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Sandra M Axiak1, Kim A Selting1, Charles J Decedue2, Carolyn J Henry1,3, Deborah Tate1, Jahna Howell2, K James Bilof1, Dae Y Kim4 1Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA; 2CritiTech Inc, Lawrence, KS, USA; 3Department of Internal Medicine, Division of Hematology and Oncology; 4Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA Background: Paclitaxel is highly effective in the treatment of many cancers in humans, but cannot be routinely used in dogs as currently formulated due to the exquisite sensitivity of this species to surfactant-solubilizing agents. CTI 52010 is a formulation of nanoparticulate paclitaxel consisting of drug and normal saline. Our objectives were to determine the maximally tolerated dose, dose-limiting toxicities, and pharmacokinetics of CTI 52010 administered intravenously to normal dogs. Methods: Three normal adult hound dogs were evaluated by physical examination, complete blood count, chemistry profile, and urinalysis. Dogs were treated with staggered escalating dosages of CTI 52010 with a 28-day washout. All dogs were treated with a starting dosage of 40 mg/m2, and subsequent dosages were escalated at 50% (dog 1), 100% (dog 2), or 200% (dog 3) with each cycle, to a maximum of 240 mg/m2. Dogs were monitored by daily physical assessment and weekly laboratory evaluation. Standard criteria were used to grade adverse events. Plasma was collected at regular intervals to determine pharmacokinetics. Dogs were euthanized humanely, and necropsy was performed one week after the last treatment. Results: The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m2. Grade 1–2 gastrointestinal toxicity was noted at higher dosages. Upon post mortem evaluation, no evidence of organ (liver, kidney, spleen) toxicity was noted. Conclusion: CTI 52010 was well tolerated when administered intravenously to normal dogs. A starting dosage for a Phase I/II trial in tumor-bearing dogs is 80 mg/m2. Keywords: paclitaxel, nanoparticle, canine

The aim of this study was to evaluate the effect of opioid exposure on CXC chemokine ligand (CXCL)-8 production in cats using whole blood culture. Morphine, buprenorphine, fentanyl, and saline control were administered intravenously to five cats and whole blood pathogen associated molecular pattern motif-induced CXCL-8 production capacity was evaluated. Morphine potentiated CXCL-8 production. To further characterize this effect of morphine, morphine was incubated with whole blood ex vivo and pathogen associated molecular pattern motif-induced CXCL-8 production capacity was measured. There was a time and concentration dependent effect on CXCL-8 production, suggesting the proinflammatory effect of morphine is at least partially mediated by direct stimulatory effects on leukocytes. Additional investigation is indicated to assess the implications of the immunomodulatory actions of opioids in cats., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Canine prostatic carcinoma is locally aggressive with a high rate of metastasis. Common metastatic sites include lymph nodes, lungs, liver, spleen, and bone. Staging relies on chest radiography, abdominal radiography, and abdominal ultrasonography, in addition to radiography of any painful regions. An enlarged, mineralized prostate is a frequent finding; in a castrated male dog, it is predictive of prostatic carcinoma. NSAIDs are an important component of treatment, although additional local and systemic therapies should be considered to improve the quality of life of these patients.

Lymphoma is associated with a higher risk of sepsis as compared to other forms of neoplasia in people and dogs which might be due to alterations in cytokine production. The objective of this study was to compare bacterial pathogen associated molecular pattern (PAMP) motif-induced TNF, IL-6, and IL-10 response of whole blood from dogs with naïve lymphoma and healthy dogs. We hypothesized that whole blood from dogs with lymphoma would exhibit an impaired cytokine response to LPS, lipoteichoic acid (LTA), and peptidoglycan (PG) stimulation compared to whole blood from healthy dogs. Whole blood was collected from dogs with lymphoma (n=20) and healthy dogs (n=15) and stimulated with PAMPs or phosphate buffered saline. Whole blood production of TNF, IL-6 and IL-10 was measured. Whole blood from dogs with lymphoma had reduced TNF, IL-6 and IL-10 production capacity after LPS, LTA and PG stimulation compared to whole blood from healthy dogs. These data could partially explain why dogs with lymphoma have a higher risk for infection compared to dogs with other forms of neoplasia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study was to compare the effect of an anaesthetic combination given either intramuscularly (IM) or intranasally (IN) for castration of piglets. Forty piglets aged 4 to 7 days were randomly assigned to receive a mixture of ketamine 15 mg kg-1, climazolam 1.5 mg kg-1 and azaperone 1.0 mg kg-1, IN or IM, 10 minutes prior to castration. Physiological parameters were measured. Castration was videotaped for evaluation by 3 independent observers using a scoring system. Reaction and vocalization to the skin incision and cutting of spermatic cord was evaluated and scored (0 = no reaction, 16 = strong reaction). The IN group had a significantly higher (P < 0.01) castration score, compared to the IM group. There was an association between castration score and room temperature in the IN group (with temperatures below 18 "C associated with a higher castration scores (P < 0.001). Heart rate was significantly higher 10 minutes after castration in the IN group (P < 0.05). Respiratory rate was significantly higher in the IM group at time points -5, -1, 10, 20 and 30 (P < 0.05). The IN group was walking significantly (P < 0.0001) faster than the IM group. In conclusion, this combination provides effective anaesthesia for routine castration of newborn piglets when administered IM. IN administration provided shorter recovery times but had significantly higher castration scores.

