Pharmacokinetics and safety of penciclovir following oral administration of famciclovir to cats

OBJECTIVE: To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats. ANIMALS: 8 adult cats. PROCEDURES: A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography-mass spectrometry at fixed time points after famciclovir administration. RESULTS: Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (C(max)) of penciclovir (350 +/- 180 ng/mL) occurred at 4.6 +/- 1.8 hours and mean +/- SD apparent elimination half-life was 3.1 +/- 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC(0-->)) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC(0-->) from phase 1. Dose-normalized penciclovir C(max)following administration of famciclovir every 12 or 8 hours (290 +/- 150 ng/mL or 780 +/- 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1. CONCLUSIONS AND CLINICAL RELEVANCE: Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.     

Tear-film osmolarity in normal cats and cats with conjunctivitis

Objective To compare the tear‐film osmolarity of normal cats and cats with conjunctivitis. Animal studied The population consisted of shelter, research, and privately owned cats. Procedures Cats were classified as normal or having conjunctivitis. An ophthalmic examination including Schirmer tear test (STT), fluorescein staining, tear‐film break‐up time (TFBUT), intraocular pressure (IOP), and slit‐lamp biomicroscopy of the anterior segment was performed. The severity of conjunctivitis was graded and assigned a numerical score. The Tear Lab^TM Osmolarity System was utilized to determine the tear‐film osmolarity. Unpaired t‐tests were used to compare tear‐film osmolarity, TFBUT, IOP, and STT of the two groups. Results A total of 93 cats (186 eyes) were examined. There were 37 normal cats (74 eyes) and 39 conjunctivitis cats (78 eyes). The mean age was 2.34 years. There was no statistical difference (P = 0.2065) between the median tear‐film osmolarity of normal cats (328.5 ± 17.94 mOsms/L) and conjunctivitis cats (325.0 ± 24.84 mOsms/L). Cats with conjunctivitis had an accelerated TFBUT (P < 0.0001) and lower IOPs (P < 0.0001) as compared to normal cats. No statistical difference was found between STT values (P = 0.1304). Conclusions The median tear‐film osmolarity of normal cats was 328.5 mOsms/L. Despite the accelerated TFBUT, conjunctivitis did not cause a statistically significant change in tear‐film osmolarity. The Tear Lab^TM Osmolarity System was easily used and well tolerated by the cats in the study.     

Evaluation of cytologic findings in feline conjunctivitis

Background

Cytologic examination of smears prepared from ocular swabs of conjunctiva from cats with conjunctivitis permits identification of the type of inflammation and possibly specific microorganisms. Results of studies of the diagnostic utility of cytology for detection of infectious causes of feline conjunctivitis have been inconsistent.

Objectives

The objectives of this study were to describe cytologic findings in cats with conjunctivitis and to compare those findings with results of PCR analysis for feline herpesvirus (FHV‐1), Chlamydophila felis (C felis), and Mycoplasma felis (M felis).

Methods

Conjunctival smears from 88 cats with conjunctivitis and 10 healthy control cats were stained with a Romanowsky stain and evaluated for the type of inflammation and evidence of an infectious agent. PCR analysis for FHV‐1, C felis, and M felis was performed.

Results

Infectious agents identified by PCR analysis were FHV‐1 in 9 cats (10%), C felis in 8 cats (9%), and M felis in 6 cats (7%). Inclusions interpreted as chlamydial inclusions were found in all cytologic smears from cats positive for C felis by PCR analysis and in 3 PCR‐negative cats. Inclusions interpreted as Mycoplasma organisms were found in 3 of 6 cats that were PCR‐positive for M felis and in 1 PCR‐negative cat. FHV‐1 inclusion bodies were not detected on cytologic examination.

Conclusions

Cytologic examination can be diagnostic for C felis infection when many typical inclusions are present. Cytologic examination was unreliable in diagnosing M felis infection, and viral inclusions of FHV‐1 were not found in specimens stained with Romanowsky stains.     

