A single-nucleotide polymorphism in the canine cytochrome b5 reductase (CYB5R3) gene is associated with sulfonamide hypersensitivity and is overrepresented in Doberman Pinschers.

Canine sulfonamide hypersensitivity (HS) has been associated with a variant in the cytochrome b5 reductase gene (CYB5R3 729A>G), which encodes a drug-detoxifying enzyme. Study objectives were to determine variant allele frequency in Doberman Pinschers (DOBE), a breed which may be predisposed to sulfonamide HS, and to characterize the effects of CYB5R3 729G on gene expression and function. CYB5R3 729A>G allele frequencies were compared between DOBE (n = 24) vs. non-Doberman (non-DOBE; n = 60) dogs. CYB5R3mRNA expression, protein expression, and reduction of sulfamethoxazole hydroxylamine were compared between banked canine liver samples of 729AA vs. GG genotype. The 729G allele was overrepresented in DOBE (1.00) vs. non-DOBE dogs (0.567, p < .0001). mRNA and protein expressions as well as cyt b5 reductase activity were similar between livers of AA and GG genotype. All Doberman Pinschers in this study were homozygous for CYB5R3 729G, which could contribute to this breed's apparent predisposition to sulfonamide HS. However, CYB5R3 729G does not alter sulfamethoxazole detoxification capacity, so a direct role could not be demonstrated. It is possible that this marker is linked to another contributing variant.

Serum 25-hydroxyvitamin D concentrations and mortality in dogs with blastomycosis.

Blastomycosis is a prominent fungal disease in the United States. Vitamin D status has been found to be altered in critical illness and various infectious diseases. The objectives of this study were to compare serum 25-hydroxyvitamin D (25[OH]D) concentrations in dogs with blastomycosis and healthy controls, to assess the change in serum 25(OH)D concentrations in dogs with blastomycosis after 30 days of treatment, and to determine if baseline serum 25(OH)D concentrations in dogs with blastomycosis were associated with in-hospital, 30-day, or end-of-study mortality. In this prospective cohort study, 19 dogs newly diagnosed with blastomycosis had serum 25(OH)D concentrations measured with a commercially available validated radioimmunoassay at the time of diagnosis and 30 days after start of treatment. These values were compared to 24 healthy control dogs. Serum 25(OH)D concentrations at the time of diagnosis were lower in dogs with blastomycosis (median, 203 nmol/L; range, 31-590 nmol/L) than in clinically healthy control dogs (259.5 nmol/L, 97-829 nmol/L; P = 0.01). Despite clinical improvement, there was no significant change in serum 25(OH)D concentrations from baseline to 30-day follow-up. Dogs with baseline serum 25(OH)D concentrations <180.5nmol/L had a greater odds of death during hospitalization (odds ratio [OR], 15.0; 95% confidence interval [CI], 1.4-191.3; P = 0.04) and at 30 days follow-up (OR, 30.0; 95% CI, 2.5-366.7; P = 0.006). These findings highlight the need for further studies evaluating the prognostic value of vitamin D status in dogs with blastomycosis at diagnosis and throughout treatment and remission.

Glutathione, cysteine, and ascorbate concentrations in clinically ill dogs and cats.

BACKGROUND: Oxidative stress plays a role in the pathogenesis of many systemic diseases. Hospitalized human patients are glutathione, cysteine, and ascorbate deficient, and antioxidant depletion has been correlated with poor clinical outcome. To date little is known about antioxidant concentrations in hospitalized veterinary patients. The purpose of this study was to determine whether ascorbate, cysteine, or glutathione depletion is present in ill dogs and cats compared with healthy controls. HYPOTHESIS: Clinically ill dogs and cats would be antioxidant depleted, and depletion would correlate with illness severity and clinical outcome. ANIMALS: Clinically ill client-owned dogs (n = 61) and cats (n = 37), healthy control dogs (n = 37) and cats (n = 33). METHODS: Prospective, observational, case control study. Erythrocyte reduced glutathione, plasma cysteine, and plasma ascorbate were quantified using high-performance liquid chromatography. RESULTS: Clinically ill dogs had significantly lower erythrocyte glutathione concentrations (1.22 mM, range 0.55-3.61) compared with controls (1.91 mM, range 0.87-3.51; P = .0004), and glutathione depletion correlated with both illness severity (P = .038) and mortality (P = .010). Cats had higher ascorbate concentrations when ill (10.65 microM, range 1.13-25.26) compared with controls (3.68 microM, range 0.36-13.57; P = .0009). CONCLUSIONS AND CLINICAL IMPORTANCE: Clinically ill dogs had decreased erythrocyte glutathione concentrations, which could be a marker of illness severity and prognostic of a poor outcome. Clinically ill cats had an unexpectedly high plasma ascorbate, which could represent a unique species response to oxidative stress.

