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Ciprofloxacin: a novel therapeutic agent for iron overload?/ Siprofloksasin: demir yuklenmesi icin yeni bir terapotik ajan mi?

Introduction

Patients with thalassemia suffer from iron overload and other complications due to the chronic red blood cell transfusions. This complication results in low life expectancy if they do not receive proper chelating agents such as deferoxamine, which is known as the gold standard for depleting the iron from tissues. Deferoxamine is highly expensive and poorly absorbed from the gastrointestinal tract, and these disadvantages limit its regular use in the clinic. A safe and effective oral iron chelator has been the goal of therapeutic research about this disease for several decades [1]. Deferasirox and deferiprone are two orally-active iron chelators that have been approved for clinical use, but they are not yet easily accessible to all patients [2].

Ciprofloxacin, 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acid (Figure 1) can form a stable green complex with [Fe.sup.3+] and red complex with Fe2+ [3-5]. This complex can lead to several interactions between iron and the absorption of ciprofloxacin [6]. It is believed that formation of ferric ion complexes is the likely cause of the reduction in ciprofloxacin bioavailability in the presence of iron [7].

Thus far, there have not been any clear documents based on investigation of the iron-lowering effect of ciprofloxacin in tissues such as the liver or heart. This led us to study the preventive effect of ciprofloxacin on iron overload in rats, as laboratory animal models of iron overload [8].

Materials and Methods

Animals

Thirty male albino Wistar rats (250-300g) were used for the present study. The animals were purchased from Pasteur Institute of Iran and housed in stainless steel cages, handled daily, and provided with food and water. A 12h light/12h dark cycle was maintained, and the animals were tested during the light cycle. The animal experiments were carried out in accordance with the recommendations from the Declaration of Helsinki and internationally accepted principles in the use of experimental animals. The animals were divided into five groups (A-E), six animals in each.

[FIGURE 1 OMITTED]

Drugs and Solvents

Ciprofloxacin was purchased from Biopharmacy Company (Tehran, Iran) and iron dextran (Venofer) from Vinfor (International) Inc. (St. Gallen, Switzerland). Ciprofloxacin was dissolved easily in saline 0.9%.

Experimental Procedure

Thirty male albino Wistar rats were included in this study. They were divided into five groups as follows:

Group A: Control, receiving iron (0.03 g/kg per day iron dextran, intra-peritoneal (i.p.), every 2 days 1 injection) for one month.

Group B: Iron treatment (0.03 g/kg per day, every 2 days 1 injection) for one month and ciprofloxacin (7 mg/kg per day, i.p.) simultaneously for one month.

Group C: Iron treatment (0.03 g/kg per day, every 2 days 1 injection) for one month, followed by ciprofloxacin administration (7 mg/kg per day, i.p.) for one month (ciprofloxacin was started after iron discontinuation).

Group D: Iron treatment (0.03 g/kg per day, every 2 days 1 injection) for one month, followed by ciprofloxacin administration (7 mg/kg per day, i.p.) for two months (ciprofloxacin was started after iron discontinuation).

Group E: Iron treatment (0.03 g/kg per day, every 2 days 1 injection) for one month, followed by ciprofloxacin administration (14 mg/kg per day, i.p.) for one month (ciprofloxacin was started after iron discontinuation).

After the above-mentioned procedures, the rats were sacrificed with ether. Following sacrifice, one lobe of the liver and a portion of the myocardium were perfused with saline to deplete the blood. The removed liver and heart were stored at -20[degrees]C until further experiments were performed. For sample preparation, the tissue was homogenized and prepared for atomic absorption using nitric acid digestion. The tissues were dried at 120[degrees]C for 24 h. Nitric acid (1.0 ml HN[O.sub.3] (1N) per 0.2 g dried tissue) was added and the samples were incubated at 50[degrees]C for 16 h and then diluted with deionized water (3.5 ml deionized water per 1.0 ml HN[O.sub.3] (1N)). After centrifugation at 2700 x g for 10 min, 1 ml aliquots was stored in a sealed container at 4[degrees]C. Iron determinations were performed using an atomic absorption spectrometer (Varian Spectra 220 Atomic Absorption Spectrometer) [9]. Atomic absorption parameters were set as follows: wavelength: 248.3, slit width: 0.2 nm, gain: 63%, lamp current: 7.0 mA, measurement time: 10.0 sec, flame type: air/acetylene, air flow: 10.00 L/min, acetylene flow: 1.50 L/min, expansion factor: 1.0, and smoothing: 7 points.

