Phase I Evaluation of Doxorubicin and Whole-body Hyperthermia in Dogs with Lymphoma

Fifteen previously untreated dogs with histologically confirmed, high-grade multicentric lymphoma were entered into a phase I study to evaluate combined doxorubicin and whole-body hyperthermia (DOX/WBH). Groups of three, four, and eight dogs were treated with whole-body hyperthermia and concurrent doxorubicin at 12 mg/m2, 24 mg/m2 and 30 mg/m2, respectively, after one doxorubicin induction dose at 30 mg/m2. Plateau temperature (42 +/- 0.1 degree C) was maintained for 90 minutes using a radiant heating device. A total of five DOX/WBH treatments per dog were planned, and these were given every 21 days. Treatment-related toxicity was not seen in the 12-mg/m2 doxorubicin dose group. Tumor progression prohibited administration of more than three DOX/WBH treatments to any dog in the 12-mg/m2 group. Premature ventricular contractions developed after the fifth treatment in one of the four dogs treated with 24 mg/m2 of doxorubicin. Two dogs (25%) in the 30-mg/m2 dose group had treatment-related toxicity. One dog experienced acute serious myelosuppression 1 week after the third treatment. This dog received all planned DOX/WBH treatments. Asymptomatic cardiac toxicosis consisting of decreased ejection fraction and fractional shortening developed in the second dog. This dog received only two DOX/WBH treatments. The three dogs treated at 12 mg/m2 had partial responses of short duration (60-83 days). Four dogs treated at 24 mg/m2 had complete responses for 150, 164, 186, and 200 days. Eight dogs treated at 30 mg/m2 had complete responses with a mean and median duration of 241 and 190 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined Gemcitabine and Carboplatin Therapy for Carcinomas in Dogs

Background: Response and adverse reactions to combined gemcitabine (GEM) and carboplatin (CARBO) therapy in dogs with carcinomas are not documented.
Hypothesis: GEM and CARBO are safe for the treatment of dogs with carcinomas.
Animals: Thirty-seven dogs with histologically or cytologically confirmed carcinomas.
Methods: Prospective clinical trial. Dogs were treated with GEM (2 mg/kg, 20–30-minute infusion IV) on Days 1 and 8 and 4 hours later, CARBO (10 mg/kg IV) on Day 1. The cycle was repeated on Day 22.
Results: Thirty-seven dogs (29 with measurable tumor) received a median of 2 cycles (range 0.5–6) for a total of 101 cycles administered. Twelve dogs (32%) developed neutropenia (3 Grade 3, and 5 Grade 4) and 9 (24%) thrombocytopenia (2 Grade 3, and 1 Grade 4). Dogs >20 kg were twice as likely to develop thrombocytopenia ( P = .023). Twenty-seven dogs (73%) had evidence of gastrointestinal (GI) toxicosis, but most signs were of mild to moderate severity and self-limiting. One dog died of treatment-related complications. Overall tumor response rate was 13%. One dog with metastatic prostatic carcinoma achieved a complete remission and 1 dog with intestinal adenocarcinoma and 1 with tonsillar squamous cell carcinoma achieved partial remission. Twelve dogs achieved stable disease for a median of 72 days.
Conclusion and Clinical Importance: GEM and CARBO combination causes mild to moderate hematologic and GI toxicosis in dogs with carcinoma. Response rate in this study was modest, and optimization of dosing of this combination is required.     

Adverse Effects of Concurrent Carboplatin Chemotherapy and Radiation Therapy in Dogs

