The Fluoroquinolone Toxicity Research Foundation

 
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Prof. Dr. Ralf Stahlmann



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I. Arthropathies

Antibacterial quinolones induce joint cartilage lesions in juvenile animals at relatively low doses. They are therefore contraindicated in children and adolescents as well as in pregnant and lactating women.

Despite their chondrotoxic effects in juvenile animals restricted use in pediatrics has repeatedly been demanded and is considered to be justified in well-defined indications (e.g. ciprofloxacin treatment of infections due to P. aeruginosa in cystic fibrosis patients).

Observations made so far in man do not give a clear-cut answer to the question as to the degree of a quinolone therapy risk. The arthropathogenic risk of therapeutic doses certainly differs among the individual fluoroquinolones.

Quinolones differ especially in their antibacterial spectrum. The most important fluoroquinolnes now available include:

Group* Generic Name Trade Name
Group I Norfloxacin Barazan
Group II Ciprofloxacin Ciprobay
Ofloxacin Tarivid
Group III Levofloxacin Tavanic
Group IV Moxifloxacin Avalox

*Classification according to Paul-Ehrlich-Gesellschaft
[Naber KG, Adam D (1998) Classification of fluoroquinolones. Int J Antimicrob Agents 10: 255-257]

In animal studies we were able to show that

(1) feeding an Mg2+-deficient diet to juvenile rats causes joint cartilage lesions that cannot be distinguished from quinolone-induced lesions [Stahlmann et al., Antimicrob Agents Chemother 39: 2013-2018, 1995]
(2) Mg2+ substitution prevents fluoroquinolone-induced lesions in the rat [Stahlmann et al., Drugs 58 (Suppl 2): 393-394, 1999]
(3) treatment of an animal with subtoxic doses of a quinolone at slight Mg2+ deficiency induces lesions [Schwabe et al., Naunyn-Schmiedeberg's Arch Pharmacol 359/3: R163, 1999, Abstract 638]
(4) after fluoroquinolone administration concentrations are reached in cartilage that are higher than the corresponding concentrations in plasma at the same stage [Schwabe et al., Drugs 58 (Suppl 2): 385-387, 1999]

Symposium: In October 1995 a scientific, interdisciplinary symposium of the PEG (Paul-Ehrlich-Gesellschaft für Chemotherapie) was held in Berlin [title: "Quinolones in Pediatrics - Indications and Restrictions" (scientific management and organisation: Prof. Dr. Ralf Stahlmann and Dr. Christian Förster)]. Toxicologists, pediatricians, clinical pharmacologists and other scientists presented and discussed their views of this problem at this meeting. The most important contributions to this symposium were published in a supplement volume of Chemotherapy Journal [Vol. 5, Suppl 13: 1-40, 1996].

Current Topics of our Investigations: Our research team is now investigating the question whether, in addition to changes in immature joint cartilage, the growth process can be irreversibly inhibited by a lesion of cartilage of the epiphyseal growth plate. Corresponding effects have so far only been shown with one quinolone [Trovafloxacin (no longer on the market)]. The results from the manufacturer were described briefly in a review article [Stahlmann and Lode, in: The Quinolones, 2nd Edition, Andriole V, ed., Academic Press, London, pp 369-415, 1998].

A close cooperation exists predominantly with

(1) PD Dr. Mehdi Shakibaei, Institute of Anatomy, Freie Universität Berlin
(2) Dr. David van Sickle, School of Veterinary Medicine, Purdue University, West Lafayette, IN, USA).

II. Tendopathies

In co-operation with the research team of PD Dr. Mehdi Shakibaei (Institute of Anatomy, Freie Universität Berlin) we are investigating the mechanisms and risk factors of quinolone-induced tendopathies in animal studies as well as in in vitro experiments.

All known fluoroquinolones are likely to induce lesions of Achilles tendons, although this is a rare side effect. Nevertheless, several hundreds of cases have so far been described in the literature.

In view of the aspect of drug safety it is of special importance that after treatment with these drugs several months may go by before - possibly also caused by additional factors - tendinitis or ruptures occur. Therefore, it is very difficult to clearly define the causal relationship between drug exposure and side effects so that a systematic investigation of this unusual effect in an animal model gains in importance.

In electron microscopic investigations we were able to show that

(1) tendons of juvenile rats are more sensitive than those of adult animals
(2) simultaneous Mg2+ deficiency increases the degree of lesions
(3) electron microscopically demonstrable changes persist for several months

[Shakibaei et al., Drugs 58 (Suppl 2): 390-392, 1999;
Shakibaei et al., Antimicrob Agents Chemother 44/2: 261-266, 2000].

The main topics of our present investigations include:

(1) an exact biochemical characterisation of the changes using the immunoblotting method and other techniques
(2) comparisons of the tendotoxic potential of various quinolones
(3) determination of threshold concentrations of fluoroquinolones that do not induce tendon lesions
(4) recognition of risk factors and development of possibilities to prevent effects in patients at special risks.

