Ciprofloxacin

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of ciprofloxacin
General
Non-proprietary name Ciprofloxacin
other names
  • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid
  • Ciloxan
Molecular formula C 17 H 18 FN 3 O 3
Brief description

pale yellow, powdery solid

External identifiers / databases
CAS number
  • 85721-33-1 (ciprofloxacin)
  • 86393-32-0 (Ciprofloxacin · hydrochloride · mono hydrate )
  • 86483-48-9 (ciprofloxacin hydrochloride )
  • 93107-08-5 (ciprofloxacin monohydrochloride )
  • 93107-09-6 (ciprofloxacin mono sodium salt)
  • 97867-33-9 (ciprofloxacin lactate , 1: 1)
  • 130244-47-2 (Ciprofloxacin mixture with rimexolone)
EC number 617-751-0
ECHA InfoCard 100.123.026
PubChem 2764
ChemSpider 2662
DrugBank DB00537
Wikidata Q256602
Drug information
ATC code
Drug class

antibiotic

Mechanism of action

Gyrase inhibitors

properties
Molar mass
  • 331.34 g mol −1 (ciprofloxacin)
  • 385.82 g mol −1 (ciprofloxacin hydrochloride monohydrate)
Physical state

firmly

Melting point

318-320 ° C (ciprofloxacin hydrochloride monohydrate)

pK s value

6.09

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ciprofloxacin is a synthetic antibiotic with a broad spectrum of activity from the group of fluoroquinolones . The substance was developed in 1981 by a research chemist from Bayer ( Klaus Grohe ) and patented in 1983. Antibiotics in this group inhibit the gyrase of bacteria and thus their DNA replication and cell division . This prevents cells from dividing, especially gram-negative germs. Fluoroquinolones also have a bactericidal effect, the cause of which has not yet been clarified.

The drug came under increasing criticism because of its strong side effects. In 2008 and 2013, the FDA reported on newly observed serious side effects with systemically used fluoroquinolones and ordered appropriate measures. In 2015, according to medical reports, it reassessed the risk-benefit ratio of Cipro-, Levo-, Moxi- and Ofloxacin and significantly restricted its use in 2016. Warnings and restrictions on use of fluoroquinolones have also been issued several times in EU countries. The European Medicines Agency last reassessed the serious, potentially permanent and quality of life-impairing side effects in 2018 and recommended restrictions on use. As a result, the Federal Institute for Drugs and Medical Devices issued a comprehensive notification on April 8, 2019, further restricting the indications for fluoroquinolones and ordering a further update of the instructions for use and specialist information in order to point out possibly irreversible side effects. Doctors were informed via a Rote-Hand-Brief on April 8, 2019 that they would no longer use fluoroquinolones for simple infections.

Spectrum of activity

In addition to enterobacteria, the spectrum of activity includes other gram-negative pathogens such as Haemophilus and Salmonella species and pseudomonads ( problem germ Pseudomonas aeruginosa ). Ciprofloxacin is thus suitable against bacterial pathogens of an infectious bowel disease . In the case of complicated urinary tract infections , which are also triggered by intestinal bacteria or possibly by pseudomonads, it is considered a reserve antibiotic . Further areas of application are infections of the prostate gland, the biliary tract, the respiratory tract, the abdominal cavity ( peritonitis ) and many other infectious diseases if a correspondingly sensitive pathogen is detected; on this proof z. B. be dispensed with infections of the external auditory canal. Ciprofloxacin is also approved for prophylaxis and curative treatment after inhalation of anthrax pathogens. Like other modern quinolones, ciprofloxacin can be used in addition to macrolides and rifampicin to treat pneumonia caused by Legionella .

Ciprofloxacin inhibits E. Coli topoisomerases from a concentration of 0.012 mg / l. This is the minimum inhibitory concentration (MIC). It causes reversible but verifiable DNA damage in E. Coli . The MIC of other species is: Enterobacter cloacae 0.03–1 mg / l, Proteus mirabilis 0.03–0.5 mg / l, Pseudomonas aeruginosa 0.25–8 mg / l, Klebsiella spp. 0.06-1 mg / l, Streptococcus spp. 0.5-4 mg / l, Bacteroides spp. 8 mg / l, Enterococcus faecalis 0.5-64 mg / l and Staphylococcus aureus 0.46-2 mg / l.

Ciprofloxacin continues to have cytotoxic and cytostatic effects on human tissue: necrosis of cartilage cells was observed from 1 mg / l, DNA fragmentation and apoptosis of T cells from 2.5 mg / l, mitochondrial damage and apoptosis of tendon cells from 3 mg / l, Inhibition of the proliferation of fibroblasts from 5 mg / l, damage to mitochondrial DNA ( mtDNA ) and growth inhibition from 20 mg / l, and interruption of the cell cycle , genome mutation and loss of mtDNA from 25 mg / l. The cytotoxic and cytostatic effects of ciprofloxacin are of interest for possible use in chemotherapy for the treatment of cancer cells. In the umu test , however, ciprofloxacin showed a significantly stronger genotoxic effect than the chemotherapeutic agents etoposide , doxorubicin , cisplatin , fluorouracil , dacarbazine , bleomycin and mitomycin C (see also genotoxic potential ).

application

The use and thus also the dosage of ciprofloxacin depends on the infectious disease to be treated. In general, ciprofloxacin is administered twice a day, preferably orally (po), alternatively also intravenously. A single administration of 500 mg ciprofloxacin po in tablet form is sufficient for the treatment of gonorrhea (gonorrhea). Preparations for topical use as ear and eye drops are also available.

