Hematologic Toxicosis Associated with Doxorubicin Administration in Cats

The hematologic toxicity of doxorubicin, 30 mg/m2 body surface area (BSA) every 21 days to a cumulative dose of 300 mg/m2, was evaluated in six cats. Complete blood and platelet counts were performed daily during the first treatment cycle. They were monitored before treatment for all remaining cycles, and at the average neutrophil nadir (day 8) starting with cycle 4. Significant poikilocytosis developed after the first treatment and remained throughout the study, although anemia did not occur. No other red blood cell abnormalities were seen. Platelet counts remained within the reference range throughout the first treatment cycle, but mild thrombocytopenia (88,000-288,000/uL) was found in 11.3% of subsequent complete blood counts (CBCs). Thrombocytosis was seen in 30.9% of CBCs. Neutropenia did not occur during the first treatment cycle although neutrophil counts did decrease, with the nadir occurring between days 8 and 11. All neutrophil counts returned to pretreatment values by day 14. Neutropenia was documented after 14 of 46 (30.4%) doxorubicin treatments, and was associated with fever in 5 cats (10.9%). All fevers responded to oral antibiotic therapy. Neutropenia that lasted more than 14 days developed in two cats, necessitating dosage reduction to 25 mg/m2 BSA. At the dose used in this study, doxorubicin administration was associated with acceptable hematologic toxicosis in most cats.     

Single agent gemcitabine chemotherapy in dogs with spontaneously occurring lymphoma

BACKGROUND: Gemcitabine has been shown to be effective as a single agent in a variety of tumors including nonHodgkin's lymphoma. Its use in veterinary medicine has been limited and to date this drug has not been used as a first-line therapy in dogs with lymphoma. HYPOTHESIS: Gemcitabine as a single agent may be efficacious in dogs presented for the first time with lymphoma. ANIMALS: Twenty-four dogs with spontaneously occurring lymphoma. METHODS: All dogs were clinically staged and given gemcitabine at 400 mg/m(2) over a 30-minute intravenous infusion weekly for 3 weeks and then given 1 week off treatment before starting a second cycle. RESULTS: A single dose of gemcitabine lowered both neutrophil count (decrease in mean neutrophil count from 10,640 cells/ microL to 3,140 cells/microL) and platelet count (decrease in mean platelet count from 201,290 cells/microL to 139,190 cells/microL) 7 days after administration. Consequently gemcitabine dosage was reduced at the second treatment in 8 of 21 dogs or a dose delay of 1-7 days and a reduction of dosage was used in 7 of 21 dogs. Seven dogs completed the assigned 4-week cycle. Two of these dogs had progressive disease and 5 had stable disease. No objective responses were seen in dogs treated with a second cycle of gemcitabine. CONCLUSIONS AND CLINICAL IMPORTANCE: Gemcitabine administration as a single agent resulted in hematologic toxicity and did not reduce lymphoma burden. If gemcitabine is to be used in veterinary medicine, additional prospective pharmacologic studies should be done to determine the appropriate dosage, regimen, and schedule of use before it can be recommended for use in the treatment of dogs with lymphoma as a single agent.     

Treatment of canine mast cell tumors with CCNU (lomustine)

The efficacy and toxicity of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosourea) were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy of their original mass performed and 4 (17%) had aspiration cytology of masses. Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were treated with CCNU at a dosage of 90 mg/m2 body surface area every 3 weeks. Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs (37%) had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, 21-254 days). Treatment with CCNU resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78 days and 122 days, respectively (range, 42-347 days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU. The median and mean neutrophil counts 7 days after CCNU were 1,452 cells/microL and 1,683 cells/microL, respectively (n = 17). Other toxicoses were uncommon. CCNU should be considered an active agent in the treatment of MCT in dogs.     

