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- Author or Editor: Sara M. Thomasy x
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Abstract
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 (Cmax) 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 (AUC0→∞) 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 AUC0→∞ from phase 1. Dose-normalized penciclovir Cmaxfollowing 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.
Abstract
Objective—To detect feline herpesvirus type 1 (FHV-1) in blood of cats undergoing experimental primary herpetic disease or with spontaneous disease presumed to be caused by FHV-1 reactivation.
Animals—6 young specific-pathogen–free (SPF) cats and 34 adult cats from a shelter.
Procedures—Conjunctiva and nares of SPF cats were inoculated with FHV-1, and cats were monitored for 21 days. Periodically, blood was collected for CBC, serum biochemical analyses, and detection of FHV-1 DNA via PCR assay. For shelter cats, a conjunctival swab specimen was collected for FHV-1 PCR assay, and blood mononuclear cells were tested via virus isolation (with or without hydrocortisone) and FHV-1 PCR assay.
Results—All SPF cats developed clinical and clinicopathologic evidence of upper respiratory tract and ocular disease only. Via PCR assay, FHV-1 DNA was detected in blood of all SPF cats at least once between 2 and 15 days after inoculation. Feline herpesvirus type 1 DNA was detected in conjunctival swabs of 27 shelter cats; 25 had clinical signs of herpetic infection. However, virus was not isolated from mononuclear cell samples of any shelter cat regardless of passage number or whether hydrocortisone was present in the culture medium; FHV-1 DNA was not detected in any mononuclear cell sample collected from shelter cats.
Conclusions and Clinical Relevance—A brief period of viremia occurred in cats undergoing primary herpetic disease but not in cats undergoing presumed recrudescent herpetic disease. Viremia may be important in the pathogenesis of primary herpetic disease but seems unlikely to be associated with recrudescent disease.
Abstract
Objective—To determine the effect of feline herpesvirus type 1 (FHV-1) on tear film breakup time (TFBUT) and Schirmer tear test (STT) values in cats with primary experimental infection and to determine the relationship betweenTFBUT and STT values and conjunctival goblet cell density (GCD).
Sample Population—9 specific-pathogen–free cats of approximately 6 months of age.
Procedures—6 cats were inoculated with FHV-1; 3 control cats were sham inoculated. Clinical and histologic evidence of conjunctivitis and TFBUT, GCD, and STT values were assessed at multiple times until postinoculation day (PID) 29.
Results—In infected cats, mean clinical and histologic conjunctivitis scores peaked at PID 7 and remained above baseline at PID 29. In control cats, these 2 variables did not change from baseline throughout the study. MeanTFBUT declined rapidly in infected cats up to PID 15 and at PID 29 remained less than baseline, less than for control cats, and below refer-ence range values. Mean STT value for infected cats at PID 29 was increased from baseline but was within the reference range and not different from the value for control cats. Mean GCD in infected cats declined precipitously by PID 7 and remained below reference range values at PID 29. Mean GCD in control cats remained unchanged for the duration of the study period.
Conclusions and Clinical Relevance—FHV-1 induced qualitative tear film abnormalities in experimentally infected cats, as measured by TFBUT and GCD. Assessment of TFBUT provided a reasonable clinical estimate of GCD.
Abstract
Objective—To evaluate orally administered famciclovir for treatment of cats with experimentally induced disease attributable to feline herpesvirus type-1 (FHV-1).
Animals—16 nonvaccinated specific-pathogen-free cats.
Procedures—Cats were treated orally with famciclovir (90 mg/kg; n = 10) or a similar volume of lactose (400 mg; 6) 3 times/d for 21 days. Cats were inoculated with FHV-1 and administered the first treatment dose on day 0. Disease score; weight; results of urinalysis, serum biochemical analysis, and CBC; histologic conjunctivitis score; herpetic DNA shedding; goblet cell density; anti-FHV-1 antibody concentration; and plasma penciclovir concentration were measured.
