Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose-finding study

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2) every other week) concurrent with toceranib (3.25 mg kg(-1) PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.     

Accuracy of computed tomography in determining lesion size in canine appendicular osteosarcoma

Multidetector contrast enhanced computed tomography with acquisition of 0.625-mm thick transverse images was used to measure the extent of appendicular osteosarcoma in 10 dogs. The measured length of tumor based on CT was compared to the true length of tumor using histopathology. There was a statistically significant association with good correlation between the true length of osteosarcoma compared to the length of intramedullary/endosteal abnormalities on CT with a mean overestimation of 1.8% (SD = 15%). There was not a statistically significant association between the true tumor length and the length of periosteal proliferation on CT with a mean overestimation of 9.7% (SD = 30.3%). There was a statistically significant association, but with poor correlation, between the true tumor length compared to the length of abnormal contrast enhancement with a mean overestimation of 9.6% (SD = 34.8%). The extent of intramedullary/endosteal CT abnormalities assessed from submillimeter transverse images may be of value in assessing patient candidacy and surgical margins for limb-sparing surgery.     

Evaluation of Efficacy and Safety of Zinc Gluconate Associated with Dimethyl Sulphoxide for Sexually Mature Canine Males Chemical Neutering

The aim of this research was to evaluate the efficacy of zinc gluconate associated with dimethyl sulphoxide (DMSO) for chemical neutering in canine males. Fifteen sexually mature male dogs were divided in two groups, named control and treated. An injection was administered to both testicles, at a concentration of 26.2 mg zinc gluconate per ml and 0.5% DMSO in the treated group (11 dogs). The control group was given injections of saline solution (four dogs). Clinical examination and blood collection for a haemogram were done both before and after drug injection. There were 12 spermograms performed to analyse sperm motility, sperm vigour, ejaculate volume, testicle size, pathology and sperm concentrations. Libido was also measured. An ultrasound examination and histopathology were performed at the end of the experiment. Dogs’ libido after chemical injection was reduced by over 50%. The spermogram analysis showed final mean results of 14.54% for sperm motility, 0.72 of sperm vigour and 37 150 per million spermatozoa per millilitre, values considered below the necessary levels at which fertilization can occur. Ultrasound and histopathology analyses of testicles for the treated group revealed more intense injuries when compared with the control group, with compromised testicular parenchyma and a decrease of germ cell number leading to total atrophy, indicating that the treatment reduced the fertilizing potential of male dogs, promoting a possible subfertile status.     

Lignocaine versus bupivacaine for flank anaesthesia using multiport catheters via a caudal epidural approach in cattle

Objective To determine the anaesthetic and systemic effects of dorsolumbar epidural anaesthesia using non-stylet multiport catheters via the caudal approach to administer hypertonic 5% lignocaine (HL) or hypertonic 0.5% bupivacaine (HB) to the flank in standing cattle. Materials and methods Six healthy adult cattle weighing 310–455 kg received 0.2 mg/kg HL or 0.025 mg/kg of HB; control animals received 0.9% saline solution. All drugs were injected into the dorsolumbar epidural space via a caudal approach through a non-stylet multiport catheter. Each animal received each treatment at random. Evaluations of anaesthesia, ataxia, heart rate, arterial pressures, respiratory rate and rectal temperature were obtained at 0 (basal), 5, 10, 15, 30, 45, 60, 75, and 90 min after epidural injection and then at 30-min intervals until loss of anaesthesia. All animals received a standard noxious stimulus and a 4-point scale was used to score the response. A second scale was used to score ataxia. Results The duration of anaesthesia in the upper and lower flanks in cattle was 68 ± 12 and 110 ± 15 min (mean ± SD) after dorsolumbar epidural HL or HB, respectively. Both hypertonic local anaesthetics produced a mild ataxia. The systemic changes were within acceptable limits in these clinically healthy cattle. Conclusion In standing cattle the dorsolumbar epidural injection of hypertonic lignocaine provided faster onset of anaesthesia and fewer cardiovascular effects, but had a shorter duration of anaesthesia than hypertonic bupivacaine.     