Background: Concurrent chemo- and radiotherapy improves outcome of certain human neoplasms but with increased signs of toxicity. Reports on adverse effects of concurrent chemo- and radiotherapy in the veterinary literature are scant.
Objective: To report adverse hematologic and gastrointestinal effects of combined carboplatin and radiation therapy in dogs.
Animals: Client-owned dogs with spontaneously occurring neoplasia.
Methods: Retrospective case study. Medical records of 65 dogs were reviewed. Criteria for inclusion were administration of radiation according to 1 of 3 fractionation schemes (19 × 3, 16 × 3, or 12 × 4 Gy) and administration of at least 1 concurrent carboplatin treatment at a dosage of 200–300 mg/m². Dog and treatment-related variables were analyzed for association with signs of intoxication.
Results: Median carboplatin dosage was 200 mg/m² (range, 200–250 mg/m²). Twelve of 58 dogs (21%) developed grade 3 or 4 neutropenia. Eleven of 56 dogs (20%) developed grade 3 or 4 thrombocytopenia. Six of 62 dogs (10%) developed grade 3, 4, or 5 gastrointestinal toxicosis. Analysis of association of dog and treatment-related variables with signs of intoxication was hampered by the small numbers of dogs in individual groups, and no statistically significant associations were found.
Conclusions and Clinical Importance: Combined modality therapy resulted in myelosuppression and gastrointestinal toxicosis. Future studies are needed to determine whether the potential benefit of combined modality therapy outweighs the risk of decreasing chemotherapy and radiation treatment intensity.     

Phase I Dose Escalation of Single‐Agent Vinblastine in Dogs

Background: Vinblastine (VBL) is commonly used in dogs at a dosage of 2.0 mg/m². The minimal toxicity observed at this dosage indicates that higher dosages might be well tolerated. Hypothesis: The maximum tolerated dosage (MTD) for a single VBL treatment is higher than the previously published dosage of 2.0 mg/m². Animals: Twenty‐three dogs with lymphoma or cutaneous mast cell tumors. Methods: Dogs received 1 single‐agent VBL treatment IV. The starting dosage was 3.0 mg/m², and dosages were increased in increments of 0.5 mg/m² in cohorts of 3 dogs. Hematologic toxicity was assessed with weekly CBCs. Gastrointestinal toxicity was assessed from medical histories from owners. Once the MTD was determined, additional dogs were treated with VBL at that dosage. Dogs whose cancers responded to VBL continued to receive treatments q2–3 weeks. Results: VBL dosages ranged from 3.0 to 4.0 mg/m². Neutropenia was the dose‐limiting toxicity, with the nadir identified 7 days after treatment and resolving by 14 days after treatment. The MTD was 3.5 mg/m². Sixteen dogs were treated at this dosage, and 3 experienced severe toxicity characterized by asymptomatic grade 4 neutropenia, febrile grade 4 neutropenia, and death. Gastrointestinal toxicity was mild and self‐limiting. Preliminary evidence of antitumor activity was identified in 2 of 12 dogs with lymphoma treated at the MTD. Conclusions and Clinical Importance: In dogs, single‐agent VBL is well tolerated at a dosage of 3.5 mg/m² IV. At this dosage, the minimum safe treatment interval is q2 weeks, and adjunct treatment with prophylactic antibiotics should be considered.     

Randomized Phase III Trial of Piroxicam in Combination with Mitoxantrone or Carboplatin for First‐Line Treatment of Urogenital Tract Transitional Cell Carcinoma in Dogs

Background

Reported response rates of transitional cell carcinoma (TCC) in dogs to piroxicam in combination with either mitoxantrone or carboplatin are similar; however, it is unknown whether either drug might provide superior duration of response.

Hypothesis/Objectives

To determine if the progression‐free interval (PFI) of dogs with TCC treated with mitoxantrone and piroxicam was different than that of dogs receiving carboplatin and piroxicam. The hypothesis was that the efficacy of mitoxantrone is no different from carboplatin.

Animals

Fifty dogs with TCC without azotemia.

Methods

Prospective open‐label phase III randomized study. Either mitoxantrone or carboplatin was administered every 3 weeks concurrently with piroxicam with restaging at 6‐week intervals. Twenty‐four dogs received carboplatin and 26 received mitoxantrone.

Results

Response was not different between groups (P = .56). None of the dogs showed complete response. In the mitoxantrone group, there were 2 (8%) partial responses (PR) and 18 (69%) dogs with stable disease (SD). In the carboplatin group, there were 3 PR (13%) and 13 (54%) dogs with SD. The PFI was not significantly different between groups (mitoxantrone = 106 days; carboplatin = 73.5 days; P = .62; hazard ratio 0.86; 95% confidence interval 0.47–1.56). Dogs with prostatic involvement experienced a shorter survival (median, 109 days) compared to dogs with urethral, trigonal, or apically located tumors; this difference was significant (median 300, 190, and 645 days, respectively; P = .005).

