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    Serum gallium concentration versus time curves for 6 neonatal foals after intragastric administration of GaM (20 mg/kg).

  • 1.

    Hondalus MK, Mosser DM. Survival and replication of Rhodococcus equi in macrophages. Infect Immun 1994;62:41674175.

  • 2.

    Giguere S, Prescott JF. Clinical manifestations, diagnosis, treatment, and prevention of Rhodococcus equi infections in foals. Vet Microbiol 1997;56:313334.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Weinstock DM, Brown AE. Rhodococcus equi: an emerging pathogen. Clin Infect Dis 2002;34:13791385.

  • 4.

    Horowitz ML, Cohen ND, Takai S, et al. Application of Sartwell's model (logarithmic-normal distribution of incubation periods) to age at onset and age at death of foals with Rhodococcus equi pneumonia as evidence of perinatal infection. J Vet Intern Med 2001;15:171175.

    • Search Google Scholar
    • Export Citation
  • 5.

    Martens JG, Martens RJ, Renshaw HW. Rhodococcus (Corynebacterium) equi: bactericidal capacity of neutrophils from neonatal and adult horses. Am J Vet Res 1988;49:295299.

    • Search Google Scholar
    • Export Citation
  • 6.

    Boyd NK, Cohen ND, Lim WS, et al. Temporal changes in cytokine expression of foals during the first month of life. Vet Immunol Immunopathol 2003;92:7585.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Chaffin MK, Cohen ND, Martens RJ, et al. Hematologic and immunophenotypic factors associated with the development of Rhodococcus equi pneumonia of foals at equine breeding farms with endemic infection. Vet Immunol Immunopathol 2004;100:3348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Breathnach CC, Sturgill-Wright T, Stiltner JL, et al. Foals are interferon gamma-deficient at birth. Vet Immunol Immunopathol 2006;112:199209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Jordan MC, Harrington JR, Cohen ND, et al. Effects of iron modulation on growth and viability of Rhodococcus equi and expression of virulence-associated protein A. Am J Vet Res 2003;64:13371346.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Harrington JR, Martens RJ, Cohen ND, et al. Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo. J Vet Pharmacol Ther 2006;29:121127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Weinberg GA. Iron chelators as therapeutic agents against Pneumocystis carinii. Antimicrob Agents Chemother 1994;38:9971003.

  • 12.

    Byrd TF, Horwitz MA. Chloroquine inhibits the intracellular multiplication of Legionella pneumophilia by limiting the available iron. J Clin Invest 1991;88:351357.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Kaneko Y, Thoendel M, Olakanmi O, et al. The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Invest 2007;117:877888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Bernstein LR. Mechanisms of therapeutic activity for gallium. Pharmacol Rev 1998;50:665682.

  • 15.

    Olakanmi O, Britigan B, Schlesinger L. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect Immun 2000;68:56195627.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Bernstein LR, Tanner T, Godfrey C, et al. Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Met Based Drugs 2000;7:3347.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Tsan MF. Mechanism of gallium-67 accumulation in inflammatory lesions. J Nucl Med 1986;26:8892.

  • 18.

    Begin R, Bisson G, Lambert R, et al. Gallium-67 uptake in the lung of asbestos exposed sheep: early association with enhanced macrophage-derived fibronectin accumulation. J Nucl Med 1986;27:538544.

    • Search Google Scholar
    • Export Citation
  • 19.

    Chitambar CR, Zivkovi Z. Uptake of gallium-67 by human leukemic cells: demonstration of transferrin receptor-dependent and transferrin-independent mechanisms. Cancer Res 1987;47:39293934.

    • Search Google Scholar
    • Export Citation
  • 20.

    Martens RJ, Miller NA, Cohen ND, et al. Chemoprophylactic antimicrobial activity of gallium maltolate against intracellular Rhodococcus equi. J Equine Vet Sci 2007;27:341345.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Bernstein LR. Therapeutic gallium compounds. In: Gielen M, Tiekink ERT, eds. Metallotherapeutic drugs and metal-based diagnostic agents: the use of metal in medicine. New York: John Wiley & Sons Ltd, 2005;259277.

    • Search Google Scholar
    • Export Citation

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Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals

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  • 1 Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164
  • | 3 Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
  • | 4 Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
  • | 5 Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
  • | 6 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
  • | 7 Department of Terrametrix, 285 Willow Rd, Menlo Park, CA 94025

Abstract

Objective—To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in healthy foals.

Animals—6 healthy neonatal foals.