Anti-myeloperoxidase and anti-cathepsin G antibodies in sulphonamide hypersensitivity.

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with vasculitis in humans. Sulphonamide antimicrobials cause drug hypersensitivity (HS) reactions with some clinical signs that are suggestive of vasculitis. OBJECTIVE: The purpose of this study was to determine whether sulphonamide HS is associated with anti-neutrophil antibodies, using the dog as a spontaneous clinical model. METHODS: Thirty-four sulphonamide-HS dogs, 11 sulphonamide-'tolerant' dogs, and nine healthy sulphonamide-naïve dogs were evaluated for anti-neutrophil antibodies using a commercial ELISA against human myeloperoxidase (MPO), a commercial human ANCA Western blot protocol, and immunoblotting against whole canine neutrophils. RESULTS: Using ELISA, anti-MPO antibodies were found with an apparent higher frequency in HS dogs (50%), compared with 'tolerant' dogs (18%), which also showed significantly lower absorbances. Among HS dogs, anti-MPO antibodies were significantly more common, with significantly higher absorbances, in dogs that did not survive the HS reaction (78%) compared with survivors (35%). Using immunoblotting, ANCA were detected with similar overall frequencies in HS and 'tolerant' dogs. However, one protein targeted by several HS dogs, but no 'tolerant' dogs, was identified as cathepsin G. CONCLUSION: These data indicate that anti-MPO antibodies and anti-cathepsin G antibodies are associated with sulphonamide HS. Anti-MPO antibodies have been shown to be pathogenic both in vitro and in vivo, leading to vasculitis lesions and vasculitis-like syndromes. The present study therefore suggests that vasculitis might be one mechanism of tissue damage in this sulphonamide HS. Furthermore, the evaluation of ANCA, and its relationship to disease severity and clinical outcome, should be considered in human patients with sulphonamide drug HS.

Risk of hemolytic anemia with intravenous administration of famotidine to hospitalized cats.

BACKGROUND: Famotidine administered IV has been associated anecdotally with hemolysis in cats, and some veterinarians recommend using injectable famotidine only by the subcutaneous (SC) route for cats. However, the actual risk of such a reaction is not known. HYPOTHESIS: We hypothesized that famotidine, when given IV slowly, would not be associated with a clinically significant drop in packed cell volume (PCV) in hospitalized cats. ANIMALS: One hundred and forty-two hospitalized cats. METHODS: A retrospective medical record review was performed for hospitalized cats prescribed famotidine IV (n = 56), famotidine SC (n = 48), or no famotidine (n = 38) at a veterinary medical teaching hospital over the period from January 2004 through December 2006. RESULTS: Baseline signalment, observation times, and famotidine dosage (in treated cats) were similar among groups. Median baseline PCVs were significantly lower in the IV (31.5%) and SC (32.0%) groups compared with the control group (35.0%; P= .04). The median percent drop in PCV (3-4%), however, was no different in cats that received famotidine by either route compared with the control group (P= .90), and no cats in either famotidine group were observed to have any clinical signs of hemolysis. CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude from this retrospective study that famotidine IV was given to 56 hospitalized cats without evidence of hemolysis, and that the IV route appeared safe when famotidine was administered over 5 minutes. We could not document a safety advantage of SC versus IV administration in this group of cats.

Glutathione-S-transferase-theta genotypes and the risk of cyclophosphamide toxicity in dogs.