With normal use (500 mg single dose for a person weighing 70 kg) the concentration is 3 mg / l in serum / muscles, 6–9 mg / l in prostate / intestine, 18–21 mg / l in granulocytes , 6–30 mg / l in the lungs and 15–30 mg / l in the bile. The maximum serum concentration of ciprofloxacin is reached one hour after ingestion. The half-life is 4 hours. 40–50% of ciprofloxacin is excreted unchanged in the urine and 25–40% is metabolized. Of the identified metabolites, some are weaker and others are more potent than the original ciprofloxacin.

Fluoroquinolones are recommended not to be used for infections that get better untreated or are not severe . These include infections of the throat, abacterial (chronic) prostatitis , bronchitis , sinusitis , prophylaxis of travelers' diarrhea and recurring infections of the lower urinary tract ( urinary tract infections that do not go beyond the bladder). They should only be used to treat mild or moderate bacterial infections if other antibiotics commonly recommended for these infections cannot be used. It is important that fluoroquinolones should generally be avoided in patients who have previously had serious side effects with a fluoroquinolone or quinolone antibiotic. They should be used with particular caution in the elderly, patients with kidney disease, and patients who have had an organ transplant , as these patients are at higher risk of tendon injury .

Side effects

The most common side effects (but less than 10%) are nausea, diarrhea and rashes. After a single prophylactic dose of ciprofloxacin was given to 1,390 schoolchildren, the incidence of side effects was 44%, the most common being disorders of the nervous system. Acute liver damage occurs at a frequency of 1: 154. The risk of tendon damage with ciprofloxacin is 1: 227. In a group of 65-year-olds and older patients, 2.1% suffered a tendon rupture , 1.1% an aortic aneurysm, and 0.2% a retinal detachment after taking fluoroquinolones . Side effects can occur with a delay of days to weeks and increase in intensity over the long term. The side effects last an average of 14 months to 9 years and are often expressed as a constellation of various symptoms (exhaustion, concentration problems, neuropathies, tendinopathies and more).

Serious side effects of fluoroquinolones are not effectively treatable, so they result in physical disability in 29.3% of cases. Compared to other common antibiotics, fluoroquinolones are responsible for most of the permanent disabilities. A total of 210,705 suspected side effects and 2,991 deaths were reported to the FDA for fluoroquinolones through 2016. For ciprofloxacin, a total of 100,865 suspected side effects and 2,072 deaths were reported in 22,488 patients. Due to the low reporting rate of 1–10%, the unreported number of fluoroquinolone-associated side effects is estimated at 2–21 million and the unreported number of deaths is estimated at 29,000 to over 299,000. Deaths are possible from the first daily dose.

Ciprofloxacin can cause cartilage damage in children and adults due to its chondrotoxicity . In animal experiments, fluoroquinolones have caused cartilage growth disorders in young dogs , so they should not be used during pregnancy , breastfeeding or in children . However, due to its effectiveness against Pseudomonas , ciprofloxacin is approved for the treatment of children and adolescents (5–17 years) with acute attacks of cystic fibrosis caused by P. aeruginosa . Other side effects are neurotoxicity , liver toxicity and allergic reactions, and the Red man syndrome has also been described. Furthermore, there are several studies that have shown that ciprofloxacin can lower the seizure threshold : It should therefore only be used in patients with seizure disorders if there are strict indications.

A 2015 study showed that fluoroquinolones remove the cofactor iron through iron chelation of the α-ketoglutarate- dependent dioxygenase . This could disrupt collagen maturation and trigger epigenetic changes. The authors suggest this as a cause of the fluoroquinolone-induced kidney damage and tendinopathy (tendon damage ).

Induction of matrix metalloproteinase 1 in the cornea of ​​rats via artificial injuries (a), ciprofloxacin (b), ofloxacin (c) and levofloxacin (d).

There may be pain , swelling , tears, and inflammation of the tendons , including the back of the ankle (including shoulder, hand, or other tendon systems). This applies to people of all ages who take fluoroquinolone antibiotics including ciprofloxacin. The most common area of ​​pain and swelling is the Achilles tendon . Tendon ruptures may occur during or even several months after taking ciprofloxacin. The risk of tendon damage is higher in patients over 60 years of age, especially if they are taking steroids (corticosteroids) or have had kidney, heart or lung transplants . Tendon swellings (tendinitis) and tears (fracture) were also found in patients who took fluoroquinolones but did not show any of the other risk factors mentioned above. After ascertaining the said consequences, movements should be avoided. The side effect is explained by the increased effectiveness of matrix metalloproteinases , which can reduce the strength of the tendons.

In the USA, a black box warning is issued on the package insert for the antibiotic to warn of the sometimes irreversible serious side effects . The warning also states that the agent should not be the first choice in acute exacerbations of chronic bronchitis, in acute uncomplicated cystitis and acute sinusitis.