Statistical Analysis

The amounts of iron were shown in mg/L and they were depicted as mean [+ or -] standard error. For comparing the groups, one-way ANOVA and Tukey Post Hoct tests was used and differences with p values < 0.05 were considered significant.

Results

The quantitation of iron content in the heart and liver of the examined rats showed a significant decrease in iron load in both organs of animals receiving ciprofloxacin, when compared with tissues form rats not receiving ciprofloxacin (Figures 2, 3). This effect of ciprofloxacin was more pronounced when it was administered simultaneously with iron, when it was administered for a longer duration (2 months rather than 1 month) and when it was given in higher doses (14 mg/kg per day), as shown in Table 1.

Discussion

Iron overload in patients with thalassemia and in other patients requiring red blood cell transfusion is an important factor in decreasing life expectancy. There are some evidences that ciprofloxacin may reduce iron load in the body. The mechanism of iron-ciprofloxacin complex formation is related to the reaction between 4-keto and 3-carboxyl groups of ciprofloxacin and iron. At pH 6.0, a 3:1 (ciprofloxacin: [Fe.sup.3+]) complex is formed rapidly. Bidentate chelators typically form 3:1 complexes with the normally six coordinate ferric ion. Thus, the chemistry of the ciprofloxacin-iron interaction is consistent with the following overall reaction [5,6]:

[Fe.sup.2+] + 3 ciprofloxacin +1/4 [O.sub.2] + [H.sup.+] [right arrow] [Fe.sup.3+] [(ciprofloxacin).sub.3] +1/2 [H.sub.2]O

[FIGURE 2 OMITTED]

In this study, we used ciprofloxacin as a second generation of fluoroquinolones for this purpose. We found that concurrent injection of ciprofloxacin and iron decreased the iron level in the liver and heart. Treatment with ciprofloxacin (7 mg/kg per day) for two months after discontinuation of iron was almost similar to simultaneous administration of iron and ciprofloxacin (7 mg/ kg per day) injection for one month. It should be mentioned that during the treatment with ciprofloxacin (14 mg/kg per day), we observed an apparent darkness of the rats' urine in comparison with control rats, which may implicate the excretion of ciprofloxacin-iron complex from the urine. This may be one explanation for the effectiveness of ciprofloxacin in decreasing iron overload.

Ciprofloxacin is a broad-spectrum antibiotic that is active against both gram-positive and gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division. In the adult population, ciprofloxacin is limited to the treatment of proven serious and lifethreatening bacterial infections, such as urinary tract infections, lower respiratory tract infections, acute sinusitis, skin infections, bone and joint infections, infectious diarrhea, and typhoid fever. The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host-defense mechanisms, and the status of renal and hepatic function. The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days; however, for severe and complicated infections, more prolonged therapy may be required. A maximum dose of 15 mg/kg (maximum 500 mg per dose) has been administrated for 60 days to treat anthrax [10].

[FIGURE 3 OMITTED]

Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.0% of orally treated patients. The most frequently reported drug-related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1.0%), and rash (1.0%).

An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events. The Food and Drug Administration (FDA) is notifying the makers of fluoroquinolone antimicrobial drugs for systemic use of the need to add a boxed warning to the prescribing information about the increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones [11].

With further investigations and confirmation of ciprofloxacin effectiveness in iron overload treatment in human studies and after considering the possible long-term adverse effects, it may be used orally as an effective and preventive drug in iron overloading induced cardiac-liver diseases such as thalassemia or hemochromatosis.

Acknowledgements

The authors would like to thank Ms. G. Hajhassani for her assistance during the course of this work and the Vice Chancellor of Iran University of Medical Sciences for financially supporting this study.