Procedures—Each foal received GaM (20 mg/kg) by intragastric administration. Blood samples were obtained before (time 0) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration for determination of serum gallium concentrations by use of inductively coupled plasma mass spectroscopy.

Results—Mean ± SD pharmacokinetic variables were as follows: peak serum gallium concentration, 1,079 ± 311 ng/mL; time to peak serum concentration, 4.3 ± 2.0 hours; area under the serum concentration versus time curve, 40,215 ± 8,420 ng/mL/h; mean residence time, 39.5 ± 17.2 hours; area under the moment curve, 1,636,554 ± 931,458 ng([h]2/mL); and terminal half-life, 26.6 ± 11.6 hours. The mean serum concentration of gallium at 12 hours was 756 ± 195 ng/mL.

Conclusions and Clinical Relevance—Gallium maltolate administered via nasogastric tube at a dose of 20 mg/kg to neonatal foals resulted in gallium serum concentrations considered sufficient to suppress growth or kill Rhodococcus equi in macrophages and other infected tissues.

Abstract

Objective—To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in healthy foals.

Animals—6 healthy neonatal foals.

Procedures—Each foal received GaM (20 mg/kg) by intragastric administration. Blood samples were obtained before (time 0) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration for determination of serum gallium concentrations by use of inductively coupled plasma mass spectroscopy.

Results—Mean ± SD pharmacokinetic variables were as follows: peak serum gallium concentration, 1,079 ± 311 ng/mL; time to peak serum concentration, 4.3 ± 2.0 hours; area under the serum concentration versus time curve, 40,215 ± 8,420 ng/mL/h; mean residence time, 39.5 ± 17.2 hours; area under the moment curve, 1,636,554 ± 931,458 ng([h]2/mL); and terminal half-life, 26.6 ± 11.6 hours. The mean serum concentration of gallium at 12 hours was 756 ± 195 ng/mL.

Conclusions and Clinical Relevance—Gallium maltolate administered via nasogastric tube at a dose of 20 mg/kg to neonatal foals resulted in gallium serum concentrations considered sufficient to suppress growth or kill Rhodococcus equi in macrophages and other infected tissues.

Rhodococcus equi is a facultative intracellular bacterium that is able to survive and reproduce within macrophages1 causing severe, potentially fatal, bronchopneumonia in foals and immunocompromised people.2,3 Most foals likely become infected within the first few days of life,4 when they may have immature or ineffective innate immune responses.5-8 Thus, strategies designed to prevent or ameliorate these early infections may provide effective disease control.

Ferric iron (Fe3+) sequestration by host proteins, primarily transferrin, but also lactoferrin and ferritin, is an innate defense mechanism that limits availability of iron to most pathogenic microbes. Rhodococcus equi, however, which is dependent on adequate ferric iron for survival, can acquire and use transferrin and lactoferrin-bound iron, thereby circumventing this defense mechanism.9 Strategies designed to exploit iron dependency of various pathogenic organisms have proven effective in the management of a variety of bacterial diseases.10-13

Gallium, a trivalent semimetal that shares many similarities with ferric iron and functions as an iron mimic, has been used to control various microorganisms by exploiting their iron dependency.10,13-15 Gallium, particularly when administered orally, readily binds to plasma transferrin and lactoferrin14-16 and subsequently concentrates at sites of infection and inflammation and in macrophages,17-19 the target cell of R equi. As an iron mimic, gallium is incorporated into crucial iron-dependent DNA-synthesis enzyme systems of certain bacteria, causing inactivation of those enzymes and bacterial death.14 Gallium has bacteriostatic and bactericidal activity against R equi in vitro and in vivo.9,10

Gallium maltolate, a coordination complex of gallium and maltol, provides high gallium bioavailability following oral administration in humans and a variety of other species and has not been associated with substantial toxic effects or gastrointestinal irritation.16 Prophylactic intragastric administration of GaM to experimentally infected mice reduced their R equi tissue burdens.10 The study reported here was designed to determine the pharmacokinetics of intragastrically administered GaM in neonatal foals.

Materials and Methods

Animals and procedures—Six 1- to 2-day-old Quarter Horse foals of either sex (3 male and 3 female) weighing 38 to 52 kg (mean, 48.5 kg) were studied. Each foal received adequate transfer of maternal antibodies (serum IgG ≥ 800 mg/dL) as determined by a commercial assay.a Foals were deemed healthy on the basis of findings on physical examination, CBC, and serum biochemical profile. Each foal was housed in a box stall with its dam and allowed to nurse ad libitum. Foals received a distilled water solution of GaM (10 mg/mL) via nasogastric tube at a dose of 20 mg/kg. Foals were observed for adverse reactions during the study. Blood samples were collected for measurement of serum gallium concentration prior to (0 hours) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration. Serum was harvested and stored at −80°C, and all samples were assayed for gallium at the same time. The study was approved by the Texas A&M University Institutional Animal Care and Use Committee.