Psychotic disorders with a tendency to suicide are rare . However, study results based on WHO pharmacovigilance surveys suggest that fluoroquinolones are associated with a significantly increased risk of suicidality and committed suicide. Cases of this kind have increased significantly since 2008 and were most frequently seen after taking ciprofloxacin. According to the announcement of the drug commission of the German medical profession, a high number of unreported suicides after fluoroquinolone use can be assumed.

An increased risk of developing aortic aneurysms and dissections was also found. In Germany, the Federal Institute for Drugs and Medical Devices ordered appropriate information in the product information texts in October 2018 for all fluoroquinolones used systemically and inhalatively, including ciprofloxacin.

Due to disturbances in blood sugar levels, including hypoglycemia and hyperglycemia, caused by fluoroquinolones, the Federal Institute for Drugs and Medical Devices ordered a further update of the product information texts for ciprofloxacin (for systemic use) in February 2019. In diabetics, ciprofloxacin can cause life-threatening hypoglycaemia even after a single dose. Dysglycaemia can also occur in non-diabetics taking ciprofloxacin . Possible complications of fluoroquinolone-induced blood sugar disorders are central nervous effects (seizures, coma) with permanent neurological deficits. The pathomechanism is associated with increased cytosolic calcium concentrations and impairment of mitochondrial function in pancreatic beta cells. Fluoroquinolones are suspected to be responsible for an increase in type 2 diabetes in the United States.

Interactions

Patients with a history of cardiac arrhythmias or seizures should avoid foods containing caffeine (e.g. coffee, cola, black tea, green tea) and medicines (often combinations of painkillers, cold medicines). The breakdown of caffeine is catalyzed by cytochrome P450 ( isoenzyme 1A2). Some gyrase inhibitors intervene in the caffeine metabolism and block cytochrome P450, which affects the main breakdown pathway of N -demethylation to paraxanthin. This increases the effectiveness of the caffeine. A comparable interaction occurs with the structurally similar methylxanthine theophylline .

Ciprofloxacin also inhibits cytochrome P450 3A4 . This isoenzyme metabolizes 50% of common drugs and is therefore one of the most important members of the CYP family. Inhibition of CYP3A4 also affects the detoxification capacity of the PGP pump .

Ciprofloxacin must not be taken together with quetiapine as the breakdown of quetiapine can be slowed down significantly.

Ciprofloxacin must not be taken together with foods or drugs that have a (high) proportion of multiply charged metal ions (not together, for example, with milk or milk products ( Ca 2+ ) or antacids (e.g. Mg 2+ )), since the formation of a complex between metal ions and active ingredient leads to a relevant weakening of the effect of the same.

Since ciprofloxacin is a fluoroquinolone, like other antibiotics in this group, it could make hormonal contraceptives less effective . In the special case of ciprofloxacin, however, such a suspicion has not yet been confirmed. The current package insert for Ciprofloxacin (as of 2006) does not mention an interaction between this antibiotic and hormonal contraceptives. At least two clinical studies have shown that ciprofloxacin does not affect the effectiveness of the birth control pill. The non-interference of hormonal contraceptives was also the reason that ciprofloxacin instead rifampicin s at 4253 Student (inn) of the University of Oxford was spent to the spread of meningococcal - meningitis be prevented.

Grapefruits and their juice can significantly reduce the bioavailability, i.e. the effectiveness of ciprofloxacin (see the article on grapefruit , section "Interaction with medicinal products"). Even a time lag between taking ciprofloxacin and consuming grapefruit (juice) during the day does not prevent this interaction, as the breakdown of the responsible ingredients in the grapefruit takes several days.

Ciprofloxacin may interact with thyroid hormone replacement therapy and affect the way levothyroxine works.

Genotoxic potential

In prokaryotic test systems, ciprofloxacin has been shown to be highly genotoxic and highly mutagenic . In human-specific test systems, ciprofloxacin induces chromosome aberrations and aneuploidy . The concentrations investigated (5 - 25 µg / ml) correspond to therapeutic tissue levels. In the mouse model, ciprofloxacin caused genetic damage at an exposure level comparable to that of the human therapeutic dose range. In addition to nuclear DNA , mitochondrial DNA can also be damaged. Taking ciprofloxacin may increase the risk of skin cancer . Clinical observations suggest that ciprofloxacin can induce highly aggressive, metastatic and recurrent squamous cell carcinoma , especially in long-term treatment of immunocompromised patients .

Use during pregnancy / breastfeeding

Ciprofloxacin has teratogenic potential: in vivo was observed in therapeutically relevant doses to embryotoxic (u a.. Early , miscarriages and stillbirths , malformations and, organ damage) fertility impairing effects (u a.. Hormonal disorders , disorders of spermatogenesis , ultrastructural sperm damage testicular atrophy ). So were u. a. DNA damage of the sperm cells detected, which resulted in reduced fertility and embryonic malformations in the mouse model. Stillbirths have been observed in limited studies on exposed pregnant women. According to the technical information (as of 01/2019), available data on the use of ciprofloxacin in pregnant women show no evidence of malformations or fetal / neonatal toxicity . In addition, according to the technical information, there is no evidence from animal experiments on reproductive toxicity . It should be noted that ciprofloxacin passes into breast milk and should not be taken during pregnancy or while breastfeeding because of possible joint-damaging effects. According to approval data from the European Medicines Agency , other severe embryotoxic effects are also possible.