The antineoplastic agent cyclophosphamide (CP) has dose-limiting side effects including sterile haemorrhagic cystitis (SHC), bone marrow (BM) suppression and gastrointestinal (GI) toxicity in dogs. The metabolites acrolein and phosphoramide that mediate these toxicities are glutathione-S-transferase (GST) substrates, and low functioning GST alleles are associated with CP toxicity in humans. The aim of this study was to determine whether variants in 2 canine GST genes, GSTT1 and GSTT5, were over-represented in dogs that developed CP toxicity. Dogs undergoing pulse or metronomic CP chemotherapy were recruited (n = 101) and genotyped for 6 GSTT1 polymorphisms and 1 GSTT5 6-bp deletion that leads to non-functional enzyme. Median cumulative CP dosages for dogs with SHC (1350 mg/m2 ) were significantly higher than for dogs with GI/BM toxicity (871 mg/m2 ) or no toxicity (991 mg/m2 ; P = .0012). Dogs with SHC were more likely to have had metronomic (84.2%, 16 of 19 SHC cases) vs pulse (15.8%, 3 of 19 SHC cases) CP dosing (P < .0001). All dogs with BM or GI toxicity (n = 30) had pulse chemotherapy. GSTT1 and GSTT5 variant allele frequencies were not significantly different in CP-treated dogs with SHC or GI/BM toxicity compared to dogs without documented adverse effects. Work is underway to identify which canine GSTs detoxify acrolein and phosphoramide, so that better tools are available to predict the risk of CP toxicity in dogs.

Characterization of a low expression haplotype in canine glutathione S-transferase (GSTT1) and its prevalence in golden retrievers.

Glutathione S-transferase-theta (GSTT1) is a carcinogen detoxification enzyme, and low activity variants are associated with lymphoma in humans. We recently found a variant in the 3' untranslated region (UTR) of canine GSTT1, *101_102insT, which was predicted to change miRNA binding and was found in 5 of 17 golden retriever (GR) dogs with lymphoma but none of 14 healthy GRs. The aim of this study was to determine whether this variant led to decreased GSTT1 expression and was a discernible risk factor for lymphoma within the GR breed. On resequencing, *101_102insT appeared to be in complete linkage disequilibrium with 3 additional 3'UTR variants, leading to the inferred haplotype *3T>C; *101_102insT; *190C>A; *203T>C. In canine livers that were heterozygous for this variant haplotype, GSTT1 protein expression was significantly lower compared to the reference haplotype (densitometry .40 vs .64, P = .022), and GSTT1 transcript levels by qPCR were also significantly lower (fold difference .52, P = .012), without evidence of substantial allelic expression imbalance. The variant haplotype led to >50% decrease in expression in vitro (.31 ± .07 vs .64 ± .19; P = .019). We found no significant difference in minor allele frequencies between 71 GR dogs with lymphoma (MAF .162) and 33 healthy age-matched controls (MAF .136, P = .69). Our results indicate that the variant GSTT1 3'UTR haplotype containing *101_102insT reduces gene expression, which could lead to impaired carcinogen detoxification, but was not a detectable risk factor for lymphoma in GR dogs.

Plasma l-citrulline concentrations in l-arginine-supplemented healthy dogs.

INTRODUCTION: To determine whether oral l-arginine increases plasma [l-citrulline] in dogs. ANIMALS: Eleven healthy staff-owned dogs were used in this study. MATERIALS AND METHODS: Dogs (n = 3) were given l-arginine (50mg/kg PO q8h) for 7 days, and plasma [l-arginine] and [l-citrulline] were analyzed by high performance liquid chromatography at baseline (BL), steady state trough, and 0.5, 1, 1.5, 2, 4, 6, and 8 h after final dosing on day 7. Eleven dogs were then treated with 100mg/kg l-arginine PO q8h for 7 days, and [l-arginine] and [l-citrulline] were measured at BL, steady state trough, and at peak 4 hrs after dosing (T4 hrs). RESULTS: - Plasma [l-arginine] and [l-citrulline] peaked at T4 hrs on the 50mg/kg dosage. Target outcome, modeled after human study results, of a doubling of [l-arginine] and a 25-30% increase in [l-citrulline] from BL were not reached. After the 100mg/kg dosage, plasma [l-arginine] increased from a BL median of 160.1 µM (range, 100.2-231.4 µM) to a peak of 417.4 µM (206.5-807.3 µM) at T4 hrs, and plasma [l-citrulline] increased from a BL median of 87.8 µM (59.1-117.1 µM) to peak of 102.2 µM (47.4-192.6 µM) at T4 hrs. Ten of eleven dogs showed a doubling of plasma [l-arginine] and 4/11 dogs achieved 25-30% or greater increases in plasma [l-citrulline]. No adverse effects on heart rate or blood pressure were noted. CONCLUSIONS: - Oral l-arginine dosage of 100mg/kg q8h doubles plasma [l-arginine] in healthy dogs, but conversion to l-citrulline is quite variable. Further evaluation of this dosage regimen in dogs with pulmonary hypertension is warranted.

