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- Author or Editor: Katrina Mealey x
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Abstract
Objective—To determine whether antiepileptic drugs (AEDs) are substrates for canine P-glycoprotein (P-gp).
Sample Population—OS2.4/Doxo cells (canine osteosarcoma cells induced via exposure to doxorubicin to highly express P-gp).
Procedures—Competitive inhibition of rhodamine 123 efflux from OS2.4/Doxo cells was used to determine whether AEDs were substrates for canine P-gp. Flow cytometry was used to quantify mean fluorescence intensity of cells treated with rhodamine alone and in combination with each experimental drug.
Results—Known P-gp substrate drugs ivermectin and cyclosporin A altered rhodamine efflux by 90% and 95%, respectively. Experimental drugs altered rhodamine efflux weakly (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or not at all (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide).
Conclusions and Clinical Relevance—At clinically relevant doses, it appeared that AEDs were weak substrates (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or were not substrates (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide) for canine P-gp. Therefore, it seems unlikely that efficacy of these AEDs is affected by P-gp expression at the blood-brain barrier in dogs.
Abstract
OBJECTIVE
To determine whether ABCB11930_1931del TC predisposed cats to macrocyclic-lactone toxicosis and the frequency of the ABCB11930_1931del TC gene mutation in banked feline DNA samples.
SAMPLE
DNA samples from 5 cats presented for neurologic clinical signs presumed to be caused by exposure to macrocyclic lactones and 1,006 banked feline DNA samples.
PROCEDURES
The medical history pertaining to 5 cats was obtained from veterinarians who examined, treated, or performed necropsies on them. The DNA from these 5 cats and 1,006 banked feline samples were analyzed for the presence of the ABCB11930_1931del TC genotype.
RESULTS
4 of the 5 cats with neurologic signs presumed to be associated with macro-cyclic-lactone exposure were homozygous for ABCB11930_1931del TC. The other cat had unilateral vestibular signs not typical of macrocyclic-lactone toxicosis. The distribution of genotypes from the banked feline DNA samples was as follows: 0 homozygous for ABCB11930_1931del TC, 47 heterozygous for ABCB11930_1931del TC, and 959 homozygous for the wild-type ABCB1 allele. Among the 47 cats with the mutant ABCB1 allele, only 3 were purebred (Ragdoll, Russian Blue, and Siamese).
CONCLUSIONS AND CLINICAL RELEVANCE
Results suggested a strong relationship between homozygosity for ABCB11930_1931del TC and neurologic toxicosis after topical application with eprinomectin-containing antiparasitic products labeled for use in cats. Although this genotype is likely rare in the general cat population, veterinarians should be aware of this genetic mutation in cats and its potential for enhancing susceptibility to adverse drug reactions. (J Am Vet Med Assoc 2021;259:72–76)
Abstract
Objective—To determine the frequency of the MDR1 gene mutation (polymorphism) associated with ivermectin sensitivity in a sample population of Collies in Washington and Idaho.
Animals—40 healthy client-owned Collies.
Procedure—A blood sample (8 ml) was collected from each dog and used for RNA extraction. Reverse transcriptase was used to generate MDR1 cDNA. Polymerase chain reaction (PCR) primers were designed to amplify a 1,061-base pair region of the MDR1 gene. The PCR products were sequenced to determine whether the Collies had 0, 1, or 2 mutant alleles. Pedigrees of some dogs were available for analysis to determine relatedness of affected dogs.
Results—Of the 40 Collies, 9 (22%) were homozygous for the normal allele (normal), 17 (42%) were heterozygous (carrier), and 14 (35%) were homozygous for the mutant allele (affected). Pedigree analysis revealed that some, but not all, affected dogs were related to each other within the 4 most recent generations.
Conclusions and Clinical Relevance—A high percentage of a sample population of Collies in Washington and Idaho are affected or carriers of the mutant MDR1 allele associated with ivermectin sensitivity. A similar frequency of this mutation may be detected in dogs from other geographic areas. Pharmacologic treatment with ivermectin, loperamide, vincristine, and other drugs that are substrates of P-glycoprotein, the MDR1 gene product, may result in neurologic toxicosis in a high percentage of Collies. (Am J Vet Res 2002;63:479–481)
Abstract
Objective—To evaluate the breed distribution of the ABCB1-1Δ polymorphism in a large number of dogs in North America, including dogs of several herding breeds in which this polymorphism has been detected and other breeds in which this polymorphism has not yet been identified.
Design—Cross-sectional study.