Results of a phase II clinical trial on the use of ifosfamide for treatment of cats with vaccine-associated sarcomas

OBJECTIVE: To determine clinical activity and toxic effects of ifosfamide when used to treat cats with vaccine-associated sarcoma (VAS). ANIMALS: 27 cats with a nonresectable, recurrent, or metastatic VAS. PROCEDURE: Each cat received ifosfamide (900 mg/m(2) of body surface area) as an IV infusion during a 30-minute period. Diuresis by infusion of saline (0.9% NaCl) solution and administration of mesna were used to prevent urothelial toxicosis. Treatments were administered every 3 weeks, and tumor response was assessed after the second treatment. All ifosfamide-associated toxic effects were graded in accordance with predetermined criteria. RESULTS: 61 treatments were administered to 27 cats (median, 2 treatments/cat; range, 1 to 4 treatments/cat). After ifosfamide treatment, 1 cat had a complete response and 10 had partial responses for an overall response rate of 11 of 27 (41%; 95% confidence interval [CI], 25% to 59%). Responses lasted from 21 to 133 days (median, 70 days; 95% CI, 60 to 113 days). The acute dose-limiting toxicosis was neutropenia, which was detected 5 to 28 days (median, 7 days) after treatment. Median nadir neutrophil count was 1,600 cells/muL (range, 200 to 5,382 cells/microL). Nine (33%) cats had adverse gastrointestinal effects (primarily salivation during the ifosfamide infusion and inappetence after treatment). Two cats were euthanatized because of severe nephrotoxicosis, and 1 cat developed pulmonary edema during diuresis. CONCLUSIONS AND CLINICAL RELEVANCE: Ifosfamide has antitumor activity against VAS in cats and is tolerated well by most cats. Ifosfamide should be evaluated as an adjuvant treatment for cats with VAS.     

Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs

BACKGROUND: Pleotropic-glycoprotein (P-gp)-mediated resistance is the usual cause of relapse in dogs with lymphoma. 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) are alkylating agents that are not affected by P-gp and lack cross-resistance to each other. A combination protocol offers the advantage of improved summation dose and synergistic activity. HYPOTHESIS: A combination of CCNU and DTIC that is well tolerated can be used to treat dogs with lymphoma that developed resistance or failed to respond to previously administered chemotherapy. ANIMALS: Fifty-seven dogs with lymphoma that were resistant to treatment with standard chemotherapy (L-CHOP; L-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone). METHODS: Prospective phase I and II trials were performed. CCNU was given PO immediately before a 5-h IV infusion of DTIC. Concurrent antiemetics and prophylactic antibiotics were used. Treatments were administered every 4 weeks. RESULTS: Based on the results of 8 dogs in the phase I study, CCNU at 40 mg/m(2) PO combined with DTIC at 600 mg/m(2) IV was used to treat 57 dogs with resistant lymphoma. Thirteen (23%) dogs had a complete response (CR) for a median of 83 days and 7 (12%) had a partial response for a median of 25 days. The median L-CHOP CR duration of the dogs that did not respond to CCNU-DTIC was significantly longer than that of the dogs that did achieve remission with CCNU-DTIC (225 days versus 92 days, P= .02). The principal toxic event was neutropenia; the median neutrophil count 7 days after treatment was 1,275 cells/microL. Increases in alanine transaminase activity, possibly associated with hepatotoxicity, were detected in 7 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A combination of CCNU and DTIC can be an effective option to rescue dogs with resistant lymphoma.     

Evaluation of ifosfamide for treatment of various canine neoplasms

lfosfamide (3-[2-chloroethyl]-2[(2 chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) is an alkylating agent with a broad spectrum of antitumor activity. The efficacy and toxicity of ifosfamide were evaluated in 72 dogs with spontaneously occurring tumors. Forty dogs (56%) had lymphoma, 31 (43%) had sarcomas, and 1 had a metastatic carcinoma. Five dogs received ifosfamide at dosages <350 mg/m2 IV. Neither toxicity nor response were observed, and the remaining dogs received ifosfamide at 350 mg/m2 (n = 18) and 375 mg/m2 body surface area IV (n = 49). Saline diuresis and the thiol compound mesna were used to prevent urothelial toxicity. Fifty-two dogs had measurable tumors and could be evaluated for response. Complete responses were seen in 1 dog with metastatic leiomyosarcoma of the urinary bladder and in 1 dog with metastatic cutaneous hemangiosarcoma. One dog with lymphoma had a partial response for 112 days. Six dogs with splenic hemangiosarcoma received ifosfamide postsplenectomy and their median survival time was 147 days. The acute dose limiting toxicity was neutropenia 7 days after administration of ifosfamide. The median and mean neutrophil counts 7 days after ifosfamide at 350 mg/m2 were 2,035 cells/microL and 4,773 cells/microL, respectively (n = 12). The median and mean neutrophil counts 7 days after ifosfamide at 375 mg/m2 were 2,500 cells/microL and 3,594 cells/microL, respectively (n = 37). No dog developed clinical or microscopic evidence of hemorrhagic cystitis. Ifosfamide appears safe to use in tumor-bearing dogs, and the evaluation of combination chemotherapy protocols that include ifosfamide should be considered.     

Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma

Vincristine (VCR) and L-asparaginase (L-ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L-ASP cause severe neutropenia in some dogs. It has been recommended that L-ASP be administered 12-24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/L-ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosuppression, especially the interval between VCR and L-ASP administration. Medical records of 147 dogs were reviewed. L-ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L-ASP, and 18% had neutrophil counts of <1,000 cells/microL. The median neutrophil count was 3,712 cells/microL (range 0-30,968 cells/microL). No correlation was found between administration interval and day 7 neutrophil count (P = .84) or development of gastrointestinal signs, including vomiting (P = .80), diarrhea (P = .52), and decreased appetite (P = .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P = .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L-ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L-ASP administration may not be necessary to avoid toxicity.     

CCNU in the treatment of canine epitheliotropic lymphoma

This retrospective study examined the use of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosurea) in 36 dogs with epitheliotropic lymphoma. Thirty-one (86%) dogs had the cutaneous form of disease, and 5 (14%) dogs had the oral form of disease. Nineteen (51%) dogs were treated with other chemotherapeutic agents before receiving CCNU. All dogs had detectable disease at the time CCNU therapy was initiated. Dogs received a median starting CCNU dosage of 70 mg/m2 (range, 50-100 mg/m2). The median number of treatments administered was 3 (range, 1-12 treatments). After the initial treatment, the CCNU dosage was adjusted in 9 of 26 (35%) dogs in which CCNU was continued: 7 had dosage reductions, and 2 had dosage escalations. Twenty-eight of 36 (78%) dogs had a measurable response to CCNU for a median duration of 106 days (95% confidence interval [CI], 75-182). Six dogs (17%) had a complete response, including 5 dogs with the cutaneous form and 1 dog with the oral form. Twenty-two dogs (61%) had a partial response, including 20 dogs with the cutaneous form and 2 dogs with the oral form, for a median duration of 88 days (95% CI, 62-170). Toxicoses after CCNU chemotherapy included myelosuppression in up to 29% of the dogs, gastrointestinal signs in up to 22% of the dogs, and liver enzyme activity increases in up to 86% of the dogs. This study demonstrates that CCNU chemotherapy can be considered a reasonable option for the treatment of canine epitheliotropic lymphoma in dogs.     

Hematological and clinical responses to combined mitoxantrone and cyclophosphamide administration to normal cats.

The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three normal adult cats were administered mitoxantrone (6.5 mg/m2 intravenously) and cyclophosphamide (100 mg/m2 intravenously) every 21 days for a total of three doses. Individual white blood cell count nadirs (range, 2.0-9.5 x 10(9)/L) and neutrophil count nadirs (range, 0.3 to 5.0 x 10(9)/L) occurred between days 2 and 10 after each dose of chemotherapy. Mean white blood cell count nadirs (range of mean, 5.5 to 8.4 x 10(9)/L) occurred between days 6 and 8, as did the mean neutrophil count nadir (range of mean, 1.7-4.0 x 10(9)/L). Side effects were limited to transient appetite suppression in one cat and loose stools in two cats. Myelosuppression and gastrointestinal side effects were comparable to those observed with single-agent mitoxantrone protocols. Further investigation of this protocol is warranted.     