Determination of gallium concentrations—Gallium concentrations were measured by inductively coupled plasma mass spectroscopy. Serum samples were thawed at 37°C and diluted with 1% ultrapure HNO3 in deionized water,b in preparation for gallium analysis by inductively coupled plasma-mass spectroscopyc with the isotopes gallium Ga 71 and rhodium Rh 103 (as internal standards). Weight linear calibration was performed with a blank and 4 external standards (0.2, 2.0, 20, and 200 ng/mL). Data were acquired in peak hopping mode by use of the autolens feature and 3 replicate reads per determination. Calibration and baseline determinations were performed before and after the analytic runs. The inductively coupled plasma-mass spectroscopy detection limit for gallium in serum was 0.5 ng/mL, and method blanks averaged 0.6 ng/mL, well below the 1.5 ng/mL limit of quantification. Analytic precision and accuracy were acceptable. The relative percent difference (range divided by the mean value) of 9 duplicate pairs averaged 2%, whereas recovery of gallium added to 8 blanks (spiked blanks per laboratory control samples) and 8 samples (matrix spikes) averaged 107% and 100%, respectively. Instrumental response was linear over a calibration range (0 to 20 ng/mL), with a correlation coefficient (R2) of 0.9999 and a coefficient of variation of 1.4%.

Pharmacokinetic analysis—The AUC (calculated by the trapezoidal method), Cmax, Tpeak, and MRT of gallium were determined by use of a nonlinear curvefitting program.d Descriptive statistics were determined with commercially available software,e and all data were reported as mean ± SD.

Results

Serum concentrations of gallium were plotted versus time for each foal (Figure 1). For each foal, quantifiable gallium concentrations were detectable by the first time point (0.25 hours). Mean pharmacokinetic variables calculated for gallium included Cmax, Tpeak, AUC, MRT, area under the moment curve, and the terminal elimination half-life (Table 1). Mean Cmax for the foals was 1,079 ± 311 ng/mL, and 5 of 6 foals had a Cmax > 700 ng/mL. Mean Tpeak was 4.3 ± 2.0 hours, indicating rapid GaM absorption following intragastric administration. The mean serum concentration of gallium at 12 hours was 756 ± 195 ng/mL, with 5 of 6 foals having serum concentrations exceeding 700 ng/mL at 12 hours. Mean AUC, which is a measure of total exposure, was 40,215 ± 8,420 ng/mL/h, and MRT was 39.5 ± 17.2 hours. The area under the moment curve was 1,636,554 ± 931,458 ng([h]2/mL), and the terminal half-life was 26.6 ± 11.6 hours.

Figure 1—
Figure 1—

Serum gallium concentration versus time curves for 6 neonatal foals after intragastric administration of GaM (20 mg/kg).

Citation: American Journal of Veterinary Research 68, 10; 10.2460/ajvr.68.10.1041

Table 1—

Pharmacokinetic values of GaM (20 mg/kg) after intragastric administration in 6 neonatal foals.

Table 1—

Discussion

For the purposes of our study, a serum gallium concentration of 700 ng/mL was considered therapeutic. The therapeutic effectiveness of gallium against R equi is dependent on its concentration in infected tissues, principally macrophages, which are the target cell for R equi,1 rather than serum concentrations alone. Gallium, which exists in plasma predominantly bound to the ferric (Fe3+) sites on transferrin, is preferentially taken up by phagocytic cells at sites of inflammation, avidly accumulates at sites of infection and granulomatous lesions, and enters macrophages via both transferrin-dependent and transferrin-independent mechanisms.17-19 The designated therapeutic serum concentration (ie, 700 ng/mL) was based on a couple of factors. First, in murine macrophage-like (J774A.1) cells experimentally infected with virulent R equi, a 10μM concentration of GaM (elemental gallium, 697 ng/mL) in tissue culture media significantly reduced intracellular concentrations of R equi, compared with those in GaM-free media.20 Second, in mice treated prophylactically with GaM and experimentally infected with virulent R equi, it was deduced that a serum gallium concentration of 700 ng/mL reduces R equi tissue burdens by approximately 90%.10 Because gallium preferentially accumulates in activated phagocytic cells (eg, infection and inflammation),17,18 intracellular gallium concentrations were not assessed in macrophages from clinically normal foals in our study.

