Objective—To determine the pharmacokinetics of
itraconazole after IV or oral administration of a solution
or capsules to horses and to examine disposition
of itraconazole in the interstitial fluid (ISF), aqueous
humor, and polymorphonuclear leukocytes after oral
administration of the solution.
Animals—6 healthy horses.
Procedure—Horses were administered itraconazole
solution (5 mg/kg) by nasogastric tube, and samples of
plasma, ISF, aqueous humor, and leukocytes were
obtained. Horses were then administered itraconazole
capsules (5 mg/kg), and plasma was obtained. Three
horses were administered itraconazole (1.5 mg/kg, IV),
and plasma samples were obtained. All samples were
analyzed by use of high-performance liquid chromatography.
Plasma protein binding was determined. Data
were analyzed by compartmental and noncompartmental
Results—Itraconazole reached higher mean ± SD
plasma concentrations after administration of the
solution (0.41 ± 0.13 µg/mL) versus the capsules
(0.15 ± 0.12 µg/mL). Bioavailability after administration
of capsules relative to solution was 33.83 ±
33.08%. Similar to other species, itraconazole has a
high volume of distribution (6.3 ± 0.94 L/kg) and a
long half-life (11.3 ± 2.84 hours). Itraconazole was not
detected in the ISF, aqueous humor, or leukocytes.
Plasma protein binding was 98.81 ± 0.17%.
Conclusions and Clinical Relevance—Itraconazole
administered orally as a solution had higher, more
consistent absorption than orally administered capsules
and attained plasma concentrations that are
inhibitory against fungi that infect horses.
Administration of itraconazole solution (5 mg/kg, PO,
q 24 h) is suggested for use in clinical trials to test the
efficacy of itraconazole in horses. (Am J Vet Res
Objective—To characterize pharmacokinetics of voriconazole in horses after oral and IV administration and determine the in vitro physicochemical characteristics of the drug that may affect oral absorption and tissue distribution.
Animals—6 adult horses.
Procedures—Horses were administered voriconazole (1 mg/kg, IV, or 4 mg/kg, PO), and plasma concentrations were measured by use of high-performance liquid chromatography. In vitro plasma protein binding and the octanol:water partition coefficient were also assessed.
Results—Voriconazole was adequately absorbed after oral administration in horses, with a systemic bioavailability of 135.75 ± 18.41%. The elimination half-life after a single orally administered dose was 13.11 ± 2.85 hours, and the maximum plasma concentration was 2.43 ± 0.4 μg/mL. Plasma protein binding was 31.68%, and the octanol:water partition coefficient was 64.69. No adverse reactions were detected during the study.
Conclusions and Clinical Relevance—Voriconazole has excellent absorption after oral administration and a long half-life in horses. On the basis of the results of this study, it was concluded that administration of voriconazole at a dosage of 4 mg/kg, PO, every 24 hours will attain plasma concentrations adequate for treatment of horses with fungal infections for which the fungi have a minimum inhibitory concentration ≤ 1 μg/mL. Because of the possible nonlinearity of this drug as well as the potential for accumulation, chronic dosing studies and clinical trials are needed to determine the appropriate dosing regimen for voriconazole in horses.
Objective—To determine pharmacokinetics, safety, and penetration into interstitial fluid (ISF), polymorphonuclear leukocytes (PMNLs), and aqueous humor of doxycycline after oral administration of single and multiple doses in horses.
Animals—6 adult horses.
Procedure—The effect of feeding on drug absorption was determined. Plasma samples were obtained after administration of single or multiple doses of doxycycline (20 mg/kg) via nasogastric tube. Additionally, ISF, PMNLs, and aqueous humor samples were obtained after the final administration. Horses were monitored for adverse reactions.
Results—Feeding decreased drug absorption. After multiple doses, mean ± SD time to maximum concentration was 1.63 ± 1.36 hours, maximum concentration was 1.74 ± 0.3 μg/mL, and elimination half-life was 12.07 ± 3.17 hours. Plasma protein binding was 81.76 ± 2.43%. The ISF concentrations correlated with the calculated percentage of non-protein-bound drug. Maximum concentration was 17.27 ± 8.98 times as great in PMNLs, compared with plasma. Drug was detected in aqueous humor at 7.5% to 10% of plasma concentrations. One horse developed signs of acute colitis and required euthanasia.
Conclusions and Clinical Relevance—Results suggest that doxycycline administered at a dosage of 20 mg/kg, PO, every 24 hours will result in drug concentrations adequate for killing intracellular bacteria and bacteria with minimum inhibitory concentration ≤ 0.25 μg/mL. For bacteria with minimum inhibitory concentration of 0.5 to 1.0 μg/mL, a dosage of 20 mg/kg, PO, every 12 hours may be required; extreme caution should be exercised with the higher dosage until more safety data are available.
Objective—To determine the degree of ocular penetration and systemic absorption of commercially available topical ophthalmic solutions of 0.3% ciprofloxacin and 0.5% moxifloxacin following repeated topical ocular administration in ophthalmologically normal horses.