Trade names

Monopreparations

Agyr (A), Ciloxan (D, A, CH), Ciprobay (D), Ciproxin (A, CH), InfectoCipro (D), Keciflox (D), Otanol (A), Panotile Cipro (D), Quinox (T. ) numerous generics (D, A, CH)

Combination preparations

Ciproxin HC (CH)

Web links

Commons : Ciprofloxacin  - Collection of Images, Videos and Audio Files

further reading

  • PC Scholten, RM Droppert u. a .: No interaction between ciprofloxacin and an oral contraceptive. In: Antimicrobial agents and chemotherapy . Volume 42, Number 12, December 1998, pp. 3266-3268, PMID 9835524 . PMC 106032 (free full text).
  • R. Davis, A. Markham, JA Balfour: Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability. In: Drugs . Volume 51, Number 6, June 1996, pp. 1019-1074, PMID 8736621 .
  • Anu Hangas, Koit Aasumets, Nina J Kekäläinen, Mika Paloheinä, Jaakko L Pohjoismäki, Joachim M Gerhold, Steffi Goffart: Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of topoisomerase 2. In: Nucleic Acids Research. 46, 2018, pp. 9625-9636, doi: 10.1093 / nar / gky793 .

Individual evidence

  1. ↑ a b c d data sheet ciprofloxacin, ≥98.0% (HPLC) from Sigma-Aldrich , accessed on May 8, 2017 ( PDF ). .
  2. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, pp. 386-387, ISBN 978-0-911910-00-1 .
  3. ↑ a b c d e f Entry on ciprofloxacin in the ChemIDplus database of the United States National Library of Medicine (NLM)
  4. ^ Journal of Medicinal Chemistry . Vol. 33, pp. 1344, 1990.
  5. ↑ Zhongguo Yaoxue Zazhi. Chinese Pharmaceutical Journal . Vol. 27, p. 297, 1992.
  6. ↑ Shmuel Fuchs, Zvi Simon, Mayer Brezis: Fatal hepatic failure associated with ciprofloxacin. In: The Lancet. 343, 1994, p. 738, doi: 10.1016 / S0140-6736 (94) 91624-1 .
  7. ↑ Patent DE3142854 : 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, process for their preparation and antibacterial agents containing them. Registered on October 9, 1981 , published on May 11, 1983 , applicant: Bayer, inventor: Klaus Grohe, Hans-Joachim Zeiler, Karl Georg Metzger. ‌
  8. ↑ Patent DE3033157 : 7-Amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids, process for their preparation and antibacterial agents containing them. Registered on September 3, 1980 , published April 1, 1982 , applicant: Bayer, inventor: Klaus Grohe, Hans-Joachim Zeiler, Karl Georg Metzger. ‌
  9. ↑ María Tamayo, Rebeca Santiso, Jaime Gosalvez, Germán Bou, José Luis Fernández: Rapid assessment of the effect of ciprofloxacin on chromosomal DNA from Escherichia coli using an in situ DNA fragmentation assay . In: BMC Microbiology . tape 9 , no. April 13 , 2009, PMC 2670838 (free full text).
  10. ↑ Xilin Zhao, Robert J. Kerns, Muhammad Malik, Karl Drlica: Quinolone-Mediated Bacterial Death . In: Antimicrobial Agents and Chemotherapy . tape 52 , no. 2 , February 1, 2008, p. 385-392 , doi : 10.1128 / AAC.01617-06 , PMID 17724149 ( asm.org [accessed January 28, 2019]).
  11. ↑ Center for Drug Evaluation and Research: Drug Safety and Availability - FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. Accessed January 31, 2019 .
  12. ↑ Quinolone- and fluoroquinolone-containing medicinal products , EMA, accessed March 27, 2019.
  13. ↑ BfArM - Risk Assessment Process - Fluoroquinolones: Severe and long-lasting side effects in the muscles, joints and nervous system. Retrieved April 9, 2019 .
  14. ↑ G. Geisslinger et al .: Mutschler drug effects . 11th edition. WVG, Stuttgart 2019, p. 1015 ff.
  15. ↑ a b Technical information Ciprofloxacin Stada 100/250/500/750 mg film- coated tablets , Stadapharm GmbH, as of July 2019.
  16. ↑ Information for professionals INFECTOCIPRO® 2mg / ml ear drops | Yellow list. Retrieved September 28, 2017 .
  17. ↑ S. Ewig, P. Tuschy, G. Fätkenheuer: Diagnosis and therapy of Legionella pneumonia . In: Pneumology . tape 56 (2002) , pp. 695-703 , doi : 10.1055 / s-2002-35548 .
  18. ↑ María Tamayo, Rebeca Santiso, Jaime Gosalvez, Germán Bou, José Luis Fernández: Rapid assessment of the effect of ciprofloxacin on chromosomal DNA from Escherichia coli using an in situ DNA fragmentation assay . In: BMC Microbiology . tape 9 , no. April 13 , 2009, PMID 19364397 .