Results—On days 4 to 18 following inoculation, disease scores were lower in famciclovir-treated cats than in lactose-treated cats. Lactose-treated cats decreased in weight during the first 7 days after inoculation, but famciclovir-treated cats increased in weight throughout the study. Percentage change in weight was greater in famciclovir-treated cats on days 7 and 14 than in lactose-treated cats. Serum globulin concentration was lower on days 3 through 9, conjunctivitis histologic score was lower on day 14, herpetic DNA was shed less frequently throughout the study, goblet cell density was greater on day 21, and circulating anti-FHV-1 antibody concentration at study end was lower in famciclovir-treated cats, compared with these measurements in lactose-treated cats. Approximate peak plasma penciclovir concentration was 2.0 μg/mL.
Conclusions and Clinical Relevance—Famciclovir administration improved outcomes for systemic, ophthalmic, clinicopathologic, virologic, and histologic variables in cats experimentally infected with FHV-1. Adjunctive topical mucinomimetic and antimicrobial treatments may also be necessary.
Abstract
Objective—To determine the disposition of lidocaine after IV infusion in anesthetized horses undergoing exploratory laparotomy because of gastrointestinal tract disease.
Animals—11 horses (mean ± SD, 10.3 ± 7.4 years; 526 ± 40 kg).
Procedure—Lidocaine hydrochloride (loading infusion, 1.3 mg/kg during a 15-minute period [87.5 μg/kg/min]; maintenance infusion, 50 μg/kg/min for 60 to 90 minutes) was administered IV to dorsally recumbent anesthetized horses. Blood samples were collected before and at fixed time points during and after lidocaine infusion for analysis of serum drug concentrations by use of liquid chromatography-mass spectrometry. Serum lidocaine concentrations were evaluated by use of standard noncompartmental analysis. Selected cardiopulmonary variables, including heart rate (HR), mean arterial pressure (MAP), arterial pH, PaCO2, and PaO2, were recorded. Recovery quality was assessed and recorded.
Results—Serum lidocaine concentrations paralleled administration, increasing rapidly with the initiation of the loading infusion and decreasing rapidly following discontinuation of the maintenance infusion. Mean ± SD volume of distribution at steady state, total body clearance, and terminal half-life were 0.70 ± 0.39 L/kg, 25 ± 3 mL/kg/min, and 65 ± 33 minutes, respectively. Cardiopulmonary variables were within reference ranges for horses anesthetized with inhalation anesthetics. Mean HR ranged from 36 ± 1 beats/min to 43 ± 9 beats/min, and mean MAP ranged from 74 ± 18 mm Hg to 89 ± 10 mm Hg. Recovery quality ranged from poor to excellent.
Conclusions and Clinical Relevance—Availability of pharmacokinetic data for horses with gastrointestinal tract disease will facilitate appropriate clinical dosing of lidocaine.
Abstract
Objective—To describe the pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide (MEGX), after IV administration of a single bolus of lidocaine in cats that were awake in phase 1 and anesthetized with isoflurane in phase 2 of the study.
Animals—8 healthy adult cats.
Procedure—During phase 1, cats were administered lidocaine (2 mg/kg, IV) as a bolus injection (time 0). During phase 2, cats were anesthetized with isoflurane and maintained at 0.75 times the minimum alveolar concentration of isoflurane for each specific cat. After a 15-minute equilibration period, lidocaine (2 mg/kg, IV) was administered as a bolus injection to each cat (time 0). In both phases, plasma concentrations of lidocaine and MEGX were measured at various time points by use of liquid chromatography-mass spectrometry.
Results—Anesthesia with isoflurane significantly decreased the volume of the central compartment, clearance, and elimination half-life of lidocaine and significantly increased the extrapolated plasma drug concentration at time 0, compared with values for awake cats. Pharmacokinetics of MEGX were also changed by isoflurane-induced anesthesia because the maximum observed plasma concentration (Cmax), area under the concentration-time curve extrapolated to infinity, and time to Cmax were significantly higher in anesthetized cats, compared with values for awake cats.
Conclusions and Clinical Relevance—Pharmacokinetics of lidocaine and MEGX were substantially altered in cats anesthetized by use of isoflurane. When pharmacokinetic variables are used to determine loading and infusion doses in awake or anesthetized cats, they should be measured in cats that are awake or anesthetized, respectively. (Am J Vet Res 2005;66:1162–1166)
Abstract
OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized.