Lomustine (CCNU) for the Treatment of Resistant Lymphoma in Dogs

Forty-three dogs with lymphoma that had relapsed or had failed to achieve complete remission to previous chemotherapy were treated with lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea [CCNU]) at a dosage of 90-100 mg/m2 body surface area p.o. every 3 weeks. Durable complete or partial responses occurred in 11 dogs for a median of 86 days. The acutely dose-limiting toxicosis was neutropenia 7 days after administration, resulting in a recommended dosage of 90 mg/m2. Cumulative thrombocytopenia occurred in dogs receiving continued CCNU treatment, and a dose interval of 3 weeks may be too short for continued administration of this drug. Toxicoses evident as fever or central nervous system signs or renal damage were uncommon or rare. CCNU is effective in the treatment of relapsed lymphoma.     

Toxicologic evaluation of chlorpyrifos in cats

Twenty-four male domestic shorthair cats were used to evaluate the acute and chronic effects of a single, toxic but sublethal, orally administered dose of chlorpyrifos. A dosage of 10 mg/kg of body weight did not induce clinical signs of toxicosis, but a dosage of 40 mg/kg induced clinical signs of toxicosis, and 1 of 12 cats died. Chlorpyrifos given at a dosage of 0.1 mg/kg to 2 cats reduced whole blood and plasma cholinesterase (Che) activities to values obtained after cats were given doses that induced clinical signs of toxicosis. Regeneration time for whole blood and plasma Che activities ranged from 7 to 28 days. Brain Che activity was considerably decreased in 1 cat that died 4.5 hours after dosing, but was normal in all others at 28 days after dosing. Other than decreased Che activity, significant changes were not seen in hematologic or serum biochemical values. Toxin-related lesions were not seen during macroscopic or microscopic examination.     

Cytosine Arabinoside as a Single Agent for the Induction of Remission in Canine Lymphoma

Cytosine arabinoside (AraC) was administered as a continuous IV infusion to 15 dogs with malignant lymphoma at a dose of 300 mg/m²/d for 2 consecutive days. Dogs were re-examined 7 d after treatment for response to therapy and for hematologic toxicity. Regardless of response, all dogs were started on combination chemotherapy at this time. Other toxicities were reported by owners. No dog responded objectively to Ara-C treatment, although 1 dog with circulating lymphoblasts had partial regression of lymphadenopathy but persistent blastemia. Thrombocytopenia (platelet count < 200,000/μL) 7 days posttreatment was the most commonly encountered hematologic toxicity, occurring in 10 of 14 dogs. Three of these 10 dogs were also mildly neutropenic (neutrophil counts of 2000 to 3000 cell/μL). Nonhematologic toxicity occurred in 8 of 15 dogs and was principally gastrointestinal in nature and mild in severity. Cytosine arabinoside at a dose of 300 mg/m²/day was not considered an active drug for the induction of remission in dogs with lymphoma.     

CCNU for the treatment of dogs with histiocytic sarcoma

BACKGROUND: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis. HYPOTHESIS: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease. ANIMALS: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU. METHODS: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma. RESULTS: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (< 100,000 platelets/microL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of < 1 month survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.     

Recombinant canine granulocyte colony-stimulating factor accelerates recovery from cyclophosphamide-induced neutropenia in dogs

In dogs injected intravenously with 400mg/m(2) cyclophosphamide (CPA), the peripheral neutrophil count decreased to less than 1000 cells/μL in 5-9 days. Treatment with purified recombinant canine granulocyte colony-stimulating factor (rcG-CSF), produced by brevibacillus expression system, at the nadir of the granulocyte count accelerated recovery from the CPA-induced neutropenia by 1-3 days. Therapeutic administration of rcG-CSF at doses of 2.5-10 μg/kg did not show any significant difference on the severity of neutropenia (the period that granulocyte counts were less than 2000 cells/μL). Administration of 2.5 μg/kg rcG-CSF 3 times per day 2-4 days or 3-5 days after CPA treatment not only accelerated recovery but also decreased the severity of neutropenia. No clinical signs of the rcG-CSF were observed. These results showed that the rcG-CSF is effective for treatment of neutropenia in dogs.     

Systemic toxicosis associated with azathioprine administration in domestic cats.