Conclusions and Clinical Importance

This study did not detect a different in outcome in dogs with TCC treated with either mitoxantrone or carboplatin in combination with piroxicam.     

Pharmacokinetic Modeling of Doxorubicin Pharmacokinetics in Dogs Deficient in ABCB1 Drug Transporters

Background: The identification of dogs defective in ATP‐binding cassette transporter B1 (ABCB1, MDR1) activity has prompted questions regarding pharmacokinetics (PK), efficacy and toxicity of ABCB1 substrates in these dogs. Hypothesis/Objectives: Dogs defective in ABCB1 activity (ABCB1_null) have doxorubicin (DOX) PK different from that of normal dogs (ABCB1_wt). Utilization of a physiologically based pharmacokinetic (PBPK) model allows computer simulation to study this polymorphism's impact on DOX PK. Animals: None. Methods: A virtual ABCB1_wt dog population was generated and DOX distribution, elimination, and metabolism simulated by PBPK modeling. An in silico population of virtual dogs was generated by Monte Carlo simulation, with variability in physiologic and biochemical parameters consistent with the dog population. This population was used in the PBPK model. The ABCB1 components of the model were inactivated to generate an ABCB1_null population and simulations repeated at multiple doses. Resulting DOX levels were used to generate PK parameters. Results: DOX exposures in the ABCB1_null population were increased in all simulated tissues including serum (24%) and gut (174%). Estimated dosages in the ABCB1_null population to approximate exposure in the ABCB1_wt population at a dose of 30 mg/m² were 24.8 ± 3.5 mg/m² for serum and 10.7 ± 5.9 mg/m² for gut. Conclusions and Clinical Importance: These results suggest that serum DOX concentrations are not indicative of tissue exposure, especially those with appreciable ABCB1 activity, and that gastrointestinal (GI) toxicosis would be dose limiting in ABCB1_null populations. Dosage reductions necessary to prevent GI toxicosis likely result in subtherapeutic concentrations, thereby reducing DOXs efficacy in ABCB1_null dogs.     

A Pharmacokinetic Comparison of Meloxicam and Ketoprofen following Oral Administration to Healthy Dogs

Ketoprofen (KTP) and meloxicam (MLX) are non-steroidal anti-inflamatory drugs used extensively in veterinary medicine. The pharmacokinetics of these drugs were studied in eight dogs following a single oral dose of 1 mg/kg of KTP as a racemate or 0.2 mg/kg of MLX. The concentrations of the drugs in plasma were determined by high-performance liquid chromatography (HPLC). There were differences between the disposition curves of the KTP enantiomers, confirming that the pharmacokinetics of KTP is enantioselective. (S)-(+)-KTP was the predominant enantiomer; the S:R ratio in the plasma increased from 2.58 +/- 0.38 at 15 min to 5.72 +/- 2.35 at 1 h. The area under the concentration time curve (AUC) of (S)-(+)-KTP was approximately 6 times greater than that of (R)-(-)-KTP. The mean (+/- SD) pharmacokinetic parameters for (S)-(+)-KTP were characterized as Tmax = 0.76 +/- 0.19 h, Cmax = 2.02 +/- 0.41 microg/ml, t1/2el = 1.65 +/- 0.48 h, AUC = 6.06 +/- 1.16 microg.h/ml, Vd/F = 0.39 +/- 0.07 L/kg, Cl/F = 170 +/- 39 ml/(kg.h). The mean (+/- SD) pharmacokinetic parameters of MLX were Tmax = 8.5 +/- 1.91 h, Cmax = 0.82 +/- 0.29 microg/ml, t1/2lambda(z) = 12.13 +/- 2.15 h, AUCinf = 15.41 +/- 1.24 microg.h/ml, Vd/F = 0.23 +/- 0.03 L/ kg, and Cl/F = 10 +/- 1.4 ml/(kg.h). Our results indicate significant pharmacokinetic differences between MLX and KTP after therapeutic doses.     