Pharmacokinetics of oral rufinamide in dogs

Wright, H. M., Chen, A. V., Martinez, S. E., Davies, N. M. Pharmacokinetics of oral rufinamide in dogs. J. vet. Pharmacol. Therap.  35 , 529–533. The objective of this study was to determine the pharmacokinetic properties and short‐term adverse effect profile of single‐dose oral rufinamide in healthy dogs. Six healthy adult dogs were included in the study. The pharmacokinetics of rufinamide were calculated following administration of a single mean oral dose of 20.0 mg/kg (range 18.6–20.8 mg/kg). Plasma rufinamide concentrations were determined using high‐performance liquid chromatography, and pharmacokinetic data were analyzed using commercial software. No adverse effects were observed. The mean terminal half‐life was 9.86 ± 4.77 h. The mean maximum plasma concentration was 19.6 ± 5.8 μg/mL, and the mean time to maximum plasma concentration was 9.33 ± 4.68 h. Mean clearance was 1.45 ± 0.70 L/h. The area under the curve (to infinity) was 411 ± 176 μg·h/mL. Results of this study suggest that rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half‐life sufficient to achieve the therapeutic level extrapolated from humans without short‐term adverse effects. Further investigation into the efficacy and long‐term safety of rufinamide in the treatment of canine epilepsy is warranted.     

Feline eosinophilic conjunctivitis

Objective To review 12 cases of histologically confirmed feline eosinophilic conjunctivitis, their clinical, cytologic, histologic and electronmicroscopic findings, results on PCR for FeHV‐1, treatment and outcome. Animals studied Twelve naturally occurring cases presented during a period of 26 months. Procedures Thorough ophthalmologic examination, conjunctival scrapings performed with the cytobrush method; histologic samples from the palpebral conjunctiva; PCR for FeHV‐1 on Schirmer Tear Test (STT) strips; saliva and nasal swabs, and retrospective evaluation of all results. Results The breed most commonly affected was the Domestic Shorthair (n = 8), followed by Persians (n = 2), Somali (n = 1) and Siamese (n = 1). Age at presentation was 1–15 years with a mean age of 7.2 years. Nine cats were castrated males; three cats were females: two of them were spayed. Unilateral (n = 7) or bilateral (n = 5) involvement with depigmentation and erosions of lid margin, blepharospasm, swelling and redness of conjunctiva and third eyelid were the most common clinical findings. Frequency of eosinophils in cytologic samples was more than 10% in every patient. PCR for FeHV‐1 on STT was negative in all cases. Histologically, eosinophils, lymphocytes, plasma cells, mast cells and macrophages were involved. On electronmicroscopy, viral particles were not detected. Ten cases needed long‐term anti‐inflammatory treatment. Conclusions The 12 reviewed cases suggest that feline eosinophilic conjunctivitis is a chronic inflammatory uni‐ or bilateral disease of the adult cat. Typically the lid margin was also involved, and was thickened, depigmented and erosive. Cytological examination of conjunctival scrapings was a valuable tool for detecting eosinophilic conjunctivitis. The cytological findings correlated well with the histopathological findings in our patients. Topical or systemic anti‐inflammatory drugs resolved the clinical symptoms in our cases within a short period of time. Neither electronmicroscopy nor PCR were able to detect involvement of FHV1 in the represented cases. The etiopathogenic role of FeHV‐1 remains undetermined.     

Population pharmacokinetic modelling and simulation of single and multiple dose administration of meloxicam in cats

Lehr, T., Narbe, R., Jöns, O., Kloft, C., Staab, A. Population pharmacokinetic modelling and simulation of single and multiple dose administration of meloxicam in cats. J. vet. Pharmacol. Therap. 33 , 277–286. The objectives of these investigations were: first, to describe the pharmacokinetic properties of meloxicam in cats following single and multiple oral administration and secondly, to simulate different oral dosage regimes for meloxicam in cats after multiple dose administration to illustrate and evaluate those dosage regimes for the alleviation of inflammation and pain in cats. Six healthy domestic short hair cats were treated orally with various dosage regimes (0.05–0.2 mg/kg/day). Plasma samples were collected at predefined times and quantitatively analysed using liquid/liquid extraction followed by reverse phase HPLC with UV‐detection. Meloxicam plasma concentration data were analysed using the population pharmacokinetic approach (software: NONMEM). The final model was used to simulate different dosage regimes. The plasma concentration–time profiles of meloxicam in cats after oral single and multiple dose administration were best described by an open one‐compartment model with first‐order absorption and first‐order elimination. Pharmacokinetic parameters were estimated to be 0.00656 L/h/kg for the total apparent body clearance (CL/F), 0.245 L/kg for the apparent volume of distribution (V/F), 1.26 1/h for the absorption constant (K_A) and 25.7 h for the mean plasma terminal half‐life. Simulations showed that the median trough steady‐state concentrations of 228 ng/mL were reached after five, one or 6 days following a single initial dose of 0.05, 0.1 and 0.2 mg/kg each followed by 0.05 mg/kg/day.     