  19. ↑ Sora Schipper: Distribution and pharmacokinetics of fluoroquinolones in the rat pancreas. (PDF) Medical Faculty of the University of Rostock, 2011, accessed on January 31, 2019 .
  20. ↑ a b W. B. Graninger, W. Graninger, R. Ullrich, M. Köller, L. Erlacher: Effects of ciprofloxacin and ofloxacin on adult human cartilage in vitro. In: Antimicrobial Agents and Chemotherapy . tape 41 , no. 11 , November 1, 1997, pp. 2562-2565 , doi : 10.1128 / AAC.41.11.2562 , PMID 9371369 ( asm.org [accessed January 28, 2019]).
  21. ↑ Yong-Taek Jun, Hee-Jung Kim, Min-Jin Song, Ji-Hyang Lim, Dong-Gun Lee: In Vitro Effects of Ciprofloxacin and Roxithromycin on Apoptosis of Jurkat T Lymphocytes . In: Antimicrobial Agents and Chemotherapy . tape 47 , no. 3 , March 2003, PMID 12604563 .
  22. ↑ Judith Sendzik, Mehdi Shakibaei, Monika Schäfer-Korting, Ralf Stahlmann: Fluoroquinolones cause changes in extracellular matrix, signaling proteins, metalloproteinases and caspase-3 in cultured human tendon cells . In: Toxicology . tape 212 , no. 1 , August 15, 2005, p. 24-36 , doi : 10.1016 / j.tox.2005.04.002 .
  23. ↑ RJ Williams, E. Attia, TL Wickiewicz, JA Hannafin: The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism . In: The American Journal of Sports Medicine . tape 28 , no. May 3 , 2000, PMID 10843129 .
  24. ↑ JW Lawrence, S. Darkin-Rattray, F. Xie, AH Neims, TC Rowe: 4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells . In: Journal of Cellular Biochemistry . tape 51 , no. February 2 , 1993, PMID 8440750 .
  25. ^ R. Koziel, J. Szczepanowska, A. Magalska, K. Piwocka, J. Duszynski: Ciprofloxacin inhibits proliferation and promotes generation of aneuploidy in Jurkat cells . In: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society . tape 61 , no. April 2 , 2010, PMID 20436225 .
  26. ↑ Rafał Kozieł, Krzysztof Zabłocki, Jerzy Duszyński: Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells . In: Antimicrobial Agents and Chemotherapy . tape 50 , no. May 5 , 2006, PMID 16641433 .
  27. ↑ TOMASZ KLOSKOWSKI, NATALIA GURTOWSKA, JOANNA OLKOWSKA, JAKUB MARCIN NOWAK, JAN ADAMOWICZ: Ciprofloxacin is a potential topoisomerase II inhibitor for the treatment of NSCLC . In: International Journal of Oncology . tape 41 , no. October 6 , 2012, PMID 23042104 .
  28. ↑ a b Andreas Hartmann, Alfredo C. Alder, Theo Koller, Rosa M. Widmer: Identification of fluoroquinolone antibiotics as the main source of umuC genotoxicity in native hospital wastewater. (PDF) 1998, accessed January 20, 2019 .
  29. ↑ Quinolone Antibacterials (=  Handbook of Experimental Pharmacology ). Springer-Verlag, Berlin Heidelberg 1998, ISBN 978-3-642-80366-6 ( springer.com [accessed January 31, 2019]).
  30. ^ G Höffken, H Lode, C Prinzing, K Borner, P Koeppe: Pharmacokinetics of ciprofloxacin after oral and parenteral administration . In: Antimicrobial Agents and Chemotherapy . tape 27 , no. March 3 , 1985, PMID 3158275 .
  31. ↑ Dakshina M. Chilukuri, Jenny J. Zheng: CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW. (PDF) In: www.fda.gov. FDA, March 2004, accessed January 2019 .
  32. ↑ Siporin, Clifford, 1949-, Heifetz, Carl L., 1935-, Domagala, John M., 1951-: The New generation of quinolones . Ed .: M. Dekker. New York 1990, ISBN 0-8247-8224-0 .
  33. ^ R Wise, RM Lockley, M Webberly, J Dent: Pharmacokinetics of intravenously administered ciprofloxacin . In: Antimicrobial Agents and Chemotherapy . tape 26 , no. August 2 , 1984, PMID 6486762 .
  34. ↑ Quinolone- and fluoroquinolone-containing medicinal products | European Medicines Agency. Retrieved February 2, 2019 .
  35. ↑ Scientific Institute of the AOK (WIdO): notification. Archived from the original on February 3, 2019 ; accessed on February 3, 2019 .
  36. ↑ Los Angeles County Department of Public Health: Follow-up Survey Of Side Effects Of Single Dose Ciprofloxacin For Prophylaxis Of Meningococcal Disease In A Los Angeles County High School. (PDF) Archived from the original on April 30, 2019 ; accessed on February 21, 2018 .
  37. ↑ Xiao-Yu Wang, Yuan-Jie Xu, Man Zhu, Wang-Ping Jia, Dai-Hong Guo: Incidence, clinical features, and risk factors of fluoroquinolone-induced acute liver injury: a case-control study. March 8, 2019, accessed March 14, 2019 .