Relevant Publications of our Research Team

Original Articles:

Stahlmann R, Merker H-J, Hinz N, Chahoud I, Webb J, Heger W, Neubert D (1990) Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations. Arch Toxicol 64: 193-204

Stahlmann R, Förster C, van Sickle D (1993) Quinolones in children: are concerns over arthropathy justified? Drug Safety 9: 397-403

Shakibaei M, Förster C, Merker H-J, Stahlmann R (1995) Effects of ofloxacin on integrin expression on epiphyseal mouse chondrocytes in vitro. Toxic in Vitro 9: 107-116

Stahlmann R, Förster C, Shakibaei M, Vormann J, Günther T, Merker H-J (1995) Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy. Antimicrob Agents Chemother 39: 2013-2018

Förster C, Kociok K, Shakibaei M, Merker H-J, Vormann J, Günther T, Stahlmann R (1996) Integrins on joint cartilage chondrocytes and alterations by ofloxacin or magnesium deficiency in immature rats. Arch Toxicol 70: 261-270

Förster C, Kociok K, Shakibaei M, Merker H-J, Stahlmann R (1996) Quinolone-induced cartilage lesions are not reversible in rats. Arch Toxicol 70: 474-481

Shakibaei M, Kociok K, Förster C, Vormann J, Günther T, Stahlmann R, Merker H-J (1996) Comparative evaluation of ultrastructural changes in articular cartilage of ofloxacin-treated and magnesium-deficient rats. Toxicol Pathol 24: 580-587

Vormann J, Förster C, Zippel U, Lozo E, Günther T, Merker H-J, Stahlmann R (1997) Effects of magnesium deficiency on magnesium und calcium content in bone and cartilage in developing rats in correlation to chondrotoxicity. Calcif Tissue Int 61: 230-238

Förster C, Schwabe R, Lozo E, Zippel U, Vormann J, Günther T, Merker H-J, Stahlmann R (1997) Quinolone-induced arthropathy: Exposure of magnesium-deficient aged rats or immature rats, mineral concentrations in target tissues and pharmacokinetics. Arch Toxicol 72: 26-32

Burckhardt JE, Hill MA, Lozo E, Förster C, Stahlmann R (1997) Immunohistochemistry of articular cartilage from immature Beagle dogs dosed with difloxacin. Toxicol Pathol 25: 475-480

Stahlmann R, Zippel U, Förster C, Schwabe R, Shakibaei M, Merker H-J, Borner K (1998) Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats. Antimicrob Agents Chemother 42: 1470-1475

Förster C, Rücker M, Shakibaei M, Baumann-Wilschke I, Vormann J, Stahlmann R (1998) Effects of fluoroquinolones and magnesium deficiency in murine limb bud cultures. Arch Toxicol 72: 411-419

Stahlmann R, Lode H (1998) Safety of quinolones. The Lancet (letter) 352/9136: 1313

Stahlmann R, Schwabe R, Pfister K, Lozo E, Shakibaei M, Vormann J (1999) Supplementation with magnesium and tocopherol diminishes quinolone-induced chondrotoxicity in immature rats. Drugs 58 (Suppl 2): 393-394

Stahlmann R, Kühner S, Shakibaei M, Schwabe R, van Sickle D (1999) Chondrotoxicity of ciprofloxacin in immature Beagle dogs. Drugs 58 (Suppl 2): 388-389

Schwabe R, Lozo E, Baumann-Wilschke I, Stahlmann R (1999) Chondrotoxicity and target tissue kinetics of ofloxacin in immature rats after multiple doses. Drugs 58 (Suppl 2): 385-387

Stahlmann R, Lode H (1999) Toxicity of quinolones. Drugs 58 (Suppl 2): 37-42

Shakibaei M, Pfister K, Schwabe R, Stahlmann R (1999) Effects of ofloxacin on the ultrastructure of Achilles tendon in rats. Drugs 58 (Suppl 2): 390-392

Stahlmann R, Kühner S, Shakibaei M, Schwabe R, Flores J, Evander SA, van Sickle DC (2000) Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations. Arch Toxicol 73: 564-572

Stahlmann R, Kühner S, Shakibaei M, Flores J, Vormann J, van Sickle DC (2000) Effects of magnesium deficiency on joint cartilage in immature Beagle dogs: immunohistochemistry, electron microscopy and mineral concentrations. Arch Toxicol 73: 573-580

Shakibaei M, Pfister K, Schwabe R, Vormann J, Stahlmann R (2000) Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a normal or magnesium-deficient diet. Antimicrob Agents Chemother 44/2: 261-266

Reviews and Contributions to Books:

Stahlmann R (1990) Safety profile of the quinolones. J Antimicrob Chemother 26 (Suppl D): 31-44

Stahlmann R, Förster C, Vormann J (1996) Phototoxizität, Neurotoxizität und Chondrotoxizität der Chinolone: experimentelle Daten und klinische Erfahrungen. Fortschr Antibakt Antineoplast Chemother 14-1: 193-209

Stahlmann R, Schwabe R (1997) Safety profile of grepafloxacin as compared with other fluoroquinolones. J Antimicrob Chemother 40 (Suppl A): 83-90

Stahlmann R, Lode H (1998) Concentration-effect relationship of the fluoroqinolones. In: Handbook of Experimental Pharmacology (vol. 127). Quinolone antibacterials. Kuhlmann J, Dalhoff A, Zeiler HJ (eds). Berlin - Heidelberg - New York, Springer-Verlag, pp 407-420

Stahlmann R, Lode H (1998) Safety Overview. Toxicity, aderse effects, and interactions. In: The Quinolones. 2nd Edition. Andriole V (ed). Academic Press, London, pp 369-415

Stahlmann R (1999) Unverwünschte Wirkungen der Fluorchinolone. Chemother J 8 ( (Suppl 18): 47-52

Stahlmann R (1999) Fluorchinolone zur Therapie von Atemwegsinfektionen. Pharmakologisch-toxikologische Aspekte. Pneumologie 53: 521-529

Stahlmann R, Lode H (1999) Fluoroquinolones. In: Clinical Infectious Diseases: A Practical Approach. Root RK (ed). Oxford University, New York - Oxford, pp 305-312