Acute Reactions in Dogs Treated with Doxorubicin: Increased Frequency with the Use of a Generic Formulation

During a 4-month period, 34 dogs with tumors received a total of 60 doses of a single generic formulation of doxorubicin; 13 acute drug reactions were observed in these 34 dogs, and no acute reactions were observed after replacing the product with the proprietary brand. These reactions were characterized by one or more of the following signs: pruritus; head-shaking; urticaria; erythema of the pinnal, axillary, or inguinal regions; vocalization; vomiting; hyperemic or pale mucous membranes; high heart rate; and high respiratory rate. We propose that a component unique to generic doxorubicin was responsible for the unusually high number of acute drug reactions observed.     

ABCB1-1Δ Polymorphism Can Predict Hematologic Toxicity in Dogs Treated with Vincristine

Background: Dogs that harbor the naturally occurring ABCB1-1Δ polymorphism experience increased susceptibility to avermectin-induced neurological toxicosis as a result of deficient P-glycoprotein function. Whether or not the ABCB1-1Δ polymorphism affects susceptibility to toxicity of other P-glycoprotein substrate drugs has not been studied.
Hypothesis: Dogs that possess the ABCB1-1Δ mutation are more likely to develop hematologic toxicity associated with vincristine than ABCB1 wild-type dogs.
Animals: Thirty-four dogs diagnosed with lymphoma were included in this study.
Methods: Cheek swab samples were obtained from dogs diagnosed with lymphoma that were to be treated with vincristine. DNA was extracted from cheek swabs and the ABCB1 genotype was determined. Hematologic adverse drug reactions were recorded for each dog and graded according to the Veterinary Comparative Oncology Group's criteria for adverse event reporting (Consensus Document). In order to avoid possible bias, ABCB1 genotype results for a particular patient were not disclosed to oncologists until an initial adverse event report had been submitted.
Results: Dogs heterozygous or homozygous for the ABCB1-1Δ mutation were significantly more likely to develop hematologic toxicity, specifically neutropenia ( P = .0005) and thrombocytopenia ( P = .0001), after treatment with vincristine than ABCB1 wild-type dogs.
Conclusions and Clinical Implications: At currently recommended dosages (0.5–0.7 mg/M²), vincristine is likely to cause hematologic toxicity in dogs with the ABCB1-1Δ mutation, resulting in treatment delays and unacceptable morbidity and mortality. Assessing the ABCB1-1Δ genotype before vincristine administration and decreasing the dosage may prevent toxicity and treatment delays resulting from neutropenia or thrombocytopenia.     

Prospective evaluation of clinically relevant type B hyperlactatemia in dogs with cancer

Background: Cancer is considered a cause of type B hyperlactatemia in dogs. However, studies evaluating cancer as a cause of clinically relevant type B hyperlactatemia (>2.5 mmol/L) are lacking. Cancer cells have a higher lactate production because of increased aerobic glycolysis, known as the “Warburg effect.” The mechanisms through which aerobic glycolysis occurs are not well elucidated, but neoplasia may cause type B hyperlactatemia via this process. Objectives: To determine if malignant tumors of dogs are associated with clinically relevant type B hyperlactatemia (>2.5 mmol/L). Animals: Thirty‐seven client‐owned dogs with malignant tumors: 22 with hematopoietic and 15 with solid tumors. Methods: Histology was used to confirm the diagnosis (cytology was considered adequate for diagnosis of lymphoma). Confounding conditions associated with hyperlactatemia were excluded. Lactate measurements were immediately performed on free‐flow jugular whole blood samples using the LactatePro analyzer. Results: All dogs had lactate concentrations <2.5 mmol/L. Mean blood lactate concentration was 1.09 mmol/L. Mean blood lactate concentrations for solid and hematopoietic tumors were 0.95 and 1.19 mmol/L, respectively. Dogs with lymphoma (n = 18) had a mean blood lactate concentration of 1.15 mmol/L. Conclusions: Malignant tumors were not considered a cause of clinically relevant type B hyperlactatemia. Therefore, cancer‐related type B hyperlactatemia in dogs is uncommon, and hyperlactatemia should prompt careful investigation for causes other than cancer.     

