An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

Sebbag, Lionel; Mochel, Jonathan P.

doi:10.1002/med.21716

Cited by 38 publications

(72 citation statements)

References 290 publications

(795 reference statements)

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“…Plasma and tear samples were collected at various times on Day 4 of each dosing regimen-a day chosen to reach steady state drug levels based on previous literature (10,11). Of note, tear samples were collected in eyes with histamine-induced conjunctivitis (12,13), and results of tear concentrations were reported in another study (14). On Day 4, a sparse sampling design allowed for collection of blood from 2/6 individuals for each of the following time points: 0 (pre-dose), + 15, 30, 60, 90, 120, 240, 480, and 720 min after oral dosing.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Oral Prednisone at Various Doses in Dogs: Preliminary Findings Using a Naïve Pooled-Data Approach

Sebbag

Mochel

2020

Front. Vet. Sci.

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This pilot study aimed to determine the plasma pharmacokinetics of prednisone and its active metabolite prednisolone following oral prednisone administration in dogs-using dosing regimens that cover anti-inflammatory to immuno-suppressive biological effects. Six healthy Beagle dogs were given 0.5, 1, 2, and 4 mg/kg prednisone orally once daily for 5 days, each successive course separated by a washout period of 9 days. At steady-state (Day 4), a sparse sampling design allowed for collection of blood from 2/6 individuals for each of the following time points: 0, 15, 30, 60, 90, 120, 240, 480, and 720 min. Prednisone and prednisolone were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oral prednisone was rapidly converted to prednisolone in dogs (≤30 min), with plasma prednisolone reaching ∼6-fold greater levels (0-656.1 ng/mL) than prednisone (0-98.8 ng/mL) overall. The ratio of plasma prednisolone/prednisone was constant across the dosing regimens, indicating a non-saturation of the hepatic 11-β-hydroxysteroid dehydrogenase that converts the prodrug to the active metabolite in dogs. The level of both corticosteroids increased with increasing dosing regimens, albeit in a non-linear manner. Non-compartmental pharmacokinetic parameters are described, including peak concentration (C max), time of peak concentration (T max), area under the concentration-time curve (AUC last), and the elimination half-life (t 1/2) for both corticosteroids, as well as clearance and volume of distribution during the terminal phase (V z) for the administered drug (prednisone). In sum, the present study utilizes a sparse sampling and naïve pooled-data approach to estimate pharmacokinetic parameters for prednisone and prednisolone, providing supporting preliminary knowledge that can be used to optimize corticosteroid efficacy and minimize toxicity in canine patients.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Oral Prednisone at Various Doses in Dogs: Preliminary Findings Using a Naïve Pooled-Data Approach

Sebbag

Mochel

2020

Front. Vet. Sci.

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“…Eppendorf tubes were stored at −80 • C until analysis. A combination of centrifugation and solvent elution was used to extract tears from Schirmer strips, using a simplified and optimized method compared to previously reported technique (9,18,19): once thawed, each Schirmer strip was placed into a 0.2-mL tube that was pre-punctured at its bottom with an 18-gauge needle, secured into a 2-mL Eppendorf tube via adhesive tape and centrifuged for 2 min at 3,884 g. After the first centrifugation, the strip in the 0.2-mL tube was wetted with 75 µL of methyl tert-butyl ether (MTBE) and allowed to sit for 5 min; of note, this particular solvent was chosen based on its superior ability to extract prednisolone from Schirmer strips as compared to methanol, acetonitrile, and methanol:water 50:50 v/v (pilot experiment using 10 STT per solvent; data not shown). (20).…”

Section: Tear Film Pharmacokinetics Following Instillation Of 1 Vs 2mentioning

confidence: 99%

“…For tears, 9 standard curve solutions were prepared by spiking blank canine tears with stock solution of prednisolone acetate to obtain the following concentrations: 0.02, 0.075, 0.2, 0.5, 1.5, 5, 20, 50 and 100 µg/mL. Tear calibration curve samples were processed in a similar manner to biological tear samples, which involved wetting Schirmer strips with standard solution until the 20-mm mark was reached, spiking prednisone-d7 internal standard onto the distal (dry) portion of the strips, and extracting tears with a combination of centrifugation and elution in MTBE (9). Of note, tear samples collected at 0-30 min following topical instillation of 1% prednisolone acetate were diluted with blank tears spiked with prednisone-d7 to ensure the measured concentration would fall within the range of the generated standard curve; specifically, the dilution factors were 1:40 for samples collected at 0 min and 1 min, 1:30 for 3 min and 5 min, and 1:5 for 15 min and 30 min.…”