Urinary F2 -Isoprostanes in Cats with International Renal Interest Society Stage 1-4 Chronic Kidney Disease.

BACKGROUND: F2 -isoprostanes, a biomarker of oxidant injury, increase with advancing chronic kidney disease (CKD) in humans. In cats, the relationship between CKD and oxidative stress is poorly understood. OBJECTIVES: To determine whether cats with advancing CKD have increasing urinary F2 -isoprostanes. ANIMALS: Control cats without evidence of CKD (≥6 years old; n = 11), and cats with IRIS stage 1 (n = 8), 2 (n = 38), 3 (n = 21), and 4 (n = 10) CKD. METHODS: This was a prospective observational study. Urinary F2 -isoprostanes (specifically free 15-F2t -isoprostanes) normalized to urine creatinine (IsoPs) were compared among groups and tested for correlations with blood pressure, proteinuria, serum creatinine concentration, and urine specific gravity. The IsoPs also were compared between cats with and without hypertension or proteinuria, and in cats fed predominantly standard versus renal diets. RESULTS: Urinary IsoPs were increased, but not significantly, in cats with stage 1 CKD (median 263 pg/mg creatinine; range, 211-380) compared to controls (182 pg/mg; range, 80-348) and decreased significantly from stage 1 through advancing CKD (stage 2, 144 pg/mg; range, 49-608; stage 3, 102 pg/mg; range, 25-158; stage 4, 67 pg/mg; range, 26-117; P < .01). Urinary IsoPs were inversely correlated with serum creatinine (r = -0.66, P < .0001). CONCLUSION AND CLINICAL IMPORTANCE: Urinary IsoPs are significantly higher in early CKD (stage 1) compared to cats with more advanced CKD. Additional studies are warranted to characterize oxidative stress in cats with stage 1 CKD and determine whether early antioxidant treatments have a protective effect on CKD progression.

Opportunistic fungal infections in dogs treated with ciclosporin and glucocorticoids: eight cases.

Glucocorticoids are the standard of care for the treatment of immune-mediated disorders, and ciclosporin is increasingly being used off-label as an adjunct immunosuppressive drug in dogs. However, opportunistic infections can develop during combination immunosuppressive regimens. This case series describes atypical fungal infections in eight dogs treated with immunosuppressive dosages of glucocorticoids and ciclosporin. The median duration of combined treatment prior to the identification of fungal infection was 31 (range, 13 to 201) days, although two dogs received glucocorticoids for prolonged periods prior to the addition of ciclosporin. The estimated prevalence of serious fungal infections with this drug combination appears to be low (approximately 1 · 67%), but these infections led directly or indirectly to death or euthanasia in five of eight (63%) dogs. These cases highlight the need for frequent clinical monitoring of dogs receiving immunosuppressive dosages of glucocorticoids and ciclosporin.

Nephrotic syndrome associated with administration of sulfadimethoxine/ormetoprim in a dobermann.

This case report describes sulphonamide-induced nephrotic syndrome in a young dobermann dog. The clinical signs and laboratory abnormalities resolved shortly after discontinuation of the sulphonamide antibiotic and with generalised supportive care. Since nephrotic syndrome typically carries a guarded prognosis in veterinary medicine and is poorly responsive to therapy, a thorough drug history should be an important part of the investigation of any animal with a protein-losing nephropathy.

Incidence, timing, and risk factors of azathioprine hepatotoxicosis in dogs.