  38. ↑ Drugs Commission of the German Medical Association (AkdÄ): Fluoroquinolones: Inflammations and ruptures of the Achilles tendon. (PDF) AkdÄ, accessed on January 27, 2019 .
  39. ↑ Donald A. Redelmeier, Hong Lu, Nick Daneman: fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study . In: BMJ Open . tape 5 , no. 11 , November 1, 2015, p. e010077 , doi : 10.1136 / bmjopen-2015-010077 , PMID 26582407 ( bmj.com [accessed January 27, 2019]).
  40. ↑ Center for Drug Evaluation and Research: Drug Safety and Availability - FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. Accessed January 28, 2019 .
  41. ↑ Krzysztof Michalak, Aleksandra Sobolewska-Włodarczyk, Marcin Włodarczyk, Justyna Sobolewska, Piotr Woźniak: Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications . In: Oxidative Medicine and Cellular Longevity . tape 2017 , 2017, PMID 29147464 .
  42. ↑ FDA: FDA / CDER Drug Information Webinar - Fluoroquinolone Safety Labeling Changes. (PDF) In: www.fda.gov. FDA, April 2017, accessed January 22, 2019 .
  43. ↑ Kamaljeet Kaur, Raja Fayad, Arpit Saxena, Norma Frizzell, Anindya Chanda: Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network . In: The Journal of Community and Supportive Oncology . tape 14 , no. February 2 , 2016, PMID 26955658 .
  44. ↑ Charles Bennett MD Ph.DMPP: Should Black Box Warnings for Fluoroquinolones be Revised: Is the Bar Set Too High? (PDF) Pharmed Out Conference, June 2015, accessed on January 27, 2019 .
  45. ↑ Shmuel Fuchs, Zvi Simon, Mayer Brezis: Fatal hepatic failure associated with ciprofloxacin. In: The Lancet. 343, 1994, p. 738, doi: 10.1016 / S0140-6736 (94) 91624-1 .
  46. ↑ JM Kushner, HJ Peckman, CR Snyder: Seizures associated with fluoroquinolones. In: Ann Pharmacother . Volume 35, 2001, pp. 1194-1198.
  47. ↑ TO Grøndahl, IA Langmoen: Epileptogenic effect of antibiotic drugs. In: J Neurosurg . Volume 78, 1993, pp. 938-943.
  48. ^ S. Badal, YF Her, LJ Maher: Non-antibiotic effects of fluoroquinolones in mammalian cells. In: The Journal of biological chemistry. [electronic publication before printing] July 2015, doi: 10.1074 / jbc.M115.671222 , PMID 26205818 .
  49. ↑ Victor E Reviglio, Melinda A Hakim, Jae K Song, Terrence P O'Brien: Effect of topical fluoroquinolones on the expression of matrix metalloproteinases in the cornea. In: BMC Ophthalmology . tape 3 , October 6, 2003, PMID 14529574 .
  50. ↑ CIPRO Medication Guide - Reference ID: 2910764; BAYER Health Care Pharmaceuticals Inc, Wayne, NJ 07470 3/2011 (PDF; 281 kB)
  51. ^ H. Vyas, G. Krishnaswamy: Quinolone-associated rupture of the Achilles' tendon . In: New England Journal of Medicine , 2007. Article 357 (20): 2067.
  52. ^ Richard L. Elliott: Third World Diseases pp. 76-77.
  53. ↑ Suicidality with levofloxacin (TAVANIC) and other gyrase inhibitors. Arznei-Telegram 37: 67-8, July 1, 2006.
  54. ↑ Gyrase inhibitors and suicide. Arznei-Telegram 8: 87, 1995.
  55. ↑ J. Samyde, P. Petit, D. Hillaire-Buys, JL Faillie: Quinolone antibiotics and suicidal behavior: analysis of the World Health Organization's adverse drug reactions database and discussion of potential mechanisms . In: Psychopharmacology . April 2016, doi : 10.1007 / s00213-016-4300-3 .
  56. ↑ Suicidality during treatment with 5-fluoroquinolone antibiotics (from the ADR database). Medicines Commission of the German Medical Association, accessed on January 14, 2016 .
  57. ↑ Rote-Hand-Brief on systemic and inhalative fluoroquinolones: Risk of aortic aneurysms and aortic dissections. In: bfarm.de. Federal Institute for Drugs and Medical Devices, October 26, 2018, accessed on October 26, 2018 .
  58. ↑ Evaluation of procedure PSUSA / 00000775/201801 , Minutes of the PRAC meeting on 01-04 October 2018.
  59. ↑ BfArM - PSUR Single Assessment (PSUSA) - Implementation of the unanimous decision of the coordination group EMA / CMDh / 689167/2018 of October 17, 2018 regarding the approvals for human medicinal products with the active ingredient ciprofloxacin (systemic use). Archived from the original on April 2, 2019 ; accessed on February 19, 2019 .