ANIMALS 7 male domestic shorthair cats.
PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens.
RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens.
CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.
Abstract
OBJECTIVE To evaluate signalment, clinical signs, treatment, and factors affecting visual prognosis in dogs with uveodermatologic syndrome (UDS).
DESIGN Retrospective case series and nested cohort study.
ANIMALS 50 dogs (37 Akitas and 13 non-Akitas) with UDS evaluated at 4 ophthalmology practices.
PROCEDURES Data were collected from the medical records regarding signalment, clinical signs, biopsy results, medications, adverse effects, vision and glaucoma status at initial and subsequent examinations, and duration of follow-up. Various factors were examined for associations with development of blindness or glaucoma following initial examination.
RESULTS The most common ophthalmic signs included aqueous flare (n = 35 [70%]), iris abnormalities (29 [58%]), retinal detachment (23 [46%]), and choroidal depigmentation or chorioretinal infiltrates (10 [20%]). At initial examination, 36% (18/50) of dogs had glaucoma and 57% (26/46) were blind in both eyes. Twenty-five (50%) dogs had vision at their final visit, representing 78% of the 32 dogs that had vision at initial examination or regained vision during the follow-up period. In dogs that lost vision, median time to permanent blindness in both eyes was 13.5 months (range, 0.4 to 59 months) after initial examination. No significant associations with time to glaucoma or vision loss were identified for signalment variables, specific medications, or duration of clinical signs prior to initial examination.
CONCLUSIONS AND CLINICAL RELEVANCE UDS commonly resulted in glaucoma, vision loss, or both in affected dogs. No evaluated factor was associated with visual prognosis; however, a subset of patients maintained vision through to the final recheck examination.
Abstract
Objective—To assess tear and plasma concentrations of doxycycline following oral administration to northern elephant seals (Mirounga angustirostris).
Design—Pharmacokinetic study.
Animals—18 juvenile northern elephant seals without signs of ocular disease.
Procedures—Study seals were receiving no medications other than a multivitamin and were free from signs of ocular disease as assessed by an ophthalmic examination. Doxycycline (10 or 20 mg/kg [4.5 or 9.1 mg/lb]) was administered orally every 24 hours for 4 days. Tear and plasma samples were collected at fixed time points, and doxycycline concentration was assessed by means of liquid chromatography–tandem mass spectrometry. Concentration-time data were calculated via noncompartmental analysis.
Results—Following administration of doxycycline (10 mg/kg/d, PO), maximum plasma doxycycline concentration was 2.2 μg/mL at 6.1 hours on day 1 and was 1.5 μg/mL at 4.0 hours on day 4. Administration of doxycycline (20 mg/kg/d, PO) produced a maximum plasma doxycycline concentration of 2.4 μg/mL at 2.3 hours on day 1 and 1.9 μg/mL at 5.8 hours on day 4. Doxycycline elimination half-life on day 4 in animals receiving doxycycline at a dosage of 10 or 20 mg/kg/d was 6.7 or 5.6 hours, respectively. Mean plasma-to-tear doxycycline concentration ratios over all days were not significantly different between the low-dose (9.85) and high-dose (9.83) groups. For both groups, doxycycline was detectable in tears for at least 6 days following cessation of dosing.
Conclusions and Clinical Relevance—Oral administration of doxycycline at the doses tested in the present study resulted in concentrations in the plasma and tears of northern elephant seals likely to be clinically effective for treatment of selected cases of systemic infectious disease, bacterial ulcerative keratitis, and ocular surface inflammation. This route of administration should be considered for treatment of corneal disease in northern elephant seals and possibly other related pinniped species.
Abstract
Objective—To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir.
Animals—6 cats.
Procedures—Cats received famciclovir (40 [n = 3] or 90 [3] mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration.
Results—Mean ± SD maximum plasma concentration (Cmax) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 μg/mL and 1.28 ± 0.42 μg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively.
Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar Cmax and time to Cmax values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.
