd does a bit better though. But both sites offer an interpitation rather than the actual inserts. I am more comfortable letting the readers view the full package insert rather than some website's interpetation of what it contains. So I prefer to link to the FDA site where the latest full package insert is available instead. But even the FDA has trouble keeping up with these changes as well so my comments were not meant to chastise Webmd or Rxlist. All in all these sites do a fair job of keeping things up to date considering. Davidtfull (talk) 17:55, 22 March 2009 (UTC)

Good job thanks for doing that David. Just heard of an elderly woman who is as I write this in a coma from quinolone induced grand mal seizures. Do you have any refs on this happening out of interest? Will send you more info on your talk page.--Literaturegeek | T@1k? 20:51, 24 March 2009 (UTC)

More on the intro

Author = img888

Thanks David & others for the great job you are doing here. This article is very dense, with an obvious effort to prove every piece of information. However I think it is difficult to read, and I would certainly prefer a more “reader friendly” redaction. I believe the article should be more aimed at standard persons, such as patients who hesitate to take quinolones, or doctors who hesitate to prescribe them. As for floxed people they could rather check the “flox report” for more details: http://quinolones.free.fr/Rapport_FQ_ORG_2007.pdf

There are many issues on quinolones: chemical description, mode of action, licensed uses, drug interactions, current litigation, etc. The reader must understand first that this article is focused on “adverse effects” because some other articles in wikipedia are already catering the other points in a satisfactory way.

Next to this, the article could state that quinolones have different types of adverse effects:

(1) Allergic reactions (anaphylactic shock, Quincke’s oedema) (2) Short term adverse effects (3) Long term adverse effects (4) Death occurring as a result of (1)(2)(3)

Long time adverse effects (3) are toxic reactions, as opposed to allergic relations (1). They are either immediate (3.1) or delayed (3.2), in some cases they may turn into permanent disabilities. Immediate long time adverse effects (3.1) are starting exactly like short term adverse effects (2) but not every short term effect can become a long term effect, as the link below explains better than I can do:

(link blocked for unknown reason)

QUOTE Fluoroquinolones are a class of antibiotics used to treat many kinds of infections, such as respiratory infections and urinary tract infections, including prostatitis. Like all drugs they have side effects, but they appear more likely than antibiotics of other classes to cause severe, permanent adverse effects. Antibiotics are only supposed to affect bacteria, not our own cells. Most side effects of antibiotic therapy are caused by the reduction of beneficial bacterial flora in the intestine, which can lead to nausea, diarrhea and stomach upset. Allergic reactions are also possible, as with all medications. Fluoroquinolones, however, … END OF QUOTE – Source : Maija Haavisto

I assume that the main focus of this article is the long term adverse effects (3) because they are THE big issue with quinolones. There is a need to insist on the fact that the delayed effects (3.2) are unpredictable. Thus the FDA warning on tendinitis though useful is not enough. If the effect is delayed the patient cannot stop the treatment “at the first sign of tendon pain” since the first sign will occur after the end of the treatment.

QUOTE Physicians should advise patients, at the first sign of tendon pain, swelling, or inflammation, to stop taking the fluoroquinolone, to avoid exercise and use of the affected area, and to promptly contact their doctor about changing to a non-fluoroquinolone antimicrobial drug. END OF QUOTE – Source: FDA

16:07, 5 September 2009 (UTC)

End of Author = img888 —Preceding unsigned comment added by Img888 (talk • contribs) 16:07, 5 September 2009 (UTC)

Thanks for the feed back. Due to the number of editors who fought this article every step of the way we were forced to cite just about every statement made. Which precludes making it user friendly to read as it will just come under attack again as being original research or uncited statements. Kind of a catch 22 here. If you dumb it down it gets shot down. If you prove every statement to avoid this it becomes burdensome to read. So we are damned if we do and damned if we don't.

Nor can we cite to statements similar to those made by Maija Haavisto as these are blog statements (original research) and not published research. We are only allowed to state in the article what someone else had stated in a published article somewhere.

But you are correct the advise to quit taking the drug is frivolous and retarded, though well intentioned. By the time you have symptoms the damage has already been done. And since a number of these reactions are delayed reactions you had already stopped taking the drugs by the time they manifest anyhow. Kind of like suggesting a person quit shooting themselves as they may bleed to death, after they shot themselves a couple of dozen times. Stupid. BTW the quinolone article by T. Boomer you referred to has been taken off line, so you can no longer refer people to it.Davidtfull (talk) 19:24, 5 September 2009 (UTC)

More on eyes

Well I don’t want to join the catch 22 game so I will not edit the article directly. This week I moved to the “Ocular Toxicity” section. Interestingly I noticed that you are using forum statistics as an element of proof [133]. I understand better now why the quinolone yahoo group was deleted. Does the fqresearch.org site publish similar forum statistics on the other adverse effects of fluoroquinolones?

As you already know the human eye consists in optical elements (pupil, iris, lens, retina) and of muscles to activate those elements. The ciliary muscle controls the lens, the circular and radial muscles control the iris and the extra-ocular muscles control the movements of the eye itself. Then as you have stated in the article the action of fluoroquinolones on eyes can bring different types of side effects:

• Phototoxicity: cataract, floaters, flashes, retina tear, retina detachment, macular or retinal degeneration, photophobia.
• Damage in muscles and tendons: focusing and accommodation problems (on distance and on quantity of light), diplopia.
• Neurological issues: zigzag lights, altered colour perception
• Increased ocular tension: halos
• Decreased blood pressure: stars, grey-out (transitory loss of colour vision)
• Transitory or permanent loss of vision
• Eye pain
• Dry eyes (related with dry mouth)

Blurred vision is a typical adverse effect of fluoroquinolones but I don’t know to which cause it belongs.

Due to the action of fluoroquinolones one can get three different of lights in eyes:

• stars (as in “seeing stars”): multiple small moving white light spots,
• sparks or flashes: sudden white flashing lights, generally seen with open eyes, which (together with floaters) can be the sign of a retinal tear or detachment,
• zigzag lights: waving rows of lights of different colours which are better seen with closed eyes (probably coming from a neurological disorder).

As for the article, I believe that Iquix could stand under “Oral and intravenous route” rather than “Ophtalmic use”.

All the best Img888 (talk) 10:53, 12 September 2009 (UTC)

Not too sure what some other editor was trying to accomplish here but they had changed this section a bit by splitting this into two sub sections, the first being Oral and Iv and the second being topical use. And Iquix is an eye drop, so I guess that is why they put it under ophtalmic use. As such I am confused as to why you would feel this to be a oral or iv drug when it is considered to be a topical solution.

The Foundation has published any number of articles concerning these drugs where the study population was the old quinolone forum. The existing forum (supported by the Foundation) is still too new to use as a database for such studies. As such it will be a number of years before that will take place. But the old forum was online for a decade so it was indeed a valid database. And this database and the report you made reference to is what sparked the interest by the researchers who published the latest study concerning the double vision. We had discussed this with them back in 2004. Just took them five years to get an article written and published is all.Davidtfull (talk) 20:07, 12 September 2009 (UTC)

BTW The old quinolone group was deleted due to some rather unusual circumstances that had nothing to do with it being any kind of threat to the medical community or the drug manufacturers. But these are circumstances I am not free to discuss at the moment. But I can assure you it had nothing to do with the drug manufacturers or thier peons, corporate threats, or anything of that nature in the least.Davidtfull (talk) 20:17, 12 September 2009 (UTC)