  60. ↑ Elvia Canseco, Theodoros Kelesidis: Quinolone-induced Hypoglycemia: A Life-threatening but Potentially Reversible Side Effect . In: The American Journal of Medicine . tape 123 , no. 2 , February 1, 2010, p. e5 – e6 , doi : 10.1016 / j.amjmed.2009.07.022 ( amjmed.com [accessed February 19, 2019]).
  61. ↑ Wissam K Kabbara, Wijdan H Ramadan, Peggy Rahbany, Souhaila Al-Natour: Evaluation of the appropriate use of commonly prescribed fluoroquinolones and the risk of dysglycemia . In: Therapeutics and Clinical Risk Management . tape 11 , no. 22 , 2015, PMID 25960658 .
  62. ^ Anita Rachlis, Sandra Knowles, Elizabeth Phillips, William Cornish, Andrew E. Simor: Analysis of Spontaneous Reports of Hypoglycemia and Hyperglycemia Associated with Marketed Systemic Fluoroquinolones Made to the Canadian Adverse Drug Reaction Monitoring Program . In: The Canadian Journal of Hospital Pharmacy . tape 57 , no. 1 , 2004, doi : 10.4212 / cjhp.v57i1.345 ( cjhp-online.ca [accessed February 19, 2019]).
  63. ↑ Hany Ghaly, Christine Kriete, Seher Sahin, Anja Pflöger, Ulrike Holzgrabe: The insulinotropic effect of fluoroquinolones . In: Biochemical Pharmacology . tape 77 , no. 6 , 2009, PMID 19073153 .
  64. Jump up ↑ H. Ghaly, K. Hatlapatka, I. Rustenbeck: The insulinotropic effect of fluoroquinolones is counteracted by their inhibitory effect on pancreatic beta cell energy metabolism . In: Diabetology and Metabolism . tape 5 , no. 3 , 2010, doi : 10.1055 / s-0030-1255203 .
  65. ↑ Effect of fluoroquinolones on mitochondrial function in pancreatic beta cells | Request PDF. Retrieved February 19, 2019 .
  66. ↑ Stephen J. Telfer: Fluoroquinolone antibiotics and type 2 diabetes mellitus . In: Medical Hypotheses . tape 83 , no. 3 , 2014, PMID 24947193 .
  67. ↑ Deutscher Ärzteverlag GmbH, editorial office of the Deutsches Ärzteblatt: Pharmacokinetic interactions: The interaction potential of the fluoroquinolones . Ed .: Holger Petri. 2016 ( aerzteblatt.de [accessed on February 24, 2018]).
  68. ↑ R. Stahlmann: CYP450 and p-glycoprotein mediated drug interactions. (PDF) Spring Conference Section Antimycotic Therapy of the PEG., May 7, 2004, archived from the original on June 18, 2018 ; accessed on February 24, 2018 .
  69. ↑ Yellow list: Cipro - 1 A Pharma® 500 mg, film tab.
  70. ^ F. Maggiolo, G. Puricelli, M. Dottorini, S. Caprioli, W. Bianchi, F. Suter: The effect of ciprofloxacin on oral contraceptive steroid treatments , Drugs under Experimental and Clinical Research 17 (1991) 451-454.
  71. ↑ PC Scholten PC, Droppert RM, Zwinkels MGJ, Moesker HL, Nauta JJP, Hoepelman IM: No Interaction between Ciprofloxacin and an Oral Contraceptive . In: Antimicrobial Agents and Chemotherapy 42 (12), 1998: 3266-3268.
  72. ↑ P. Burke, SR Burne: Allergy associated with ciprofloxacin. In: BMJ. Volume 320, Number 7236, March 2000, p. 679, PMID 10710576 . PMC 27310 (free full text).
  73. ^ John G Cooper, Knut Harboe, Sofia K Frost, Øyvind Skadberg: Ciprofloxacin interacts with thyroid replacement therapy . In: BMJ: British Medical Journal . tape 330 , no. 7498 , April 2005, PMID 15860826 .
  74. ↑ SW Mamber, B Kolek, KW Brookshire, DP Bonner, J Fung-Tomc: Activity of quinolones in the Ames Salmonella TA102 mutagenicity test and other bacterial genotoxicity assays. In: Antimicrobial Agents and Chemotherapy . tape 37 , no. 2 , February 1993, p. 213-217 , PMID 8452351 , PMC 187641 (free full text).
  75. ^ DNA damage caused by antibiotic drugs - quinolones. Retrieved January 20, 2019 .
  76. ↑ L '. Majtánová, V. Majtán: Quinolone effects in the SOS chromotest and in the synthesis of biomacromolecules . In: Folia Microbiologica . tape 41 , no. 3 , June 1, 1996, p. 233-236 , doi : 10.1007 / BF02814622 .
  77. ↑ N Gorla, H Garcı́a Ovando, I Larripa: Chromosomal aberrations in human lymphocytes exposed in vitro to enrofloxacin and ciprofloxacin . In: Toxicology Letters . tape 104 , no. 1 , January 11, 1999, p. 43-48 , doi : 10.1016 / S0378-4274 (98) 00230-6 .
  78. ↑ (PDF) Ciprofloxacin inhibits proliferation and promotes generation of aneuploidy in Jurkat cells. Retrieved January 20, 2019 .
  79. ↑ J. Kuhlmann, A. Dalhoff, H.-J. Zeiler (Ed.): Quinolone Antibacterials . 1st edition. Springer, Berlin / Heidelberg 1998, ISBN 978-3-642-80364-2 , p. 7 .