Amputation and Carboplatin for Treatment of Dogs With Osteosarcoma: 48 Cases (1991 to 1993)

Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial evaluating treatment with amputation and up to 4 doses of carboplatin given every 21 days. The median disease-free interval (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI (P = .016) and survival (P = .037) times than dogs with OSA at other locations. Dogs with lower body weights (40 kg) had longer DFI (P = .0056) and survival (P = .007) times than larger dogs. Survival times for dogs that received carboplatin were statistically longer than those previously reported for amputation alone (P < .001). DFI and survival times are similar to those previously reported for 2 to 4 doses of cisplatin. Carboplatin appears to be a well-tolerated chemotherapeutic drug that can be given safely every 21 days at a dose of 300 mg/m². Neutropenia was the dose-limiting toxicity in this study. J Vet Intern Med 1996_;10:76–81. Copyright © 1996 by the American College of Veterinary Internal Medicine .     

Phase I Clinical Trial and Pharmacokinetics of Intravesical Mitomycin C in Dogs with Localized Transitional Cell Carcinoma of the Urinary Bladder

Background: Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. The most frequent cause of death is urinary obstruction from the primary tumor. Standard medical therapy for TCC is only partially effective. Hypothesis/Objectives: Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption. Animals: Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder. Methods: A prospective phase I trial was performed. MMC was given intravesically (600 μg/mL initial concentration) for 1 h/d for 2 consecutive days each month. The MMC concentration was escalated to a maximum of 800 μg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined. Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC. Results: The MTD of MMC based on local toxicoses was 700 μg/mL (1‐h dwell time, 2 consecutive days). In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC. Five dogs had partial remission, and 7 dogs had stable disease. Conclusions: Intravesical MMC has antitumor activity in dogs with invasive TCC. Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk.     

Clinical and Radiographic Evaluation of Intertrochanteric Osteotomy in Dogs: A Retrospective Study of 18 Dogs

Objective- To determine whether intertrochanteric osteotomy (ITO) can prevent the progression of degenerative joint disease (DJD) in dysplastic hip joints.
Study Design- The results of ITO were assessed retrospectively by using owner questionnaires, physical examination, and radiographic evaluation.
Animals- Eighteen client-owned dogs (29 coxofemoral joints were evaluated).
Methods- Lameness was scored according to a grading system. A scoring system was also developed to assess radiographically evident osteoarthritis on a ventrodorsal projection of the coxofemoral joints in extension.
Results- Twenty-nine ITO were performed in 18 dogs with varying degrees of hip dysplasia. The dogs were lame on 19 of 29 rear limbs on physical examination before surgery. In 22 of the 29 hip joints, palpation caused signs of pain. The median age at the first and second surgical procedure was 14.5 months and 18 months, respectively. Follow-up evaluation was performed on average at 9.77 (FU I), 22.52 (FU II), and 47.50 months (FU in) after surgery. Based on the owners' evaluation, there was a tendency toward improvement after surgery. The results of the physical examination at the preoperative examination and at the three follow-up examinations did not differ significantly. The follow-up radiographic scores showed significantly worse DJD than the preoperative scores.
Conclusions- ITO does not prevent progression of DJD in the dysplastic hip.
Clinical Relevance- Knowledge of the long-term effects of ITO is essential for surgeons trying to achieve improvement in dogs with hip dysplasia.     

Evaluation of Aldosterone Concentrations in Dogs with Hypoadrenocorticism

Background

Some dogs with primary hypoadrenocorticism (HA) have normal sodium and potassium concentrations, a phenomenon called atypical Addison''s disease. The assumption that the zona glomerulosa and aldosterone secretion in these dogs are normal seems widely accepted; however, aldosterone measurements are missing in most published cases.

Objectives

To measure aldosterone in dogs with HA with and without electrolyte abnormalities and to determine the time point of aldosterone peak concentrations during ACTH stimulation.

Animals

Seventy dogs with HA, 22 dogs with diseases mimicking HA, and 19 healthy dogs.

Methods

Prospective study. Blood samples were taken before and 60 minutes after injection of 250 μg ACTH in all dogs. Additional blood samples were taken 15, 30, and 45 minutes after ACTH in 7 dogs with HA and in 22 with diseases mimicking HA.