Animals—7 healthy adult horses with clinically normal eyes as evaluated prior to each treatment.
Procedures—6 horses were used for assessment of each antimicrobial, and 1 eye of each horse was treated with topically administered 0.3% ciprofloxacin or 0.5% moxifloxacin (n = 6 eyes/drug) every 4 hours for 7 doses. Anterior chamber paracentesis was performed 1 hour after the final dose was administered, and blood samples were collected at 24 (immediately after the final dose), 24.25, 24.5, and 25 hours (time of aqueous humor [AH] collection). Plasma and AH concentrations of ciprofloxacin or moxifloxacin were determined by use of high-performance liquid chromatography.
Results—Mean ± SD AH concentrations of ciprofloxacin and moxifloxacin were 0.009 ± 0.008 μg/mL and 0.071 ± 0.029 μg/mL, respectively. The AH moxifloxacin concentrations were significantly greater than those of ciprofloxacin. Mean ± SD plasma concentrations of ciprofloxacin were less than the lower limit of quantification. Moxifloxacin was detected in the plasma of all horses at all sample collection times, with a peak value of 0.015 μg/mL at 24 and 24.25 hours, decreasing to < 0.004 μg/mL at 25 hours.
Conclusions and Clinical Relevance—Moxifloxacin was better able to penetrate healthy equine corneas and reach measurable AH concentrations than was ciprofloxacin, suggesting moxifloxacin might be of greater value in the treatment of deep corneal or intraocular bacterial infections caused by susceptible organisms. Topical administration of moxifloxacin also resulted in detectable plasma concentrations.
Objective—To determine penetration of topically and orally administered voriconazole into ocular tissues and evaluate concentrations of the drug in blood and signs of toxicosis after topical application in horses.
Animals—11 healthy adult horses.
Procedure—Each eye in 6 horses was treated with a single concentration (0.5%, 1.0%, or 3.0%) of a topically administered voriconazole solution every 4 hours for 7 doses. Anterior chamber paracentesis was performed and plasma samples were collected after application of the final dose. Voriconazole concentrations in aqueous humor (AH) and plasma were measured via high-performance liquid chromatography. Five horses received a single orally administered dose of voriconazole (4 mg/kg); anterior chamber paracentesis was performed, and voriconazole concentrations in AH were measured.
Results—Mean ± SD voriconazole concentrations in AH after topical administration of 0.5%, 1.0%, and 3.0% solutions (n = 4 eyes for each concentration) were 1.43 ± 0.37 μg/mL, 2.35 ± 0.78 μg/mL, and 2.40 ± 0.29 μg/mL, respectively. The 1.0% and 3.0% solutions resulted in significantly higher AH concentrations than the 0.5% solution, and only the 3.0% solution induced signs of ocular toxicosis. Voriconazole was detected in the plasma for 1 hour after the final topically administered dose of all solutions. Mean ± SD voriconazole concentration in AH after a single orally administered dose was 0.86 ± 0.22 μg/mL.
Conclusions and Clinical Relevance—Results indicated that voriconazole effectively penetrated the cornea in clinically normal eyes and reached detectable concentrations in the AH after topical administration. The drug also penetrated noninflamed equine eyes after oral administration. Low plasma concentrations of voriconazole were detected after topical administration.
Objective—To determine whether a chemokine
(RANTES)-like protein expressed by ciliary epithelium
plays a role in uveitis.
Sample Population—3 clinically normal horses intradermal,
5 eyes from 5 horses with recurrent uveitis,
and 10 normal eyes from 5 age- and sex-matched
Procedure—Cross-reactivity and sensitivity of recombinant
human (rh)-regulated upon activation, normal
T-cell expressed and secreted (RANTES) protein were
evaluated in horses by use of intradermal hypersensitivity
reactions and a chemotaxis assay. Aqueous
humor and ciliary body of eyes from clinically normal
horses and horses with uveitis were examined for
RANTES expression by use of an ELISA and reverse
transcription-polymerase chain reaction (RT-PCR).
Expression of RANTES mRNA and protein content of
primary cultures of equine ciliary pigmented epithelial
cells (RT-PCR) and culture supernatant (ELISA) were
measured 6 or 24 hours, respectively, after cultures
were stimulated with interleukin-1β and tumor necrosis
Results—Strong reactions to intradermal hypersensitivity
testing and significant chemotaxis of equine
leukocytes to rh-RANTES wereas observed. Aqueous
humor of eyes from horses with uveitis contained
increased concentrations of rh-RANTES-like protein
(mean ± SD, 45.9 ± 31.7 pg/ml), compared with aqueous
humor from clinically normal horses (0 pg/ml).
Ciliary body from horses with uveitis expressed
RANTES mRNA, whereas ciliary body from clinically
normal horses had low mRNA expression. Stimulated
ciliary pigmented epithelial cells expressed increased
amounts of rh-RANTES-like protein (506.1 ± 298.3
pg/ml) and mRNA, compared with unstimulated samples.
Conclusions and Clinical Relevance—Ciliary epithelium
may play a role in recruitment and activation of
leukocytes through expression of RANTES.
