Evaluation of the Amount of Compounded Chemotherapy Drugs: A Comparison Between Nine Compounding Pharmacies.

The use of compounded formulations of chemotherapy in veterinary medicine is common. The purpose of this study was to evaluate the drug amount of two compounded chemotherapeutics (chlorambucil and cyclophosphamide) from multiple veterinary compounding pharmacies, to determine if there was a difference in drug amounts between those that came from 503A versus 503B pharmacies, and finally to determine heterogeneity in drug amounts within each individual pharmacy. Nine veterinary compounding pharmacies (eight 503A, one 503B) were sampled in total, with two different batches sampled from each pharmacy. Each capsule's actual concentration was compared to the intended (prescribed) concentration. Of the 68 total samples obtained, 20 (29%) tested outside the FDA-acceptable discrepancy of ±10%. Of these, 12 (60%) were chlorambucil and 8 (40%) were cyclophosphamide. 503A cyclophosphamide samples had an average discrepancy of 6.6% from the intended dose while samples from the 503B pharmacy had a discrepancy of 1.8%. 503A chlorambucil samples had an average discrepancy of 10.4% from the intended dose while samples from the 503B pharmacy had a discrepancy of 9.6%. Heterogeneity within the same pharmacy and batch ranged from 0.1% to 51% for the 503A pharmacies and 2.6% to 7.5% for the 503B pharmacy. Heterogeneity between different batches within the same pharmacy ranged from 0.4% to 58.3% for the 503A pharmacies and 5% to 14.8% for the 503B pharmacy. Although the drug amounts of compounded cyclophosphamide and chlorambucil manufactured by the 503B compounding pharmacy was more reliably maintained compared to that compounded by the 503A pharmacies, there was ultimately still potential for variability in drug amounts regardless of the pharmacy designation.

Safety of TCMCB07, a melanocortin-4 antagonist peptide, in dogs with naturally occurring cachexia.

BACKGROUND: The melanocortin 4 antagonist TCMCB07 is safe and effective in reversing cachexia caused by sepsis or cancer in rodents. The safety and pharmacokinetics of TCMCB07 are demonstrated in healthy beagle dogs. HYPOTHESIS/OBJECTIVES: The objectives of this study were to investigate the safety, peak plasma concentrations, and potential for efficacy of TCMCB07 in pet dogs with naturally occurring cachexia over a 4-week time period. ANIMALS: Fourteen dogs with cachexia of any underlying cause, except cancer of the oral cavity or gastrointestinal tract, were eligible for enrollment with informed client consent. METHODS: This study was a prospective, 1-armed open-label trial. Physical examination, complete blood count, chemistry panel, and owner-assessed quality of life surveys were checked at weeks 1, 2, and 4. Due to potential for bradycardia and hypotension, Holter monitoring and blood pressure evaluations were scheduled at pre-enrollment and week 4. RESULTS: Fourteen dogs completed the trial. Significant changes detected included increased mean body weight (18.6-19.5 kg, P < .02), increased body condition score (median Tufts 5-point thin dog scale score P < .004 and WSAVA muscle condition score P < .02) and increased mean blood urea nitrogen (21.79-30.43 mg dL-1 , P < .004). On quality of life surveys, pet owners perceived their dog appeared to be panting less (P < .002) and that the general health improved (P < .03). Four dogs had a change in coat pigmentation. The peak plasma concentration of TCMCB07 in cachectic dogs was similar to that in healthy beagle dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: TCMCB07 was safe and has potential efficacy in pet dogs with cachexia.

Evaluation of factors associated with second remission in dogs with lymphoma undergoing retreatment with a cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol: 95 cases (2000-2007).