Results

Baseline and ACTH‐stimulated aldosterone was significantly lower in dogs with HA than in the other groups. Aldosterone was low or undetectable in 67/70 dogs with HA independently of sodium and potassium levels. In 3 dogs, sodium/potassium concentrations were normal; in 1 dog, sodium was normal and potassium decreased. In all 4, ACTH‐stimulated aldosterone concentrations were below the detection limit of the assay. Aldosterone concentrations were not different at 30, 45, or 60 minutes after ACTH administration.

Conclusion and Clinical Importance

Cortisol and aldosterone secretion is compromised in dogs with HA with and without electrolyte abnormalities. The term atypical Addison''s disease, used for dogs with primary HA and normal electrolytes, must be reconsidered; other mechanisms allowing normal electrolyte balance without aldosterone should be evaluated in these dogs.     

Wound Drainage from Under Full-thickness Skin Grafts in Dogs Part I. Quantitative Evaluation of Four Techniques

The formation of hematomas or seromas under skin grafts is reported to be the most common cause of graft failure. Several techniques have been developed to prevent fluid accumulation by increasing drainage, but their effectiveness has not been evaluated. In this study, four full-thickness skin grafting procedures were performed on both sides of the chests of 12 dogs, and the amount of wound drainage was quantitated for the first 10 postoperative days. The techniques evaluated were a sheet graft (control), continuous low level suction, piecrust incisions, and nonexpanded mesh graft. Significantly more drainage fluid was removed by continuous low level suction than the other techniques evaluated. Meshing allowed significantly more drainage than the piecrust or sheet grafts but was not as effective as continuous low level suction. Piecrust incisions had no significant effect on wound drainage.     

Early Biomarkers of Inflammation in Dogs and Cats: The Acute Phase Proteins

Veterinary Research Communications - Paltrinieri, S., 2007. Early biomarkers of inflammation in dogs and cats: the acute phase proteins. Veterinary Research Communications, 31(Suppl. 1), 125–129     

Phase II Clinical Trial of Carboplatin in Canine Transitional Cell Carcinoma of the Urinary Bladder

Fourteen dogs with histologically-confirmed transitional cell carcinoma (TCC) of the urinary bladder were treated with 300 mg/m² carboplatin every 3 weeks. Response to therapy was assessed with abdominal radiography, double contrast cystography, urinary bladder ultrasonography and thoracic radiography before therapy and at 6–week intervals during therapy. Dogs were monitored for hematologic toxicity with a CBC and platelet count performed immediately before and 10 to 14 days after carboplatin treatment. Tumor responses included progressive disease in 11 dogs and stable disease in 1 dog. Two dogs were euthanized due to carboplatin toxicity before assessment of tumor response. Toxicity included thrombocytopenia with or without neutropenia in 7 dogs and gastrointestinal toxicity in 6 dogs. Carboplatin therapy was not beneficial in the treatment of TCC in the 14 dogs in this study.     

Evaluation of Three Midazolam-Xylazine Mixtures Preliminary Trials in Dogs

The depressant effects of midazolam and xylazine on the central nervous system (CNS) were evaluated in 12 dogs. Xylazine was administered to six dogs (1.1 mg/kg intravenously [IV]) followed in 5 minutes by midazolam (1.0 mg/kg intramuscularly [IM]). In a second group of six dogs, xylazine (2.2 mg/kg IM) was followed in 5 minutes by midazolam (1.0 mg/kg IV). Both drug regimens induced rapid and profound sedation or anesthesia. Duration of action varied with the doses and routes of administration. Dogs given the high dose of xylazine IM had an arousal time of 95.4 +/- 8.9 minutes and a walking time of 155.4 +/- 8.8 minutes. These values exceeded the IV xylazine values threefold. Partial reversal of CNS depression was accomplished with either a benzodiazepine antagonist (flumazenil) or an alpha-2 antagonist (yohimbine). In a separate trial, a mixture of xylazine (0.55 mg/kg), midazolam (1.0 mg/kg), and butorphanol (0.1 mg/kg) with and without glycopyrrolate was evaluated in eight dogs. As with the xylazine-midazolam combinations, the CNS depressant effect of this mixture was clinically indistinguishable from anesthesia achieved with other rapid-acting injectable agents. Clinical signs of CNS depression were readily and completely antagonized by the simultaneous injection of flumazenil and yohimbine.