Animals—5,368 dogs from which buccal swab samples were collected for purposes of ABCB1 genotyping.
Procedures—From May 1, 2004, to September 30, 2007, DNA specimens derived from buccal swab samples collected from 5,368 dogs underwent ABCB1 genotyping. These data were reviewed, and results for each dog were recorded in a spreadsheet, along with the dog's breed. The genotypes for each breed were tallied by use of a sorting function.
Results—The ABCB1-1Δ allele was identified in 9 breeds of dogs and in many mixed-breed dogs. Breeds that had the ABCB1-1Δ allele included Collie, Longhaired Whippet, Australian Shepherd (standard and miniature), Shetland Sheepdog, Old English Sheepdog, Border Collie, Silken Windhound, and German Shepherd Dog (a breed in which this mutation had not been detected previously).
Conclusions and Clinical Relevance—The ABCB1-1Δ polymorphism is associated with increased susceptibility to many adverse drug reactions and with suppression of the hypothalamic-pituitary-adrenal axis and is present in many herding breeds of dog. Veterinarians should be familiar with the breeds that have the ABCB1-1Δ polymorphism to make appropriate pharmacologic choices for these patients.
Abstract
Objective—To validate use of high-performance liquid chromatography (HPLC) in determining imipramine concentrations in equine serum and to determine pharmacokinetics of imipramine in narcoleptic horses.
Animals—5 horses with adult-onset narcolepsy.
Procedure—Blood samples were collected before (time 0) and 3, 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, and 24 hours after IV administration of imipramine hydrochloride (2 or 4 mg/kg of body weight). Serum was analyzed, using HPLC, to determine imipramine concentration. The serum concentration-versus-time curve for each horse was analyzed separately to estimate pharmacokinetic values.
Results—Adverse effects (muscle fasciculations, tachycardia, hyperresponsiveness to sound, and hemolysis) were detected in most horses when serum imipramine concentrations were high, and these effects were most severe in horses receiving 4 mg of imipramine/kg. Residual adverse effects were not apparent. Value (mean ± SD) for area under the curve was 3.9 ± 0.7 h × μg/ml, whereas volume of distribution was 584 ± 161.7 ml/kg, total body clearance was 522 ± 102 ml/kg/h, and mean residence time was 1.8 ± 0.6 hours. One horse had signs of narcolepsy 6 and 12 hours after imipramine administration; corrresponding serum imipramine concentrations were less than the therapeutic range.
Conclusions and Clinical Relevance—Potentially serious adverse effects may be seen in horses administered doses of imipramine that exceed a dosage of 2 mg/kg. Total body clearance of imipramine in horses is slower than that in humans; thus, the interval between subsequent doses should be longer in horses. (Am J Vet Res 2001;62:783–786)
Abstract
Objective—To compare serum disposition of sulfamethoxazole and trimethoprim after IV administration to donkeys, mules, and horses.
Animals—5 donkeys, 5 mules, and 3 horses.
Procedure—Blood samples were collected before (time 0) and 5, 15, 30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, and 24 hours after IV administration of sulfamethoxazole (12.5 mg/kg) and trimethoprim (2.5 mg/kg). Serum was analyzed in triplicate with high-performance liquid chromatography for determination of sulfamethoxazole and trimethoprim concentrations. Serum concentration-time curve for each animal was analyzed separately to estimate noncompartmental pharmacokinetic variables.
Results—Clearance of trimethoprim and sulfamethoxazole in donkeys was significantly faster than in mules or horses. In donkeys, mean residence time (MRT) of sulfamethoxazole (2.5 hours) was less than half the MRT in mules (6.2 hours); MRT of trimethoprim in donkeys (0.8 hours) was half that in horses (1.5 hours). Volume of distribution at steady state (Vdss) for sulfamethoxazole did not differ, but Vdss of trimethoprim was significantly greater in horses than mules or donkeys. Area under the curve for sulfamethoxazole and trimethoprim was higher in mules than in horses or donkeys.
Conclusions and Clinical Relevance—Dosing intervals for IV administration of trimethoprim-sulfamethoxazole in horses may not be appropriate for use in donkeys or mules. Donkeys eliminate the drugs rapidly, compared with horses. Ratios of trimethoprim and sulfamethoxazole optimum for antibacterial activity are maintained for only a short duration in horses, donkeys, and mules. (Am J Vet Res 2002;63:349–353)
Abstract
Objective—To describe the pharmacokinetics of phenylbutazone and oxyphenbutazone after IV administration in miniature donkeys.