Feline calicivirus: a neglected cause of feline ocular surface infections?

Objective To investigate the prevalence of feline calicivirus (FCV) infection in relation to ocular surface lesions in cats with upper respiratory tract diseases (URTD). Animals studied Ninety‐nine cats with ocular surface infection and symptoms or recent history of URTD were examined at various rescue shelters and hospitals. Procedure A complete general and ophthalmic examination was performed including Schirmer tear test, slit‐lamp biomicroscopy, fluorescein and lissamine green staining. Clinical and ocular symptoms were scored and recorded. Conjunctival samples were collected using a cytobrush, and nucleic acid extraction using RT‐PCR was carried out to analyze for the presence of various infectious agents. Results RT‐PCR detected either FCV, feline herpes virus type 1 (FHV‐1), Chlamydophila felis or Mycoplasma spp. in 63/99 samples. 30/63 samples were positive for FCV, 23/63 for C. felis, 21/63 for Mycoplasma spp., and 16/63 for FHV‐1. Out of the 30 FCV‐positive samples, 11 were positive only for FCV and in 19 samples FCV was seen in combination with other agents. FCV infection was highest in animals examined at the rescue centers and in the age group of 0–2 months. Erosive conjunctivitis was an important ocular finding. Oral ulcers were detected in all FCV‐infected cats. Conclusion Results indicate that FCV is highly prevalent in cats with URTD either as a sole infectious agent or in combination with other pathogens and therefore is a potential cause for ocular surface lesions during the URTD.     

The in vitro effects of proxymetacaine, fluorescein, and fusidic acid on real-time PCR assays used for the diagnosis of Feline herpesvirus 1 and Chlamydophila felis infections

Purpose To investigate the possible inhibition of qPCR assays used for the diagnosis of ocular infections in cats by proxymetacaine, fluorescein, and fusidic acid, which are commonly used in veterinary ophthalmology. Methods Fluorescein, proxymetacaine, and fusidic acid were tested for possible inhibition of a triplex qPCR assay designed to detect Chamydophila felis, Feline herpesvirus 1 (FHV‐1), and the feline 28S ribosomal DNA (28S rDNA) gene by comparing threshold cycle (C_t) values of samples with and without the three products. A second experiment was carried out to measure the effects of various dilutions of fusidic acid. Results No statistically significant differences were detected between the C. felis, FHV‐1, and 28S rDNA C_t values with and without proxymetacaine or fluorescein. However, there was a statistically significant increase in FHV‐1 (P < 0.01), C. felis (P < 0.01), and 28S rDNA (P < 0.05) C_t values when fusidic acid was used. When dilutions of fusidic acid were tested, the results revealed that only the 1:2 dilution caused a statistically significant increase (P < 0.01) in the FHV‐1 Ct values. Conclusion Proxymetacaine and fluorescein did not interfere with our qPCR assays for the detection of C. felis and FHV‐1. The presence of fusidic acid caused a small inhibitory effect of doubtful clinical significance. In vivo studies are required to establish the clinical relevance of this study and to confirm our findings.     

Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats

Albarellos, G. A., Montoya, L., Denamiel, G. A. A., Velo, M. C., Landoni, M. F. Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats. J. vet. Pharmacol. Therap.  35 , 534–540. The pharmacokinetic properties and bone concentrations of lincomycin in cats after single intravenous and intramuscular administrations at a dosage rate of 10 mg/kg were investigated. Lincomycin minimum inhibitory concentration (MIC) for some gram‐positive strains isolated from clinical cases was determined. Serum lincomycin disposition was best‐fitted to a bicompartmental and a monocompartmental open models with first‐order elimination after intravenous and intramuscular dosing, respectively. After intravenous administration, distribution was rapid (T_1/2(d) = 0.22 ± 0.09 h) and wide as reflected by the volume of distribution (V_(d(ss))) of 1.24 ± 0.08 L/kg. Plasma clearance was 0.28 ± 0.09 L/h·kg and elimination half‐life (T_1/2) 3.56 ± 0.62 h. Peak serum concentration (C_max), T_max, and bioavailability for the intramuscular administration were 7.97 ± 2.31 μg/mL, 0.12 ± 0.05 h, and 82.55 ± 23.64%, respectively. Thirty to 45 min after intravenous administration, lincomycin bone concentrations were 9.31 ± 1.75 μg/mL. At the same time after intramuscular administration, bone concentrations were 3.53 ± 0.28 μg/mL. The corresponding bone/serum ratios were 0.77 ± 0.04 (intravenous) and 0.69 ± 0.18 (intramuscular). Lincomycin MIC for Staphylococcus spp. ranged from 0.25 to 16 μg/mL and for Streptococcus spp. from 0.25 to 8 μg/mL.     

Doxycycline levels in preocular tear film of horses following oral administration

Objective To determine the concentration of doxycycline in preocular tear film following oral administration in horses as a possible therapeutic modality for infectious and keratomalacic equine keratitis. Procedure Eight broodmares without ocular disease from a Thoroughbred breeding facility were included in this study. Each mare received 20 mg/kg of doxycycline by mouth once daily in the morning for five consecutive days. Tears were collected 1 h after doxycycline administration starting on day one of administration and continuing for 10 consecutive days. Doxycycline levels in the tears were measured using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS). Results Doxycycline was present in the tears of each mare at low µg/mL levels with the highest concentration appearing on the third to fifth days (8.21–9.83 µg/mL). Doxycycline levels had fallen below quantifiable ranges by day 10. No systemic side-effects were noted in any of the horses included in this study. Conclusions Oral doxycycline is present in preocular tear film of normal horses with noninflamed eyes and may be useful as treatment in equine ulcerative keratomalacia. The oral dose listed was tolerated well by the horses in this study. The drug levels attained at 20 mg/kg once daily orally of doxycycline may aid in the treatment of corneal ulceration in horses, but further study is warranted.     

Pharmacokinetics and preliminary safety data of a single oral dose of bosentan,a dual endothelin receptor antagonist,in cats

The objective of this study was to evaluate the pharmacokinetic properties and adverse effect profile of single‐dose oral bosentan, a dual endothelin receptor antagonist, in healthy cats. Pharmacokinetic parameters were determined following a single mean ± SD oral dose of 3.2 ± 0.6 mg/kg of bosentan in 6 adult cats. Blood was collected for quantification of bosentan via high‐performance liquid chromatography with ultraviolet detection. Blood and urine were evaluated for CBC, plasma biochemical profile, and urinalysis, and repeat physical examinations were performed to evaluate for adverse effects. The mean terminal half‐life of bosentan was 20.4 ± 17.2 h. The mean peak plasma concentration was 0.49 ± 0.24 g/mL, and the mean time to maximum plasma concentration was 6.8 ± 8.6 h. The area under the curve was 5.14 ± 3.81 h·μg/mL. Oral bosentan tablets were absorbed in cats, and no clinically important adverse events were noted. Further evaluation of repeat dosing, investigation into the in vivo efficacy of decreasing endothelin‐1 concentrations in cats, as well as safety in conjunction with other medications is warranted.     