OBJECTIVE: To evaluate factors associated with second remission in dogs with lymphoma retreated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) protocol after relapse following initial treatment with a first-line 6-month CHOP protocol. DESIGN: Retrospective case series. ANIMALS: 95 dogs with lymphoma. PROCEDURES: Medical records were reviewed. Remission duration was estimated by use of the Kaplan-Meier method. Factors potentially associated with prognosis were examined. RESULTS: Median remission duration after the first-line CHOP protocol was 289 days (range, 150 to 1,457 days). Overall, 78% (95% confidence interval [CI], 69% to 86%) of dogs achieved a complete remission following retreatment, with a median second remission duration of 159 days (95% CI, 126 to 212 days). Duration of time off chemotherapy was associated with likelihood of response to retreatment; median time off chemotherapy was 140 days for dogs that achieved a complete remission after retreatment and 84 days for dogs that failed to respond to retreatment. Second remission duration was associated with remission duration after initial chemotherapy; median second remission duration for dogs with initial remission duration ≥ 289 days was 214 days (95% CI, 168 to 491 days), compared with 98 days (95% CI, 70 to 144 days) for dogs with initial remission duration < 289 days. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that retreatment with the CHOP protocol can be effective in dogs with lymphoma that successfully complete an initial 6-month CHOP protocol.

Evaluation of the Tolerability of Combination Chemotherapy with Mitoxantrone and Dacarbazine in Dogs with Lymphoma.

Combination chemotherapy can be an effective option for treating resistant lymphoma in dogs. This retrospective study examined the tolerability and efficacy of the combination of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (dacarbazine) (DTIC) in a population of dogs with lymphoma resistant to a doxorubicin-containing chemotherapy protocol. Mitoxantrone was administered at 5 mg/m2 IV over 10 min followed by DTIC at 600 mg/m2 IV over 5 hr, every 3 wk. All dogs were treated with prophylactic trimethoprim-sulfadiazine and metoclopramide. The frequency of grade 4 neutropenia was 18%, and 5% of dogs were hospitalized from sepsis. Gastrointestinal toxicity was uncommon. The overall response rate was 34% (15 of 44; 95% confidence interval 20-48%) for a median duration of 97 days (range 24-636 days, 95% confidence interval 44-150 days). Fourteen of 15 dogs who received mitoxantrone and DTIC as first rescue responded to treatment. Dogs who achieved complete remission to their initial L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol were more likely to respond to mitoxantrone and DTIC (23 versus 11%, P = .035). The combination of mitoxantrone and DTIC is a safe treatment option for resistant lymphoma in dogs.

Diagnosis and treatment of a feline oral mast cell tumor.

A cat was diagnosed with an oral mast cell tumor following incisional biopsy. The location of the tumor, possible metastasis, financial restraint and patient disposition severely limited therapeutic options. The patient was treated with six doses of 1-(2-chloroethyl)3-cyclohexyl-1-nitrosurea (CCNU) and methylprednisolone acetate. Complete remission was obtained after the third dosing regimen. This is the first documented case of feline oral mast cell tumor and one of a small group of cats with various cancers to be responsive to CCNU treatment.

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.

Low apparent risk of CCNU (lomustine)-associated clinical hepatotoxicity in cats.

The purpose of this study was to evaluate the prevalence of serum alanine transaminase (ALT) increases in cats treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, lomustine). The medical records of 95 cats treated with CCNU were reviewed, 29 of which met study criteria (at least one treatment with CCNU as a single agent, and at least one pretreatment and one post-treatment complete biochemical profile). Cats that received concurrent prednisone or dexamethasone were included, but those that received concurrent hepatoprotective or hepatotoxic medications were excluded. Cats included in the study were diagnosed with hepatic carcinoma, mammary carcinoma, lymphoma, mast cell tumor, plasma cell tumor and gastrointestinal leiomyoma. CCNU was given as a single agent at 31-60 mg/m(2), once every 4-8 weeks. Serum alanine transaminase (ALT) activity was measured after at least one dose of CCNU. Four cats (13.7%) had increased ALT activity above the reference interval before starting treatment. Two additional cats (6.8%) developed increased ALT activity above the reference interval 1 month after treatment with CCNU. One cat developed clinical signs potentially associated with hepatotoxicity, without a concurrent increase in ALT, 3 weeks following the final dose of CCNU. No association between dosing frequency, cumulative dose, initial starting dose or concurrent medications, and increases in ALT were found. Clinically significant hepatic injury is seemingly uncommon in cats treated with CCNU.