Feline lymphoma in the post-feline leukemia virus era

Lymphoma (lymphosarcoma or malignant lymphoma) is the most common neoplasm of the hematopoietic system of cats and reportedly the cat has the highest incidence for lymphoma of any species. A 21-year retrospective survey of feline lymphoma covering the period 1983-2003 was conducted with the patient database at the Veterinary Medicine Teaching Hospital (VMTH) at the University of California, Davis, School of Veterinary Medicine. This period comprises the post-feline leukemia virus (FeLV) era. Feline lymphoma historically has been highly associated with retrovirus infection. Mass testing and elimination and quarantine programs beginning in the 1970s and vaccination programs in the 1980s dramatically reduced the subsequent FeLV infection rate among pet cats. The results of this survey confirm a significant decrease in the importance of FeLV-associated types of lymphoma in cats. In spite of this decrease in FeLV infection, the incidence of lymphoma in cats treated at the VMTH actually increased from 1982 to 2003. This increase was due largely to a rise in the incidence of intestinal lymphoma, and to a lesser degree, of atypical lymphoma. A high incidence of mediastinal lymphomas in young Siamese or Oriental breeds also was observed, supporting previous studies. Associations of intestinal lymphoma and inflammatory bowel disease and diet should be further considered.     

Prevalence and importance of internal tandem duplications in exons 11 and 12 of c-kit in mast cell tumors of dogs

OBJECTIVE: To determine the prevalence of activating internal tandem duplications (ITDs) in exons 11 and 12 of c-kit in mast cell tumors (MCTs) of dogs and to correlate these mutations with prognosis. SAMPLE POPULATION: 157 formalin-fixed, paraffin-embedded MCTs from dogs in the pathology database of the Veterinary Medical Teaching Hospital at the University of California, Davis. PROCEDURE: Genomic DNA was isolated from tumor specimens and a polymerase chain reaction procedure was performed to determine whether there were ITDs in exons 11 and 12. RESULTS: We identified ITDs in 1 of 12 (8%) grade-I, 42 of 119 (35%) grade-lI, and 9 of 26 (35%) grade-ll tumors (overall prevalence, 52 of 157 [33%]). Logistic regression analysis revealed that the odds of grade-II and -III tumors possessing an ITD were approximately 5 times greater than that for grade-I tumors, although these odds did not differ significantly. Although MCTs possessing an ITD were twice as likely to recur after excision and twice as likely to result in metastasis as those without an ITD, these values also did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide evidence that ITDs in c-kit occur frequently in MCTs of dogs. The high prevalence of c-kit activating mutations in MCTs of dogs combined with the relative abundance of mast cell disease in dogs provide an ideal naturally developing tumor in which to test the safety and efficacy of novel small-molecule kinase inhibitors such as imatinib mesylate.     

Acute cortisol responses of calves to four methods of dehorning by amputation

Objective To measure the plasma cortisol response in calves dehorned by four different methods (scoop, guillotine shears, saw, embryotomy wire) for 9 h after dehorning.
Design A physiological study with controls.
Procedure Horn amputation was carried out on calves restrained manually in a race.
Results The four methods of dehorning provoked similarly increased cortisol responses which lasted for 6 h. During the first hour after dehorning the plasma cortisol concentrations were similar to those following ACTH injection. The overall cortisol response to control handling was about 30% of the responses to dehorning.
Conclusions The similarity of the cortisol responses produced by the four methods of dehorning suggests that the distress experienced by calves following dehorning by amputation is similar regardless of method used.     

Biological activity of dihydroartemisinin in canine osteosarcoma cell lines

OBJECTIVE: To evaluate the biological activity of dihydroartemisinin on canine osteosarcoma cell lines in vitro. SAMPLE POPULATION: 4 canine osteosarcoma cell lines. PROCEDURES: Cell viability assays were performed on canine osteosarcoma cell lines OSCA2, OSCA16, OSCA50, and D17 after 24, 48, and 72 hours of treatment with dihydroartemisinin at concentrations of 0.1 to 100 microM. Apoptosis was assessed by use of an ELISA for free nuclosomal DNA fragmentation and by western blot analysis for cleavage of caspase 3. Cell cycle analysis was performed by use of staining with propidium iodide and flow cytometry. Detection of reactive oxygen species (ROS) was conducted in the D17 cell line by use of 6-carboxy-2',7'-dihydrofluorescein diacetate and flow cytometry. RESULTS: The concentration of dihydroartemisinin required for 50% inhibition of cell viability (IC50) was achieved in all 4 canine osteosarcoma cell lines and ranged from 8.7 to 43.6 microM. Induction of apoptosis was evident as an increase in nucleosomal DNA fragmentation, cleavage of caspase 3, and an increase in the population in the sub G0/G1 phase of the cell cycle detected by flow cytometry. Exposure to dihydroartemisinin also resulted in a decrease in the G0/G1 population. Iron-dependent generation of ROS was detected in dihydroartemisinin-treated D17 cells; ROS generation increased in a dose-dependent manner. CONCLUSIONS AND CLINICAL RELEVANCE: Incubation with dihydroartemisinin resulted in biological activity against canine osteosarcoma cell lines, which included induction of apoptosis and arrest of the cell cycle. Clinical trials of dihydroartemisinin in dogs with osteosarcoma should be conducted.