Pharmacokinetics of ceftiofur crystalline-free acid sterile suspension in the equine

Collard, W. T., Cox, S. R., Lesman, S. P., Grover, G. S., Boucher, J. F., Hallberg, J. W., Robinson, J. A., Brown, S. A. Pharmacokinetics of ceftiofur crystalline‐free acid sterile suspension in the equine. J. vet. Pharmacol. Therap. 34 , 476–481. Absolute bioavailability and dose proportionality studies were performed with ceftiofur in horses. In the absolute bioavailability study, thirty animals received either an intravenous dose of ceftiofur sodium at 1.0 mg/kg or an intramuscular (i.m.) dose of ceftiofur crystalline‐free acid (CCFA) at 6.6 mg/kg. In the dose proportionality study, 48 animals received daily i.m. ceftiofur sodium injections at 1.0 mg/kg for ten doses or two doses of CCFA separated by 96 h, with CCFA doses of 3.3, 6.6, or 13.2 mg/kg. Noncompartmental and mixed‐effect modeling procedures were used to assess pharmacokinetics (PK). CCFA was well absorbed with a bioavailability of 100%. AUC_0–∞ and C_max increased in a dose‐related manner following administration of the two doses of CCFA at 3.3, 6.6, and 13.2 mg/kg. The least‐squares mean terminal half‐life (t_½) following the tenth daily i.m. injection of ceftiofur sodium at 2.2 mg/kg was 40.8 h, but the least‐squares mean t_½ following the second i.m. injection of CCFA at 6.6 mg/kg was 100 h. The time that plasma ceftiofur equivalent concentrations remain above a threshold concentration of 0.2 μg/mL has been associated with efficacy, and following administration of two 6.6 mg/kg doses of CCFA, the mean time above 0.2 μg/mL was 262 h. Simulations with the nonlinear mixed‐effect PK model predicted that more than 97.5% of horses will have plasma ceftiofur equivalent concentrations >0.2 μg/mL for 96 h after the second 6.6 mg/kg dose of CCFA.     

A preliminary study of changes in tear film proteins in the feline eye following nictitating membrane removal

Objective To investigate the influence of nictitating membrane (third eyelid) removal on selected proteins in feline tears. Animal studied Domestic short‐haired cats (7–17 months; 2.6–5.2 kg) were used. Procedures Eye‐flush tears were collected periodically for up to 18 weeks from both eyes of animals with nictitating membranes removed, but nictitating gland left intact, (n = 4) or with nictitating membranes intact (n = 4). Tear comparisons were based on total protein content (TPC) using micro bicinchoninic acid assay, immunoglobulin A (IgA), and matrix‐metalloproteinase (MMP)‐9 measurements using sandwich enzyme‐linked immunosorbent assay (ELISA) and tear gelatinase activity using gelatin zymography. Expression of MMP‐2 and ‐9 in nictitating membranes removed at baseline (week 0) and eyes collected at 18 weeks were also investigated in histological sections using immunoperoxidase for visualization. Results Nictitating membrane removal did not significantly change TPC and MMP‐9 in tears within the first 4 weeks. MMP‐9 was not detected by ELISA in tears from eyes without nictitating membranes from week 5 onwards. IgA (%IgA of TPC) data varied between animals. Gelatin zymography showed increased MMP‐2 and ‐9 activity in tears from eyes without nictitating membranes at week 1 and a decrease following week 2 post‐surgery. MMP‐2 and ‐9 were immunolocalised to conjunctival goblet cells of removed nictitating membranes and to the conjunctival epithelium, respectively. After 18 weeks, the distribution of MMPs in tissue was comparable between eyes with and without nictitating membranes. Conclusions Based on this preliminary study, nictitating membrane removal appeared to cause long‐term changes in expression of tear proteins, including reduced MMP‐9 expression.     

Clinical and antiviral effect of a single oral dose of famciclovir administered to cats at intake to a shelter