Received: November 19, 2008 Accepted: April 8, 2009

Gelis tarihi: 19 Kasim 2008 Kabul tarihi: 08 Nisan 2009

References

[1.] Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Se'chau R, Krebs- Brown AJ, Anderson JR, Alberti D, Sizer KC, Nathan DG. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomized, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361:1597-602.

[2.] Dubey AP, Sudha S, Parakh A. Deferasirox: the new oral iron chelator. Indian Pediatr. 2007;44:603-7.

[3.] Issopoulos PB. Spectrophotometric determination of trace amounts of iron (III) with norfloxacin as complexing reagent. Analyst 1989;189:627-30.

[4.] Eboka CJ, Aigbavboa SO, Akerele JO. Colorimetric determination of fluoroquinolones. J Antimicrob Chemother 1997;39:639-41.

[5.] Nagaralli BS, Seetharamappa J, Melwanki MB. Sensitive spectrophotometric methods for the determination of amoxicillin, ciprofloxacin and piroxicam in pure and pharmaceutical formulations. Pharm Biomed Anal 2002;29:859-64.

[6.] Lehto P, Kivisto KT, Pertti JN. The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin. Br J Clin Pharmacol 1994;37:82-5.

[7.] Kara M, Hasinoff BB, Mckay DW, Campell NR. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol 1991;31:257-61.

[8.] Kang JO, Jones C, Brothwell B. Toxicity associated with iron overload found in haemochromatosis: possible mechanism in a rat model. Clin Lab Sci 1998;11:350-4.

[9.] Schwartz KA, Fisher J, Adams ET. Morphologic investigations of the guinea pig model of iron overload. Toxicol Pathol 1993;21:311-20.

[10.] Chambers HF. Sulfonamides, trimethoprim and quinolones. In: Katzung BG, editor. Basic and Clinical Pharmacology. San Francisco, CA, USA: Lange Publication, 2007: 763-70.

[11.] FDA ALERT [7/8/2008]: (http: //www.fda.gov/medwatch/safety/2008/safety08.htm#Fluoroquinolone).

Address for Correspondence: Dr. Massoud Mahmoudian, Razi Institute for Drug Research Department of Pharmacology College of Medicine Iran University of Medical Sciences Tehran, Iran Phone: +98 21 88058696 E-mail: masmah99@iums.ac.ir

Mitra Elmi (1, 2), Parvaneh Rahimi-Moghaddam (1, 2), Khosrou Abdi (3), Mehdi Shafiee-Ardestani (3), Massoud Mahmoudian (1, 2)

(1) Razi Institute for Drug Research, Tehran, Iran

(2) Department of Pharmacology, College of Medicine, Iran University of Medical Sciences, Tehran, Iran

(3) Department of Medicinal Chemistry, College of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Table 1. A comparison of the iron levels in the liver and heart between
the various groups based on p-values

 P values for the groups

Organs B and C B and D B and E C and D C and E D and E

Liver 0.0001 0.949 0.0.019 0.0001 0.0001 0.093
Heart 0.001 0.999 0.014 0.001 0.0001 0.024

A- Control group (0.03 g/kg per day iron dextran, i.p., every other day
for one month); B- simultaneous i.p. injection of 0.03 g/kg per day
iron dextran and 7 mg/kg per day ciprofloxacin every other day for one
month; C- One-month i.p. injection of iron dextran (0.03 g/kg per day,
every other day), followed by ciprofloxacin administration (7 mg/kg
per day, i.p.) for one month; D- One-month i.p. injection of iron
dextran (0.03 g/kg per day, every other day), followed by ciprofloxacin
administration (7 mg/kg per day, i.p.) for two months; E- One-month
i.p. injection of iron dextran (0.03 g/kg per day, every other day),
followed by ciprofloxacin administration (14 mg/kg per day, i.p.) for
one month
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Title Annotation:Research Article
Author:Elmi, Mitra; Rahimi-Moghaddam, Parvaneh; Abdi, Khosrou; Shafiee-Ardestani, Mehdi; Mahmoudian, Massou
Publication:Turkish Journal of Hematology
Article Type:Clinical report
Geographic Code:7IRAN
Date:Sep 1, 2009
Words:2119
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