  80. ↑ A. Mukherjee, S. Sen, K. Agarwal: Ciprofloxacin: mammalian DNA topoisomerase type II poison in vivo . In: Mutation Research . tape 301 , no. 2 , February 1993, p. 87-92 , PMID 7678175 .
  81. ↑ (PDF) Scholars Research Library Induction of micronucleus and abnormal sperm cells in albino mice exposed to ciprofloxacin. Retrieved January 20, 2019 .
  82. ↑ Jerzy Duszyński, Krzysztof Zabłocki, Rafał Kozieł: Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells . In: Antimicrobial Agents and Chemotherapy . tape 50 , no. 5 , May 1, 2006, pp. 1664–1671 , doi : 10.1128 / AAC.50.5.1664-1671.2006 , PMID 16641433 ( asm.org [accessed January 20, 2019]).
  83. ↑ Peter Karran, Peter Macpherson, Reto Brem, Matthew Peacock: DNA repair inhibition by UVA photoactivated fluoroquinolones and vemurafenib . In: Nucleic Acids Research . tape 42 , no. 22 , December 16, 2014, p. 13714–13722 , doi : 10.1093 / nar / gku1213 ( oup.com [accessed January 20, 2019]).
  84. ↑ AD Katsambas, TM Lotti, C. Dessinioti, AM D'Erme (Ed.): European Handbook of Dermatological Treatments . 3. Edition. Springer, Berlin / Heidelberg 2015, ISBN 978-3-662-45139-7 , pp. 242 .
  85. ↑ (PDF) Evaluation of the teratogenic potentials of Ciprofloxacin in Albino Rat. Accessed February 11, 2019 .
  86. ↑ Hamida Hamdi, Abd El-Wahab El-Ghareeb, Eman Sharawy: Fetal exposure to the antibiotic drug (ciprofloxacin) in Albino rats. (PDF) J Pharm Chem Pharmacol, December 7, 2018, accessed February 11, 2019 .
  87. ↑ (PDF) Reproductive performance of pregnant rats and embryotoxic effects of ciprofloxacin. Accessed February 11, 2019 .
  88. ↑ Nadia H. Ismail: Assessment of histopathological and histochemical changes in liver of pregnant female rats and their fetuses following Ciprofloxacin administration. (PDF) J. Egypt. Soc. Toxicol., July 17, 2006, accessed February 11, 2019 .
  89. ↑ Zumrut Dogan, Aymelek Cetin, Ebru Elibol, Nigar Vardi, Yusuf Turkoz: Effects of ciprofloxacin and quercetin on fetal brain development: a biochemical and histopathological study . In: The Journal of Maternal-Fetal & Neonatal Medicine . January 10, 2018, p. 1–9 , doi : 10.1080 / 14767058.2017.1418222 .
  90. ↑ (PDF) Adverse effects of ciprofloxacin on testis apoptosis and sperm parameters in rats. Accessed February 11, 2019 .
  91. ↑ Fatemeh Zobeiri, Rajab-Ali Sadrkhanlou, Siamak Salami, Karim Mardani, Abbas Ahmadi: The effect of ciprofloxacin on sperm DNA damage, fertility potential and early embryonic development in NMRI mice . In: Veterinary Research Forum . tape 3 , no. 2 , 2012, p. 131-135 , PMID 25653759 , PMC 4312808 (free full text).
  92. ↑ Fatemeh Zobeiri, Rajab-Ali Sadrkhanlou, Siamak Salami, Karim Mardani: Long-Term Effect of Ciprofloxacin on Testicular Tissue: Evidence for Biochemical and Histochemical Changes . In: International Journal of Fertility & Sterility . tape 6 , no. 4 , 2013, p. 294-303 , PMID 24520454 , PMC 3850316 (free full text).
  93. ↑ Fatemeh Zobeiri, Siamak Salami, Rajabali Sadrkhanlou, Tahmineh Peirouvi: Role of Mitochondria in Ciprofloxacin-Induced Apoptosis in Murine Sperm Cells . In: Reproductive Sciences . tape 20 , no. 9 , February 18, 2013, p. 1090-1095 , doi : 10.1177 / 1933719113477482 .
  94. ^ D. Raoult, G. Verghese, P. Jasper, M. Mathai, L. Verghese: Case reports: scrub typhus during pregnancy in India . In: Transactions of The Royal Society of Tropical Medicine and Hygiene . tape 97 , no. 5 , October 1, 2003, p. 570-572 , doi : 10.1016 / S0035-9203 (03) 80032-9 ( oup.com [accessed February 11, 2019]).
  95. ↑ Chhaya Goyal, Mohammad Rafi, Ghazala Khan: Anaphylaxis to parenteral ciprofloxacin in mother leading to fetal death. (PDF) Indian Journal of Pharmacy and Pharmacology, 2016, accessed February 11, 2019 .
  96. ↑ a b c Product information Ciprofloxacin Aristo® 250 mg / 500 mg / 750 mg film-coated tablets. (PDF) Aristo Pharma GmbH, January 2019, accessed on February 11, 2019 .
  97. ↑ Ciprofloxacin Kabi Annexes I - II - III. (PDF) European Medicines Agency, accessed on November 2, 2019 .
  98. ↑ Red List online, as of September 2009.
  99. ↑ AM comp. d. Switzerland, as of September 2009.
  100. ↑ AGES-PharmMed, as of September 2009.