BACKGROUND: The use of azathioprine (AZA) in dogs is limited by the development of hepatotoxicosis and cytopenias. HYPOTHESIS AND OBJECTIVES: To characterize the observed incidence, timing, and risk factors for AZA hepatotoxicosis in dogs treated clinically, and to determine the relationship between the development of hepatotoxicosis and cytopenias. ANIMALS: Fifty-two dogs treated with AZA with clinical and biochemical follow-up, with a subset of 34 dogs available for determination of changes in liver enzyme activities in serum. METHODS: Retrospective medical record review, from January 2009 through December 2013. RESULTS: Hepatotoxicosis (as defined by a >2-fold increase in serum ALT) was observed in 5 of 34 dogs (15%) within a median onset of 14 days (range, 13-22 days). Dogs had a median 9-fold increase in ALT and 8-fold increase in ALP, which stabilized or resolved with drug discontinuation or dose reduction. German shepherds were significantly over-represented (3 of 5 dogs with hepatotoxicosis; P = .0017). Thrombocytopenia or neutropenia were seen in 4 of 48 dogs with CBC follow-up (8% of dogs), but occurred significantly later in treatment (median onset, 53 days; range 45-196 days) compared to hepatotoxicosis (P = .016). CONCLUSIONS AND CLINICAL IMPORTANCE: These results support the routine monitoring of liver enzymes during the first 1-4 weeks of AZA treatment in dogs, with continued monitoring of the CBC. Additional studies are warranted to characterize the apparently higher risk of AZA hepatotoxicosis in German shepherds.

Deficiency of cytosolic arylamine N-acetylation in the domestic cat and wild felids caused by the presence of a single NAT1-like gene.

The purpose of this study was to determine the molecular basis for a relative deficiency in the cat of cytosolic arylamine N-acetyltransferase (NAT), an enzyme family that is important in the metabolism of xenobiotics and that normally consists of at least two related enzymes, NAT1 and NAT2. N-acetyltransferase in feline liver showed high affinity (mean Km = 2.1 microM) for p-aminobenzoic acid, an NAT1 selective substrate in humans and rabbits, but showed a very poor affinity (mean Km > 10 mM) for sulfamethazine, an NAT2 selective substrate in humans and rabbits. Immunoreactive N-acetyltransferase was detected in feline liver, bladder and colon using an NAT1-specific antipeptide antibody, but was not detected in any tissues using an NAT2-specific antibody. Southern blot analysis of genomic DNA demonstrated a single band in domestic cats using each of six restriction digests; single bands were also found on Southern blot analysis of six wild felids. The deduced amino acid sequence of the central portion of feline N-acetyltransferase, obtained by polymerase chain reaction amplification in both domestic cats and seven wild felids (lion, tiger, lynx, snow leopard, bobcat, Asian leopard cat and cheetah), contained three residues, Phe125, Arg127, and Tyr129, which determine NAT1-like substrate specificity in humans. These results support the conclusion that cytosolic arylamine N-acetylation activity is low in the cat because of the presence of a single N-acetyltransferase that has substrate specificity, immunogenicity and sequence characteristics similar to human NAT1, and that the unusual presence of only a single N-acetyltransferase gene appears to be a family wide trait shared by other felids.

Cytosolic arylamine N-acetyltransferase (NAT) deficiency in the dog and other canids due to an absence of NAT genes.

The purpose of this study was to determine the molecular basis in the dog for an unusual and absolute deficiency in the activity of cytosolic N-acetyltransferase (NAT), an enzyme important for the metabolism of arylamine and hydrazine compounds. NAT activity towards two NAT substrates, p-aminobenzoic acid and sulfamethazine, was undetectable in dog liver cytosol, despite substrate concentrations ranging from 10 microM to 4 mM and a wide range of incubation times. Similarly, no protein immunoreactive to NAT antibody was evident on western blot analysis of canine liver cytosol. Southern blot analysis of genomic DNA from a total of twenty-five purebred and mixed bred dogs, and eight wild canids, probed with a full-length human NAT2 cDNA, suggested an absence of NAT sequences in all canids. Polymerase chain reaction amplification of genomic DNA using degenerate primers designed to mammalian NAT1 and NAT2 consensus sequences generated products of the expected size in human, mouse, rabbit, and cat DNA, but no NAT products in any dog or wild canids. These results support the conclusion that cytosolic NAT deficiency in the domestic dog is due to a complete absence of NAT genes, and that this defect is shared by other canids.

Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses.

Bromide (20 mg kg-1) was administered intravenously and orally to normal beagle dogs. The mean (SD) apparent elimination half life (t1/2 beta) after oral administration (46 +/- 9 days) was not significantly different from the mean t1/2 beta after intravenous administration (37 +/- 10 days). The mean total body clearance was 9.0 +/- 3.9 ml day-1 kg-1 and the mean apparent volume of distribution was 0.45 +/- 0.07 litre kg-1. The mean area under the serum concentration time curve (AUC) was significantly smaller after oral administration than after intravenous administration, and from a comparison of the two values the oral bioavailability of bromide was estimated to be 46 per cent. Assuming this degree of bioavailability, the daily dose of bromide necessary to maintain serum bromide concentrations within the therapeutic range of 1000 to 2000 mg litre-1 recommended for epileptic dogs was estimated to be approximately 21 mg kg-1. The intravenous loading dose of sodium bromide necessary to reach minimal therapeutic serum bromide concentrations was predicted to be 570 +/- 90 mg kg-1.

Effect of dietary chloride content on the elimination of bromide by dogs.

The effect of dietary chloride content (0.2, 0.4 and 1.3 per cent chloride on a dry matter basis) on the disposition of a single oral dose of bromide (14 mg kg-1) was evaluated in normal beagles. Increasing the dietary chloride content from 0.2 to 1.3 per cent resulted in a significant decrease in the mean apparent elimination half-life from 69 +/- 22 days to 24 +/- 7 days. The mean area under the concentration curve (AUC) for dogs fed 1.3 per cent chloride was significantly smaller than the AUC for dogs fed 0.2 per cent chloride. Dietary chloride had no effect on the maximum serum concentrations (Cmax) or on the time (Tmax) to reach the maximum concentrations. The steady-state serum bromide concentrations predicted from the single dose data for daily doses of 14 mg kg-1 of bromide were significantly lower in dogs fed 1.3 per cent chloride (310 +/- 150 mg litre-1) than in dogs fed 0.2 per cent chloride (1950 +/- 1140 mg litre-1). The predicted mean daily doses of bromide necessary to maintain serum levels within the therapeutic range for dogs fed 1.3 per cent chloride (43 +/- 13 mg kg-1) were almost twice as high as the dose estimated for dogs fed 0.4 per cent chloride (22 +/- 3 mg kg-1) and nearly three times as high as the dose estimated for dogs fed 0.2 per cent chloride (15 +/- 4 mg kg-1). These differences were statistically significant (P = 0.002).

Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism.

The intravenous and oral disposition of the antithyroid drug methimazole was determined in 10 clinically normal cats and nine cats with naturally occurring hyperthyroidism. After intravenous administration of 5 mg methimazole, the mean residence time was significantly (P less than 0.05) shorter in the cats with hyperthyroidism than in the normal cats, but there was no significant difference between the mean values for total body clearance (CL), steady state volume of distribution (Vdss), terminal elimination rate constant (ke), or serum terminal half-life (t1/2) in the two groups of cats. After oral administration, the mean bioavailability of methimazole was high in both the normal cats (77.6 per cent) and cats with hyperthyroidism (79.5 per cent). The values for mean residence time, ke and serum terminal t1/2 after oral dosing were significantly shorter in the cats with hyperthyroidism than in the normal cats. However, after oral administration of methimazole there were no significant differences between the mean values for CL, Vdss, bioavailability and maximum serum concentrations or the time for maximal concentrations to be reached in the two groups of cats. Overall, most pharmacokinetic parameters for methimazole were not altered by the hyperthyroid state. However, the cats with hyperthyroidism did show a trend toward faster elimination of the drug compared with the normal cats, similar to what has been previously described for the antithyroid drug propylthiouracil in cats. These results also indicate that methimazole is well absorbed when administered orally and has a higher bioavailability than that of propylthiouracil in cats with hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ceftazidime in dogs following subcutaneous administration and continuous infusion and the association with in vitro susceptibility of Pseudomonas aeruginosa.