When gallium salts, such as chloride or nitrate, are dissolved in aqueous solution, they dissociate into gallium hydroxide species and the corresponding acids (eg, hydrochloric or nitric), leaving the resulting solution highly acidic and unsuitable for oral or parenteral administration.14 In addition, precipitation of the gallium as insoluble hydrated hydroxides in the gastrointestinal tract contributes to the low bioavailability of gallium from orally administered salts. A citrate-chelated gallium nitrate solution for injectionf is approved in the United States for the treatment of human cancer-related hypercalcemia. This formulation is administered as a continuous IV infusion for 5 days at 5 mg/kg/d to avoid toxic effects on the renal system that can occur with bolus IV administration.21 Toxic effects of GaM on the renal system has not been associated with GaM; presumably, this is because nearly all the gallium from GaM following oral administration becomes protein bound in the blood, whereas that from gallium nitrate following IV administration is largely present as ionic species that rapidly concentrate in and are eliminated by the kidneys.16

Gallium maltolate, developed by an author of our study (LRB), has gallium bioavailability of ≥ 25% to 57% after oral administration in healthy humans, with roughly linear absorption and elimination kinetics following single doses of 100 to 500 mg and a mean Cmax of 569 ng/mL at the 500-mg dose.16 The actual oral bio- availability of gallium in foals was not determined in our study because this calculation requires AUC data obtained following IV administration, which was not performed because a suitable IV formulation of GaM was not available. However, bioavailability appears to be sufficient to achieve gallium concentrations considered therapeutic.

The disposition of GaM in neonatal foals would be expected to differ somewhat from older foals. Changes in the physiologic processes that affect drug absorption, distribution, and metabolism and excretion occur as the foal matures. For example, absorption of an orally administered drug depends on gastric emptying time, which may be different in an older foal. Similarly, differences in body fluid compartments and plasma proteins can alter drug distribution. Finally, maturation of liver and kidney function can substantially alter drug metabolism and excretion.

Estimated pharmacokinetic parameters for GaM versus gallium nitrate after intraduodenal administration in dogs at a dose of 1.5 mg gallium/kg were as follows, respectively: Cmax, 2,200 ng/mL versus 310 ng/mL; Tpeak, 0.5 hours versus 3.1 hours; and AUC, 37,000 ng/mL/h versus 5,600 ng/mL/h.16 In mice, serum concentrations of gallium were measured after 10 days of GaM treatment (10 mg/kg or 50 mg/kg, oral gavage, q 24 h); at 2 hours after oral administration on treatment day 10, mean serum concentrations of gallium were 110.5 ng/mL and 559.3 ng/mL for GaM doses of 10 mg/kg and 50 mg/kg, respectively.10 For GaM administration on a milligram per kilogram basis, serum gallium concentrations were substantially less in mice than in foals. Whether this represents greater bioavailability in foals, compared with mice, is unknown.

To our knowledge, our study provides the first data on GaM administration to horses and gallium disposition in horses. At a dose of 20 mg/kg, GaM appears to be adequately bioavailable in foals and might therefore be useful for prophylaxis or treatment against R equi. Furthermore, GaM (20 mg/kg) is rapidly absorbed following intragastric administration, achieving gallium serum concentrations and ostensibly tissue concentrations that, on the basis of findings on murine and macrophage cell lines, should be adequate to suppress growth and kill intracellular R equi for at least 24 hours. However, additional studies involving multiple doses of GaM are necessary to determine appropriate dose regimens of GaM for neonatal and older foals. Prophylactic GaM treatment during the first weeks of the life of a foal may afford adequate protection against early infection with R equi, thereby providing additional time for maturation of requisite innate and adaptive immune functions. This could substantially reduce the incidence of disease on R equi endemic farms. In addition, GaM used alone or in conjunction with standard antimicrobial protocols may be valuable for the treatment of established R equi infections.

ABBREVIATIONS

GaM

Gallium maltolate

AUC

Area under the serum concentration versus time curve

Cmax

Maximum serum concentration

Tpeak

Time to reach maximum serum concentration

MRT

Mean residence time

a.

Snap Test, IDEXX Laboratories, Westbrook, Me.

b.

Seastar Baseline, Seastar Chemicals Inc, Sidney, BC, Canada.

c.