Although famciclovir is efficacious in feline herpesvirus type 1 (FHV-1)-infected cats, effects of a single dose early in disease course have not been reported. In this two part, randomized, masked, placebo controlled study, cats received a single dose of 125 mg famciclovir (n = 43) or placebo (n = 43; pilot study), or 500 mg famciclovir (n = 41) or placebo (n = 40; clinical trial) on entering a shelter. FHV-1 PCR testing was performed, bodyweight and food intake were recorded, and signs of respiratory disease were scored prior to and 7 days following treatment. FHV-1 DNA was detected in 40% of cats in both parts at study entry. In the pilot study, ocular and nasal discharge scores increased from days 1 to 7 in famciclovir and placebo treated cats. Sneezing scores increased and bodyweight decreased in famciclovir-treated cats. The proportion of cats in which FHV-1 DNA was detected increased over time in all cats in the pilot study. In the clinical trial, food intake and median clinical disease scores for nasal discharge and sneezing increased from days 1 to 7 in both groups and demeanor scores worsened in famciclovir-treated cats. The proportion of cats shedding FHV-1 DNA was greater on day 7 than on day 1 in cats receiving 500 mg famciclovir. A single dose of famciclovir (125 or 500 mg) administered at shelter intake was not efficacious in a feline population in which 40% were already shedding FHV-1.     

Effects of bovine lactoferrin on in vitro replication of feline herpesvirus

Objective To investigate the effects of bovine lactoferrin on in vitro replication of feline herpes virus (FHV‐1) and to determine at what points during viral replication these effects occur. Sample population Cultured Crandell‐Reese feline kidney (CRFK) cells and FHV‐1 strain 727. Procedure Five concentrations of bovine lactoferrin (0.5, 1, 2, 5, and 10 mg/mL) were added at one or more of three time points during conventional plaque reduction assays: (a) uninfected CRFK cells were incubated in lactoferrin‐containing medium for 30 min prior to viral adsorption; (b) virus was suspended in lactoferrin‐containing medium prior to and during adsorption, or (c) CRFK cells were incubated with lactoferrin‐containing medium for 48 h following viral adsorption. Plaques were counted and antiviral effect expressed as percent inhibition relative to control medium that contained no lactoferrin. Results Exposure of CRFK cells to lactoferrin prior to or during viral adsorption inhibited FHV‐1 replication by 87–96% (mean: 91%). Application of lactoferrin following viral adsorption had no appreciable effect on FHV‐1 replication. No additive or synergistic effects were noted when lactoferrin was added at multiple steps. These effects were similar at all concentrations of lactoferrin tested. Cytotoxic effects of lactoferrin on CRFK cells were not observed at any concentration tested. Conclusions and clinical relevance Bovine lactoferrin has a notable inhibitory effect on the in vitro replication of FHV‐1 prior to and during, but not following viral adsorption. These findings strongly suggest that lactoferrin inhibits FHV‐1 adsorption to the cell surface and/or penetration of the virus into the cell. Clinical effects of topical lactoferrin in acute or recrudescent herpetic episodes in cats warrant investigation.     

Tear film breakup times in young healthy cats before and after anesthesia

The objectives of this study were: (i) to determine tear film breakup times (BUTs) in young healthy cats; (ii) to determine tear film BUTs in feline eyes within 8-20 h following general anesthesia; (iii) to determine if tear film BUTs vary significantly preoperatively when compared with values obtained 8-20 h postoperatively; (iv) to determine if Schirmer tear test (STT) values correlate with tear film BUTs in young healthy cats; and (v) to determine if the isolation of particular etiologic agents from conjunctival swabs of healthy cats affects tear film BUTs. We studied eighteen healthy Domestic Short-haired (n=14) and Domestic Long-haired (n=4) cats, with normal ocular examinations, ranging in age from 0.5 to 3 years. Complete ophthalmic examinations, including tear film BUTs, were performed on all cats. Conjunctival swabs from each eye of all cats and blood samples from all cats were collected and submitted for polymerase chain reaction screening for feline herpes virus, Chlamydophila felis, Mycoplasma spp., and calicivirus. In 10 of 18 cats, STT values and tear film BUTs were measured before general anesthesia was administered and again within 8-20 h following the end of anesthesia. Mean preanesthesia tear film BUTs for all 18 cats were 17.4+/-4.6 s OD and 16.0+/-4.5 s OS. Mean postanesthesia tear film BUT results were 12.5+/-4.3 and 13.1+/-4.0 s OD and OS, respectively. Postanesthesia tear film BUTs were significantly more rapid than those measured before anesthesia (OD only). There was also a positive correlation, both before and after anesthesia, between STT values in both eyes (OU) and tear film BUTs OU. The isolation or lack of isolation of conjunctival microorganisms using PCR did not significantly affect tear film BUTs. Mean tear film BUT in young healthy domestic cats is 16.7+/-4.5 s. Tear BUT is positively correlated with STT values. Although mean tear film BUTs OD at 8-20 h following anesthesia were more rapid than preanesthesia values, this difference did not appear clinically relevant.     