A non-radiometric method for measuring serum thymidine kinase activity in malignant lymphoma in dogs

The aim of this study was to evaluate an enzyme-linked immunosorbent assay (ELISA), for determination of serum thymidine kinase 1 (sTK1) activity in dogs with malignant lymphoma (ML) and compare it with a thymidine kinase (TK) radioenzymatic assay (TK-REA). The TK-REA has recently been shown to be useful in determining the clinical stage and prognosis in canine ML. In addition, serum lactate dehydrogenase (LDH) was measured. Forty-five dogs were included in the study. Sixty serum samples from these dogs, stored in a tumour serum sample bank (stored at -20 degrees C), were analysed. Apart from 37 dogs with ML, four normal dogs as well as two dogs with mammary carcinomas, one dog with bladder carcinoma, and one dog with malignant fibrous histiocytoma were included. Staging of ML was based on the modified World Health Organization (WHO) staging system for canine ML. The diagnosis of all tumours was verified by histopathology. The TK activity (units per litre [U/L]) ranged from 1.0 to 607.9 in the TK-REA analysis and from 1.1 to 510 in the TK-ELISA (normal reference value <7U/L). The range for LDH was between 12 and 1194 U/L (normal reference value <228 U/L). There was a significant correlation between the TK-REA and the TK-ELISA. The correlation coefficient (CC) was 0.97 and the standard error of the estimate (SEE) was 3.7 U/L. There was no correlation between LDH and either the TK-REA or the TK-ELISA (CC=0.53 for both assays; SEE=26.7 and 12.7 U/L, respectively). Most of the variation in LDH was still within the normal reference range. The mean LDH in dogs with high-stage (stage IV+V) disease was 201.9 U/L. The corresponding values for the TK-REA and TK-ELISA were 109 and 109.9 U/L, respectively. The significant relation between the TK-REA and the TK-ELISA was confirmed by Bland-Altman analysis. The TK-ELISA assay, because of its relative simplicity, will permit measurement of TK in cases of ML in dogs to become a routine procedure.     

Lymphoma as a model for chronic illness: effects on adrenocortical function testing

Many dogs with chronic illness have serum biochemical abnormalities consistent with hyperadrenocorticism (HAC). Lymphoma (LSA) is a chronic disease of dogs. The purpose of this study was to evaluate adrenocortical screening test results in dogs with LSA to evaluate their specificity. Criteria for inclusion in the study included a diagnosis of LSA, an expected survival time of 16-56 weeks, no glucocorticoid treatment beyond 4 weeks after the initiation of chemotherapy, no evidence of HAC, and owner consent. Post-ACTH stimulation plasma cortisol concentrations (PACs), urine cortisol : creatinine (UC : Cr) ratios, and maximal left adrenal width measurements were performed at the time of LSA diagnosis before the initiation of chemotherapy and at 16, 24, 32, 40, and 52 weeks or until the loss of remission or the development of another disease. Ten dogs met the criteria for inclusion. Forty-two PACs were performed; 1 abnormal, 2 borderline, and 39 normal values were detected. Thirty-five maximal left adrenal width measurements were obtained; 0 abnormal, 5 borderline, and 30 normal measurements were detected. Thirty-six UC : Cr ratios were obtained, with 26 abnormal, 4 borderline, and 6 normal values detected and 9 of 10 dogs having at least 1 abnormal value. These data suggest that in dogs with LSA, the UC : Cr ratio frequently is abnormal and may not be a specific test for HAC, or it may be the most sensitive test for increases in cortisol secretion due to chronic illness. Maximal left adrenal width measurements and PACs were almost always normal and may be more specific for HAC or less sensitive for demonstrating chronic increases in cortisol secretion.     

Preliminary studies of serum acute-phase protein concentrations in hematologic and neoplastic diseases of the dog

Serum concentrations of acute-phase proteins (APPs): haptoglobin (Hp), ceruloplasmin (Cp), serum amyloid A (SAA), and C-reactive protein (CRP) were determined in healthy dogs (n = 15) and dogs with different diseases grouped as acute inflammation (I, n = 12), hematologic neoplasias (HT, including leukemia and lymphoma, n = 16), nonhematologic neoplasias (NHT, including epithelial, mesenchymal, and mixed, n = 20), and autoimmune hemolytic anemia (AIHA, n = 8). SAA and CRP were analyzed using commercially available enzyme-linked immunosorbent assay (ELISA) kits, and Hp and Cp were measured using colorimetric methods, all previously validated for use in dogs. Increased concentrations of all APPs were observed in all groups of diseased dogs, but statistical significance only was observed with Hp (I, P < .001; HT, P < .05), Cp (I, P < .05; AIHA, P < .01), and CRP (I, P < .001; HT, P < .001; AIHA, CRP P < .05). High variability in individual APPs within each group of diseases was found with no significant differences between leukemia and lymphoma as well as among different types of neoplasia. The AIHA group had smaller increases in Hp, SAA, and CRP but higher concentrations of Cp. When follow-up of individual cases was possible, a decrease in APPs generally was found in cases with favorable outcome. The results of this study suggest that neoplasia and hematologic diseases such as AIHA should be considered as possible causes of mild increases in APPs in dogs. Measurement of APPs may be helpful to assess clinical evolution and monitor treatment of these processes.