Section: Drug Quantification In Tears and Plasma Samplesmentioning

confidence: 99%

Tear Film Pharmacokinetics and Systemic Absorption Following Topical Administration of 1% Prednisolone Acetate Ophthalmic Suspension in Dogs

et al. 2020

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The study aimed to determine the tear film pharmacokinetics following topical administration of 1% prednisolone acetate-assessing whether two drops would provide a superior kinetic profile compared to one drop-and to determine the fraction of an eye drop that reaches the systemic circulation in dogs. Two separate experiments were conducted in eight healthy Beagle dogs: (i) Instillation of 1 drop (35 µL) or 2 drops (70 µL) of 1% prednisolone acetate ophthalmic suspension in each eye, followed by tear collections with Schirmer strips from 0 to 720 min; (ii) Instillation of 1 or 2 drops of 1% prednisolone acetate in both eyes 4 times daily for 3 days, followed by blood collection 10-15 min after each topical administration on Day 3. Tear and blood samples were analyzed with high performance liquid chromatography to determine the levels of prodrug (prednisolone acetate), active metabolite (prednisolone) and total prednisolone (prednisolone total = prodrug + active metabolite). Prednisolone levels represented 10 and 72% of prednisolone total concentrations in tears and plasma, respectively, indicating a greater hydrolysis of prodrug in the blood vs. tear compartment. For eyes receiving one or two drops, tear film prednisolone total concentrations were high (∼3.1 mg/mL) immediately following topical administration but rapidly decreased by ∼45% at 1 min and ∼95% at 15 min. No differences were noted between 1 vs. 2 drops in tear film prednisolone total concentrations (including maximal concentration, C max) or residual drug levels in tears at any time point (P ≥ 0.097); however, instillation of 2 drops provided a higher average tear concentration (C avg) and overall drug exposure to the ocular surface (AUC last) over the 12-h sampling period (P = 0.009). Average plasma prednisolone total concentration represented ≤ 2% of the dose applied to the ocular surface, and did not differ significantly for dogs receiving 1 drop (17 ng/mL) or 2 drops (20 ng/mL) 4 times daily for 3 days (P = 0.438). In sum, topical corticotherapy is beneficial for inflammatory conditions of the canine anterior segment given the relatively high concentrations achieved in tears, although caution is warranted to prevent unwanted local or systemic adverse effects.

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“…24,27 Despite an overall reduction in TPC, serum albumin levels increased in canine tears with experimentally induced conjunctivitis, consistent with findings in animals and humans with naturally acquired ocular inflammatory conditions. 14,17,23 Ocular disease disrupts the blood-tear barrier and allows leakage of plasma compounds into the tear film, as previously described in dogs 14,28 and other species. 19,23 Changes in serum albumin levels increased with the severity of conjunctival inflammation, ranging from 106% to 2871% in mild-to-severe cases, respectively.…”

Section: Discussionmentioning

confidence: 91%

Impact of diurnal variation, sex, tear collection method, and disease state on tear protein levels in dogs

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Allbaugh

Mochel

et al. 2020

Veterinary Ophthalmology

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Objective To investigate the effects of various biological factors on total protein concentration (TPC) and serum albumin levels in canine tears. Animals studied 10 healthy beagles (5 female, 5 male) were used. Procedures Experiments were conducted on separate days, collecting tears with either capillary tubes or Schirmer strips, as follows: (i) Tear collection at 3 hours intervals (from 6 am to 12 am); and (ii) Tear collection before and 20 minutes following topical histamine application (1, 10, 375 mg/mL) to induce mild, moderate, and severe conjunctivitis, respectively. TPC and serum albumin were measured with infrared spectroscopy and ELISA, respectively. Results Tear film TPC and serum albumin ranged from 9.7‐26.1 mg/mL and 6.4‐1662.6 µg/mL, respectively. Protein levels did not differ significantly among time points (P ≥ .080). Median coefficient of variation (CV%) was lower with Schirmer strips compared to capillary tubes for both TPC (12% vs 15%, P = .020) and serum albumin (57% vs 78%, P = .232). TPC (P < .001), but not serum albumin was greater in male vs. female dogs. Serum albumin, but not TPC (P ≥ .099), increased significantly with each grade of conjunctivitis severity (P < .001), with no differences between collection devices (P ≥ .322); median increase was 106%, 1389%, and 2871% in eyes with mild, moderate, and severe conjunctivitis, respectively. Conclusions There is no apparent diurnal variation in canine tear protein levels. Blood‐tear barrier breakdown with conjunctivitis allows serum albumin to leak into the tear film at high concentrations. Schirmer strips compare well with capillary tubes for bioanalytical purposes in healthy and diseased eyes, and this collection method may offer improved reproducibility for protein quantification.

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An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

Cited by 38 publications

References 290 publications

Pharmacokinetics of Oral Prednisone at Various Doses in Dogs: Preliminary Findings Using a Naïve Pooled-Data Approach

Pharmacokinetics of Oral Prednisone at Various Doses in Dogs: Preliminary Findings Using a Naïve Pooled-Data Approach

Tear Film Pharmacokinetics and Systemic Absorption Following Topical Administration of 1% Prednisolone Acetate Ophthalmic Suspension in Dogs

Impact of diurnal variation, sex, tear collection method, and disease state on tear protein levels in dogs

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