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross‐over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean T_max = 15.9 hr, C_max = 21.5 ng/mL, AUC_0‐24 = 100 ng*hr/mL, AUC_0‐∞ = 260 ng*hr/mL and calculated half‐life = 26.8 hr. Single oral administration of mirtazapine resulted in mean T_max = 1.1 hr, C_max = 83.1 ng/mL, AUC_0‐24 = 377 ng*hr/mL, AUC_0‐∞ = 434 ng*hr/mL and calculated half‐life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean T_max = 2.1 hr, C_max = 39.6 ng/mL, AUC_0‐24 = 400 ng*hr/mL, AUC_0‐∞ = 647 ng*hr/mL and calculated half‐life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.     

Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals

Chaffin, M. K., Fajt, V., Martens, R. J., Arnold, C. E., Cohen, N. D., O’Conor, M., Taylor, R. J., Bernstein, L. R. Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365‐2885.2009.01150.x. Gallium is a trivalent semi‐metal with anti‐microbial effects because of its incorporation into crucial iron‐dependent reproductive enzyme systems. Gallium maltolate (GaM) provides significant gallium bioavailability to people and mice following oral administration and to neonatal foals following intragastric administration. To study the prophylactic and therapeutic effects of GaM against Rhodococcus equi pneumonia in foals, we developed a methylcellulose formulation of GaM (GaM‐MCF) for oral administration to neonatal foals. Normal neonatal foals were studied. Six foals received 20 mg/kg and another six foals received 40 mg/kg of GaM‐MCF orally. Serial serum samples were collected and serum gallium concentrations were determined using inductively coupled plasma mass spectroscopy. Gallium was rapidly absorbed (T_max of 4 h), and a mean C_max of 0.90 or 1.8 μg/mL was achieved in foals receiving 20 or 40 mg/kg respectively. Marked variability existed in C_max among foals: only half of the foals receiving 20 mg/kg attained serum concentrations of >0.7 μg/mL, a level suggested to be therapeutic against R. equi by previous studies. Mean elimination half‐life was 32.8 or 32.4 h for foals receiving 20 or 40 mg/kg respectively. The results of this study suggest that at least 30 mg/kg orally every 24 h should be considered in future pharmacodynamic and efficacy studies.     

Characterization of the pharmacokinetic disposition of levofloxacin in stallions after intravenous and intramuscular administration

The target of the present study was to investigate the plasma disposition kinetics of levofloxacin in stallions (n = 6) following a single intravenous (i.v.) bolus or intramuscular (i.m.) injection at a dose rate of 4 mg/kg bwt, using a two‐phase crossover design with 15 days as an interval period. Plasma samples were collected at appropriate times during a 48‐h administration interval, and were analyzed using a microbiological assay method. The plasma levofloxacin disposition was best fitted to a two‐compartment open model after i.v. dosing. The half‐lives of distribution and elimination were 0.21 ± 0.13 and 2.58 ± 0.51 h, respectively. The volume of distribution at steady‐state was 0.81 ± 0.26 L/kg, the total body clearance (Cl_tot) was 0.21 ± 0.18 L/h/kg, and the areas under the concentration–time curves (AUCs) were 18.79 ± 4.57 μg.h/mL. Following i.m. administration, the mean t_1/2el and AUC values were 2.94 ± 0.78 h and 17.21 ± 4.36 μg.h/mL. The bioavailability was high (91.76% ± 12.68%), with a peak plasma mean concentration (C_max) of 2.85 ± 0.89 μg/mL attained at 1.56 ± 0.71 h (T_max). The in vitro protein binding percentage was 27.84%. Calculation of efficacy predictors showed that levofloxacin might have a good therapeutic profile against Gram‐negative and Gram‐positive bacteria, with an MIC ≤ 0.1 μg/mL.