OBJECTIVE: To determine the pharmacokinetics of ceftazidime following subcutaneous administration and continuous IV infusion to healthy dogs and to determine the minimum inhibitory concentration (MIC) of ceftazidime for clinical isolates of Pseudomonas aeruginosa. ANIMALS: 10 healthy adult dogs. PROCEDURE: MIC of ceftazidime for 101 clinical isolates of P aeruginosa was determined in vitro. Serum concentrations of ceftazidime were determined following subcutaneous administration of ceftazidime (30 mg/kg of body weight) to 5 dogs and continuous IV infusion of ceftazidime (loading dose, 4.4 mg/kg; infusion rate, 4.1 mg/kg/h) for 36 hours to 5 dogs. RESULTS: The MIC of ceftazidime for P aeruginosa was < or = 8 microg/ml; all isolates were considered susceptible. Following SC administration of ceftazidime, mean beta disappearance half-life was 0.8 hours, and mean serum ceftazidime concentration exceeded the MIC for P aeruginosa for only 4.3 hours. Two dogs had gastrointestinal tract effects. Mean serum ceftazidime concentration exceeded 16 microg/ml during continuous IV infusion. None of the dogs developed adverse effects. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of ceftazidime subcutaneously (30 mg/kg, q 4 h) or as a constant IV infusion (loading dose, 4.4 mg/kg; rate, 4.1 mg/kg/h) would maintain serum ceftazidime concentrations above the MIC determined for 101 clinical isolates of P aeruginosa. Use of these dosages may be appropriate for treatment of dogs with infections caused by P aeruginosa.

Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy.

OBJECTIVE: To determine whether there are therapeutically relevant changes in serum phenobarbital concentrations throughout a daily dosing interval in epileptic dogs receiving phenobarbital for > or = 3 weeks. DESIGN: Prospective study. ANIMALS: 33 epileptic dogs receiving phenobarbital. PROCEDURE: Serum phenobarbital concentrations were measured at 0 hour (trough), 3 hours, and 6 hours after oral administration of phenobarbital in epileptic dogs that had received phenobarbital twice daily for a minimum of 3 weeks. For each dog, trough, 3-hour, and 6-hour serum phenobarbital concentrations were evaluated to determine whether they were within the same therapeutic category (lower, middle, or upper end of the therapeutic range of 15 to 45 micrograms/ml), or whether there was a > 30% change in serum concentrations throughout the day. RESULTS: Ninety-one percent (30/33) of dogs had trough, 3-hour, and 6-hour serum phenobarbital concentrations in the same therapeutic category. Only 9% (3/33) of dogs had trough, 3-hour, and 6-hour serum concentrations in different therapeutic categories with a > 30% change in concentrations throughout the day. Significant differences were not detected among mean serum phenobarbital concentrations when comparing the trough, 3-hour, and 6-hour samples for all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: There is no therapeutically relevant change in serum phenobarbital concentrations throughout a daily dosing interval in most epileptic dogs. Therefore, timing is not important when collecting blood samples to measure serum phenobarbital concentrations in most epileptic dogs treated long-term with phenobarbital.

Bromide toxicosis secondary to renal insufficiency in an epileptic dog.

Bromide toxicosis was diagnosed in an 8-year-old Labrador Retriever that had been treated for epilepsy with potassium bromide, at a dosage of 29 mg/kg of body weight/d. Clinical signs included hind limb weakness, ataxia, and disorientation. Renal insufficiency, diagnosed by determination of endogenous creatinine clearance, was believed to be responsible for the development of bromide toxicosis in this dog. Diuresis with physiologic saline solution and discontinuation of bromide and phenobarbital treatment resulted in rapid resolution of abnormal neurologic signs; however, serum bromide concentrations decreased dramatically during diuresis and seizures recurred. Although saline diuresis has been recommended for the treatment of bromide intoxication in human beings, more conservative measures, such as discontinuation of bromide and short-term fluid administration, may be more appropriate for epileptic dogs.