Five cats were treated with an azathioprine suspension (2.2 mg/kg of body weight on alternate days) and 2 cats were given vehicle (controls) for 9 weeks. Complete blood and platelet counts and serum biochemistry variables were monitored weekly. Bone marrow aspirates were evaluated every 3 weeks, and core bone marrow biopsy was performed at the end of the study. Profound neutropenia (less than 600 cells/microliters) was observed in all treated cats, and 1 cat developed pancytopenia. Treatment was discontinued if the WBC count was less than 3,000 cells/microliters. Four weeks after discontinuation of azathioprine, 1 treated cat again was given azathioprine at a lower dosage (1.1 mg of azathioprine/kg on alternate days) and neutropenia recurred within 2 weeks. During treatment, 3 cats developed thrombocytosis, and 2 developed thrombocytopenia. In 4 of 5 cats, neutropenia and thrombocytopenia resolved when azathioprine was discontinued. Bone marrow cytologic examination during treatment revealed reduction of the neutrophil line, with relative increase in monocytes. Core bone marrow biopsy at the completion of the study revealed hypocellular marrow with marked decrease in the myeloid series in cats given azathioprine. One of the cats that was treated with azathioprine had a hypercellular marrow with increased numbers of mature granulocytes and precursors; however, azathioprine had been discontinued 3 weeks prior to biopsy. Alterations in serum biochemical variables were not associated with azathioprine. Two cats that were treated with azathioprine developed respiratory tract infections, and 1 of them was euthanatized during the study.     

Weekly administration of low-dose doxorubicin for treatment of malignant lymphoma in dogs

Nine dogs with intermediate- or high-grade lymphoma were prospectively entered into a protocol to be given a total of 15 weekly doses of doxorubicin (10 mg/m2 of body surface, IV) in an attempt to eliminate all clinical evidence of neoplasia, with minimal risk of drug toxicity. Eight of these dogs did not complete the protocol because of progression of the disease. The median number of doses administered to dogs that developed progressive disease before the regimen was completed was 5 (range, 2 to 9). Seven dogs achieved partial (n = 5) or complete (n = 2) remission, with median duration of 14 days (range, 7 to 231 days). The dog that was given all 15 weekly treatments remained in complete remission for 231 days. Complete remission that lasted for 14 days was observed in another dog. Toxicosis developed in 3 dogs; signs of toxicosis were generally mild and included colitis (n = 1), vomiting (n = 1), neutropenia (n = 1), and lethargy (n = 1). The lowest neutrophil count (1,876 cells/microliter) was seen in one dog after 7 doses of doxorubicin were given. Doxorubicin at dosage of 10 mg/m2/wk appears to be safe, but is generally ineffective for treatment of lymphoma.     

Phase I clinical evaluation of carboplatin in tumor-bearing cats: a Veterinary Cooperative Oncology Group study

BACKGROUND: The dosage of carboplatin in cats has been reported anecdotally and experimentally in non-tumor-bearing cats, but the dosage for carboplatin treatment in tumor-bearing cats has yet to be defined in a prospective clinical trial. PURPOSE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of carboplatin in tumor-bearing cats. CATS: Fifty-nine cats with measurable solid tumors. METHODS: The starting dose of carboplatin was 160 mg/m(2) of body surface area IV. Doses were increased by 20 mg/m(2) in cohorts of 3-14 cats until the MTD was reached. RESULTS: The 59 cats entered into this multi-institutional phase I study received 1 or more doses of carboplatin at various dosages and were evaluated for toxicity, response to treatment, or both. The MTD was 240 mg/m(2) and neutropenia was the DLT. For the 1st cycle of treatment in 44 cats evaluated for neutropenia, 6 episodes of grade 3 or greater neutropenia occurred on days 7 (n=1), 14 (n=4), and 21 (n=1). There was no evidence of drug-induced nephrotoxicosis or pulmonary edema. Preliminary evidence of antitumor activity was observed in 7 of 59 (11.9%; 95% CI, 5.6-22.8%) cats evaluated for response to treatment. There was 1 complete response (cutaneous hemangiosarcoma) and 6 partial responses (4 injection site sarcomas, 1 oral squamous cell carcinoma, 1 lymphoma). Responses were of short duration (median, 42 days; range, 7-168 days). CONCLUSIONS AND CLINICAL IMPORTANCE: The dose of carboplatin recommended to treat tumor-bearing cats is 240 mg/m(2) IV every 3-4 weeks.     

Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs

One hundred seventy-nine tumor-bearing dogs were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) between 1995 and 2001. CCNU was given as a single dose of 50-110 mg/m2 body surface area PO. Treatment interval varied, but the minimal interval between CCNU doses was 3 weeks. After treatment, 11 dogs (6.1%) developed hepatic toxicity. The median number of CCNU doses and the median total cumulative CCNU dose were significantly higher in dogs that developed hepatic toxicity (4 doses; 350 mg/m2) than in dogs without hepatic damage (3 doses; 230 mg/m2). Median duration to detection of hepatic toxicity from the last dose of CCNU was 11 weeks (range 2-49 weeks). Common biochemical abnormalities were abnormally high serum liver enzyme activities and hypoalbuminemia. Six dogs with CCNU-associated hepatic toxicity had ascites, and 3 dogs had concurrent pleural effusion. Serum concentrations of bile acids were abnormally high in 4 of 5 dogs tested. Percutaneous ultrasound-guided liver biopsies were performed in 10 dogs, and findings were nonspecific and chronic in nature. Seven dogs were euthanized because of progressive liver failure, and their median survival from diagnosis of liver disease was 9 weeks. Three dogs died of other causes and 1 dog of unknown cause. Although clinical signs resolved in 3 dogs, biochemical abnormalities and histopathologic lesions persisted 4 to 38 months from the time of diagnosis of liver disease. Our findings suggest that CCNU can cause delayed, cumulative dose-related, chronic hepatotoxicity that is irreversible and can be fatal.     

Evaluation of a short-term saline diuresis protocol for the administration of cisplatin

A study was undertaken to determine the toxic effects of cisplatin, an antineoplastic agent, on canine kidneys and bone marrow when administered during a 6-hour saline diuresis. Cisplatin (70 mg/m2 of body surface) was administered IV to 6 healthy dogs over a 20-minute period after 0.9% NaCl solution (saline) was administered IV for 4 hours at a rate of 18.3 ml/kg/hr. After cisplatin injection, saline diuresis was continued at the same rate for 2 hours. Each dog vomited within 8 hours after the drug was administered. Clinical status, weight gain, and food consumption were normal throughout the 27-day study. All measures of renal function remained unchanged and were within normal limits for 27 days after the drug was administered. Nadirs in the daily neutrophil count were observed on days 6 (3,240 +/- 404/microliters) and 15 (1,196 +/- 275/microliters). There were no important gross or histologic abnormalities referable to cisplatin administration when the dogs were necropsied at the conclusion of the study (day 27). We concluded that cisplatin can be administered safely at a dosage of 70 mg/m2 of body surface, using a short-term diuresis protocol, and that the drug induces a nadir in the neutrophil count on days 6 and 15.     

Doxorubicin area under the curve is an important predictor of neutropenia in dogs with naturally occurring cancers

Doxorubicin (DOX) area‐under‐the‐curve (AUC) was calculated for 40 dogs with spontaneously occurring cancers using a previously validated limited‐sampling approach. All dogs were administered a dose of 30 mg/m² by intravenous infusion and serum samples were collected at 5, 45 and 60 minutes post‐infusion. DOX and its major metabolite, doxorubicinol (doxol), were quantified in serum samples using high‐performance liquid chromatography tandem‐mass spectrometry. Wide interpatient variability was observed in the predicted DOX AUC with a coefficient of variation of 34%. A significant relationship was found between DOX AUC and absolute white blood cell count (P = 0.003), absolute neutrophil count (ANC; P = 0.002) and surviving fraction of neutrophils (P = 0.03) approximately 1 week after dosing (nadir). No changes in other hematologic parameters (red blood cells, platelets, lymphocytes, haemoglobin) were found to correlate with DOX AUC. The absolute dose (mg) and the dose per unit body weight (mg/kg) were not significantly correlated with nadir ANC. No relationships were found between maximum serum doxol concentration and myelosuppression. Baseline ANC was also significantly correlated to nadir ANC and a model was constructed using baseline ANC and DOX AUC that significantly described the nadir ANC. These findings demonstrate the important relationship between systemic DOX exposure and degree of neutropenia in dogs, and suggest a potential for individualized, pharmacokinetically‐guided DOX dosing in dogs.