(Am J Vet Res 2002;63:942–947)
Objective—To determine appropriate intraocular lens (IOL) implant strength to approximate emmetropia in horses.
Sample Population—16 enucleated globes and 4 adult horses.
Procedures—Lens diameter of 10 enucleated globes was measured. Results were used to determine the appropriate-sized IOL implant for insertion in 6 enucleated globes and 4 eyes of adult horses. Streak retinoscopy and ocular ultrasonography were performed before and after insertion of 30-diopter (D) IOL implants (enucleated globes) and insertion of 25-D IOL implants (adult horses).
Results—In enucleated globes, mean ± SD lens diameter was 20.14 ± 0.75 mm. Preoperative and postoperative refractive state of enucleated globes with 30-D IOL implants was −0.46 ± 1.03 D and −2.47 ± 1.03 D, respectively; preoperative and postoperative difference in refraction was 2.96 ± 0.84 D. Preoperative anterior chamber (AC) depth, crystalline lens thickness (CLT), and axial globe length (AxL) were 712 ± 0.82 mm, 11.32 ± 0.81 mm, and 40.52 ± 1.26 mm, respectively; postoperative AC depth was 10.76 ± 1.16 mm. Mean ratio of preoperative to postoperative AC depth was 0.68. In eyes receiving 25-D IOL implants, preoperative and postoperative mean refractive error was 0.08 ± 0.68 D and −3.94 ± 1.88 D, respectively. Preoperative AC depth, CLT, and AxL were 6.36 ± 0.22 mm, 10.92 ± 1.92 mm, and 38.64 ± 2.59 mm, respectively. Postoperative AC depth was 8.99 ± 1.68 mm. Mean ratio of preoperative to postoperative AC depth was 0.73.
Conclusions and Clinical Relevance—Insertion of 30-D (enucleated globes) and 25-D IOL implants (adult horses) resulted in overcorrection of refractive error.
Objective—To describe the immunopathologic characteristics of superficial stromal immune-mediated keratitis (IMMK) immunopathologically by characterizing cellular infiltrate in affected corneas of horses.
Animals—10 client-owned horses with IMMK.
Procedures—Immunohistochemical staining was performed on keratectomy samples with equine antibodies against the T-cell marker CD3 and B-cell marker CD79a (10 eyes) and the T-helper cytotoxic marker CD4 and T-cell cytotoxic marker CD8 (6 eyes). Percentage of positively stained cells was scored on a scale from 0 (no cells stained) to 4 (> 75% of cells stained). Equine IgG, IgM, and IgA antibodies were used to detect corneal immunoglobulin via direct immunofluorescence (10 eyes). Serum and aqueous humor (AH) samples from 3 horses with IMMK were used to detect circulating and intraocular IgG against corneal antigens via indirect immunofluorescence on unaffected equine cornea.
Results—Percentage scores (scale, 0 to 4) of cells expressing CD3 (median, 2.35 [range, 0.2 to 3.7]; mean ± SD, 2.36 ± 1.08) were significantly greater than scores of cells expressing CD79a (median, 0.55 [range, 0 to 1.5]; mean, 0.69 ± 0.72). All samples stained positively for CD4- and CD8-expressing cells, with no significant difference in scoring. All samples stained positively for IgG, IgM, and IgA. No serum or AH samples collected from horses with IMMK reacted with unaffected equine cornea.
Conclusions and Clinical Relevance—Pathogenesis of superficial stromal IMMK included cell-mediated inflammation governed by both cytotoxic and helper T cells. Local immunoglobulins were present in affected corneas; however, corneal-binding immunoglobulins were not detected in the serum or AH from horses with IMMK.
Objective—To determine the role of intraocular bacteria in the pathogenesis of equine recurrent uveitis (ERU) in horses from the southeastern United States by evaluating affected eyes of horses with ERU for bacterial DNA and intraocular production of antibodies against Leptospira spp.
Sample Population—Aqueous humor, vitreous humor, and serum samples of 24 clinically normal horses, 52 horses with ERU, and 17 horses with ocular inflammation not associated with ERU (ie, non-ERU inflammation).
Procedures—Ribosomal RNA quantitative PCR (real-time PCR) assay was used to detect bacterial DNA in aqueous humor and vitreous humor from clinically normal horses (n = 12) and horses with chronic (> 3-month) ERU (28). Aqueous humor and serum were also evaluated for anti-Leptospira antibody titers from clinically normal horses (n = 12), horses with non-ERU inflammation (17), and horses with confirmed chronic ERU (24).
Results—Bacterial DNA was not detected in aqueous humor or vitreous humor of horses with ERU or clinically normal horses. No significant difference was found in titers of anti-Leptospira antibodies in serum or aqueous humor among these 3 groups. Only 2 horses, 1 horse with ERU and 1 horse with non-ERU inflammation, had definitive intraocular production of antibodies against Leptospira organisms.
Conclusions and Clinical Relevance—In horses from the southeastern United States, Leptospira organisms may have helped initiate ERU in some, but the continued presence of the organisms did not play a direct role in the pathogenesis of this recurrent disease.