US Food and Drug Administration Approval of Ciprofloxacin Hydrochloride for Management of Postexposure Inhalational Anthrax

Meyerhoff, Andrea; Albrecht, Renata; Meyer, Jacob L.; Dionne, Peter; Higgins, Karen M.; Murphy, Dianne

doi:10.1086/421491

Cited by 43 publications

(28 citation statements)

References 23 publications

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“…Any selection of dose and dose regimen for eventual therapeutic use in humans, however, must consider the higher serum protein binding levels in mice compared to those in hu- mans and both pharmacokinetic and efficacy data in nonhuman primates. The currently recommended treatment strategy for postexposure anthrax requires a lengthy (60-day) course of ciprofloxacin administered q12h (34). An infrequent or even singledose dosing strategy such as that demonstrated to be effective for oritavancin in the mouse model could thus prove to be beneficial after accidental or deliberate exposure of citizens to anthrax spores because it may potentially circumvent problems of poor compliance and resulting compromised treatment efficacy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

Heine

Bassett

Miller

et al. 2008

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

Heine

Bassett

Miller

et al. 2008

Antimicrob Agents Chemother

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“…It is also a preferred agent for the prevention and treatment of anthrax (Meyerhoff et al, 2004). Its mechanism of action is through the effective inhibition of DNA gyrase, thus preventing DNA replication in susceptible bacteria (Gellert et al, 1977;Sugino et al, 1977).…”

mentioning

confidence: 99%

Organic Anion Transporter 3 (Oat3/Slc22a8) Interacts with Carboxyfluoroquinolones, and Deletion Increases Systemic Exposure to Ciprofloxacin

VanWert

Srimaroeng²,

Sweet³

2008

Mol Pharmacol

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Carboxyfluoroquinolones, such as ciprofloxacin, are used for the treatment of numerous infectious diseases. Renal secretion is a major determinant of their systemic and urinary concentration, but the specific transporters involved are virtually unknown. In vivo studies implicate the organic anion transporter (OAT) family as a pivotal component of carboxyfluoroquinolone renal secretion. Therefore, this study identified the specific renal basolateral OAT(s) involved, thereby highlighting potential sources of carboxyfluoroquinolone-drug interactions and variable efficacy. Two heterologous expression systems, Xenopus laevis oocytes and cell monolayers, were used to determine the roles of murine and human renal basolateral mOat1/hOAT1 and mOat3/hOAT3. Ciprofloxacin was transported by mOat3 in both systems (K m value, 70 Ϯ 6 M) and demonstrated no interaction with mOat1 or hOAT1. Furthermore, ciprofloxacin, norfloxacin, ofloxacin, and gatifloxacin exhibited concentration-dependent inhibition of transport on mOat3 in cells with inhibition constants of 198 Ϯ 39, 558 Ϯ 75, 745 Ϯ 165, and 941 Ϯ 232 M, respectively. Ciprofloxacin and gatifloxacin also inhibited hOAT3. Thereafter, in vivo elimination of ciprofloxacin was assessed in wild-type and Oat3 null mice [Oat3(Ϫ/Ϫ)]. Oat3(Ϫ/Ϫ) mice exhibited significantly elevated plasma levels of ciprofloxacin at clinically relevant concentrations (P Ͻ 0.05, male mice; P Ͻ 0.01, female mice). Oat3(Ϫ/Ϫ) mice also demonstrated a reduced volume of distribution (27%, P Ͻ 0.01, male mice; 14%, P Ͻ 0.01, female mice) and increased area under the concentration-time curve (25%, P Ͻ 0.05, male mice; 33%, P Ͻ 0.01, female mice). Female Oat3(Ϫ/Ϫ) mice had a 35% (P Ͻ 0.01) reduction in total clearance of ciprofloxacin relative to wild type. In addition, putative ciprofloxacin metabolites were significantly elevated in Oat3(Ϫ/Ϫ) mice. The present findings indicate that polymorphisms of and drug interactions on hOAT3 may influence carboxyfluoroquinolone efficacy, especially in urinary tract infections.Ciprofloxacin is a broad-spectrum antimicrobial that is used in the treatment of numerous infectious diseases, including those afflicting the skin (Lipsky et al., 1999) (Gogos et al., 1991). It is also a preferred agent for the prevention and treatment of anthrax (Meyerhoff et al., 2004). Its mechanism of action is through the effective inhibition of DNA gyrase, thus preventing DNA replication in susceptible bacteria (Gellert et al., 1977;Sugino et al., 1977). Ciprofloxacin is a carboxylic acidcontaining fluoroquinolone (carboxyfluoroquinolone) that undergoes renal and hepatic elimination, with ϳ50% (oral) or ϳ80% (intravenous) appearing in the urine as parent compound and metabolites 24 h after administration in humans (Höffken et al., 1985). Approximately 20 to 40% of circulating Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.107.042853.ABBREVIATIONS: LLC-PK 1 , porcine kidney cells; AUC, area under the concentration-t...

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“…The absence of an effective treatment for postexposure inhalational anthrax (19) is mostly due to the fact that antibiotics alone are not always helpful at this stage because of the accumulation of toxins. For this reason, an effective therapeutic approach would include the simultaneous blocking of bacterial growth by antibiotics and inhibition of anthrax toxin action with antitoxins (11,14,26).…”

mentioning

confidence: 99%

Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities

Karginov

Nestorovich

Yohannes

et al. 2006

Antimicrob Agents Chemother

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Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of ␤-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new ␤-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of ␤-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.

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US Food and Drug Administration Approval of Ciprofloxacin Hydrochloride for Management of Postexposure Inhalational Anthrax

Cited by 43 publications

References 23 publications

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

Organic Anion Transporter 3 (Oat3/Slc22a8) Interacts with Carboxyfluoroquinolones, and Deletion Increases Systemic Exposure to Ciprofloxacin

Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities

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