Animals—6 clinically normal miniature donkeys.
Procedure—Blood samples were collected before and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after IV administration of phenylbutazone (4.4 mg/kg of body weight). Serum was analyzed in triplicate by use of high-performance liquid chromatography for determination of phenylbutazone and oxyphenbutazone concentrations. The serum concentration-time curve for each donkey was analyzed separately to estimate model-independent pharmacokinetic variables.
Results—Serum concentrations decreased rapidly after IV administration of phenylbutazone, and they reached undetectable concentrations within 4 hours. Values for mean residence time ranged from 0.5 to 3.0 hours (median, 1.1 hour), whereas total body clearance ranged from 4.2 to 7.5 ml/kg/ min (mean, 5.8 ml/kg/ min). Oxyphenbutazone appeared rapidly in the serum; time to peak concentration ranged from 13 to 41 minutes (mean, 26.4 minutes), and peak concentration in serum ranged from 2.8 to 4.0 mg/ml (mean, 3.5 μg/ml).
Conclusion and Clinical Relevance—Clearance of phenylbutazone in miniature donkeys after injection of a single dose (4.4 mg/kg, IV) is rapid. Compared with horses, miniature donkeys may require more frequent administration of phenylbutazone to achieve therapeutic efficacy. (Am J Vet Res 2001;62:673–675)
Abstract
Objective—To determine whether Border Collies (ATP binding cassette subfamily B1 gene [ABCB1] wildtype) were more likely than other breeds to develop vincristine-associated myelosuppression (VAM) and, if so, whether this was caused by a mutation in ABCB1 distinct from ABCB1-1Δ.
Animals—Phase 1 comprised 36 dogs with the ABCB1 wildtype, including 26 dogs with lymphoma (5 Border Collies and 21 dogs representing 13 other breeds) treated with vincristine in a previous study; phase 2 comprised 10 additional Border Collies, including 3 that developed VAM and 7 with an unknown phenotype.
Procedures—For phase 1, the prevalence of VAM in ABCB1-wildtype Border Collies was compared with that for ABCB1-wildtype dogs of other breeds with data from a previous study. For phase 2, additional Border Collies were included. Hematologic adverse reactions were graded with Veterinary Co-operative Oncology Group criteria. Genomic DNA was used to amplify and sequence all 27 exons of the canine ABCB1. Sequences from affected dogs were compared with those of unaffected dogs and dogs of unknown phenotype.
Results—3 of 5 Border Collies with the ABCB1 wildtype developed VAM; this was significantly higher than the proportion of other dogs that developed VAM (0/21). A causative mutation for VAM in Border Collies was not identified, although 8 single nucleotide polymorphisms in ABCB1 were detected.
Conclusions and Clinical Relevance—Breed-associated sensitivity to vincristine unrelated to ABCB1 was detected in Border Collies. Veterinarians should be aware of this breed predisposition to VAM. Causes for this apparent breed-associated sensitivity should be explored.
Abstract
Objective—To evaluate survival time of dogs with idiopathic Fanconi syndrome.
Design—Case series.
Animals—60 dogs with idiopathic Fanconi syndrome.
Procedure—Data were collected by means of questionnaires distributed to owners and veterinarians of dogs with idiopathic Fanconi syndrome and by examination of medical records when accessible. Questionnaires and records were reviewed for criteria used in diagnosis, treatments administered, survival time, and subjective owner perceptions regarding their dogs' general condition.
Results—58 of the dogs were Basenjis. Fifty-seven dogs (95%) were reportedly managed by use of a single therapeutic regimen. Median survival time after diagnosis of Fanconi syndrome was 5.25 years; median estimated lifespan was calculated to be between 11.3 and 12.1 years. Owners of 28 of 29 (97%) dogs still alive at the time of the study subjectively assessed their dogs' general condition as good to excellent. Seizures or other neurologic dysfunction was reported for 11 dogs.
Conclusions and Clinical Relevance—Results suggest that expected lifespan for dogs with idiopathic Fanconi syndrome was not substantially reduced, compared with expected lifespan for unaffected dogs, and that affected dogs generally had a good to excellent quality of life, as subjectively assessed by their owners. What effect the treatment regimen had on survival time or lifespan could not be determined, given the small number of dogs managed with other methods. The high percentage of dogs with neurologic abnormalities was a concern, but whether this was related to Fanconi syndrome or represented a breed-related predisposition to neurologic disease could not be determined. ( J Am Vet Med Assoc 2004;225:377–383)