Model DRC 2, Perkin Elmer, Foster City, Calif.

d.

PK Analyst, MicroMath, Salt Lake City, Utah.

e.

Microsoft Excel, Microsoft Corp, Redmond, Wash.

f.

Ganite, Genta Inc, Berkeley Heights, NJ.

References

  • 1.

    Hondalus MK, Mosser DM. Survival and replication of Rhodococcus equi in macrophages. Infect Immun 1994;62:41674175.

  • 2.

    Giguere S, Prescott JF. Clinical manifestations, diagnosis, treatment, and prevention of Rhodococcus equi infections in foals. Vet Microbiol 1997;56:313334.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Weinstock DM, Brown AE. Rhodococcus equi: an emerging pathogen. Clin Infect Dis 2002;34:13791385.

  • 4.

    Horowitz ML, Cohen ND, Takai S, et al. Application of Sartwell's model (logarithmic-normal distribution of incubation periods) to age at onset and age at death of foals with Rhodococcus equi pneumonia as evidence of perinatal infection. J Vet Intern Med 2001;15:171175.

    • Search Google Scholar
    • Export Citation
  • 5.

    Martens JG, Martens RJ, Renshaw HW. Rhodococcus (Corynebacterium) equi: bactericidal capacity of neutrophils from neonatal and adult horses. Am J Vet Res 1988;49:295299.

    • Search Google Scholar
    • Export Citation
  • 6.

    Boyd NK, Cohen ND, Lim WS, et al. Temporal changes in cytokine expression of foals during the first month of life. Vet Immunol Immunopathol 2003;92:7585.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Chaffin MK, Cohen ND, Martens RJ, et al. Hematologic and immunophenotypic factors associated with the development of Rhodococcus equi pneumonia of foals at equine breeding farms with endemic infection. Vet Immunol Immunopathol 2004;100:3348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Breathnach CC, Sturgill-Wright T, Stiltner JL, et al. Foals are interferon gamma-deficient at birth. Vet Immunol Immunopathol 2006;112:199209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Jordan MC, Harrington JR, Cohen ND, et al. Effects of iron modulation on growth and viability of Rhodococcus equi and expression of virulence-associated protein A. Am J Vet Res 2003;64:13371346.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Harrington JR, Martens RJ, Cohen ND, et al. Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo. J Vet Pharmacol Ther 2006;29:121127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Weinberg GA. Iron chelators as therapeutic agents against Pneumocystis carinii. Antimicrob Agents Chemother 1994;38:9971003.

  • 12.

    Byrd TF, Horwitz MA. Chloroquine inhibits the intracellular multiplication of Legionella pneumophilia by limiting the available iron. J Clin Invest 1991;88:351357.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Kaneko Y, Thoendel M, Olakanmi O, et al. The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Invest 2007;117:877888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Bernstein LR. Mechanisms of therapeutic activity for gallium. Pharmacol Rev 1998;50:665682.

  • 15.

    Olakanmi O, Britigan B, Schlesinger L. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect Immun 2000;68:56195627.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Bernstein LR, Tanner T, Godfrey C, et al. Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Met Based Drugs 2000;7:3347.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Tsan MF. Mechanism of gallium-67 accumulation in inflammatory lesions. J Nucl Med 1986;26:8892.

  • 18.

    Begin R, Bisson G, Lambert R, et al. Gallium-67 uptake in the lung of asbestos exposed sheep: early association with enhanced macrophage-derived fibronectin accumulation. J Nucl Med 1986;27:538544.

    • Search Google Scholar
    • Export Citation
  • 19.

    Chitambar CR, Zivkovi Z. Uptake of gallium-67 by human leukemic cells: demonstration of transferrin receptor-dependent and transferrin-independent mechanisms. Cancer Res 1987;47:39293934.

    • Search Google Scholar
    • Export Citation
  • 20.

    Martens RJ, Miller NA, Cohen ND, et al. Chemoprophylactic antimicrobial activity of gallium maltolate against intracellular Rhodococcus equi. J Equine Vet Sci 2007;27:341345.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Bernstein LR. Therapeutic gallium compounds. In: Gielen M, Tiekink ERT, eds. Metallotherapeutic drugs and metal-based diagnostic agents: the use of metal in medicine. New York: John Wiley & Sons Ltd, 2005;259277.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Supported by the Grayson-Jockey Club Research Foundation, Lexington, Ky, and the Link Equine Research Endowment, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Tex.

Address correspondence to Dr. Martens.