Background: Reports describe the technique and efficacy of half-body irradiation (HBI) of dogs with lymphoma, but few describe the distinctive toxicoses associated with the combination of HBI and chemotherapy., Hypothesis: HBI would transiently affect myelocytic and erythroid variables as assessed by serial analysis of complete blood counts., Animals: Twenty-nine dogs with lymphoma treated with HBI during 2002 and 2003., Methods: A retrospective study of medical records of 29 dogs was performed. Two HBI protocols were used, resulting in delivery of either 6 Gy or 8 Gy to each half of the body, 1 month apart. Dogs received chemotherapy before, during, or after irradiation, or at multiple times. Serial hematology was available for all dogs. Data were analyzed between collection periods by analysis of variance (ANOVA) RESULTS: The mean granulocyte count significantly (P < .01) decreased from 10,017 cells/microL (data range 3,001-20,170 cells/ microL) before the first radiation treatment to 3,250 cells/microL (820-4,400 cells/microL) at week 5 (P < .01). Three weeks after this nadir, the mean increased to 10,150 cells/microL (900-26,700 cells/microL). The hematocrit did not change (36-38%). Thrombocytopenia (<100,000/microL) occurred in 10 dogs. Two dogs died because of complications associated with thrombocytopenia. No significant difference in toxicity was found between the 6 Gy and 8 Gy group., Conclusions and Clinical Importance: HBI was myelosuppressive but effects were short term and resolved in 22 of 24 dogs. Further studies are needed to elucidate the safety and role of HBI in the treatment of dogs with lymphoma.

Body mass (BM), water intake (WI), and plasma osmolality (P(osm)) and electrolyte concentrations were measured in six 2-year-old Arabian horses provided either 4 l, 8 l, or an unlimited amount of water (UW) for drinking during the initial 5 min of recovery from 45-km of treadmill exercise. After weighing, horses were placed in a stall and further WI between 20 and 60 min of recovery was measured. During exercise, horses lost 3.3+/-0.3%, 3.2+/-0.1%, and 3.3+/-0.2% (P>.05) of BM and P(osm) increased by 7.2+/-0.5, 7.9+/-0.8, and 7.7+/-0.5 mOsm/kg (P>.05) for 4 l, 8 l, and UW, respectively. WI during the first 5 min of recovery was 4.0+/-0.0, 8.0+/-0.0, and 9.0+/-1.3 l and was accompanied by 2.4+/-0.4, 5.8+/-0.9, and 6.1+/-0.7 mOsm/kg decreases (P<.05) in P(osm) for 4 l, 8 l, and UW, respectively. Between 20 and 60 min of recovery, WI was 6.2+/-1.5, 1.2+/-0.6, and 1.0+/-0.7 l (P<.05) for 4 l, 8 l, and UW, respectively. Thus, total WI was 10.2+/-1.5, 9.2+/-0.6, and 10.0+/-1.1 l (P>.05) for 4 l, 8 l, and UW, respectively. After 60 min of recovery, persisting BM loss was 1.3+/-0.5%, 1.1+/-0.2%, and 1.0+/-0.2% (P>.05) for 4 l, 8 l, and UW, respectively and P(osm) had returned to pre-exercise values for all treatments. In conclusion, limiting the volume of water initially provided to horses dehydrated by endurance exercise had no significant effect on total WI during the initial 60 min of recovery; however, persisting BM loss was observed with all treatments. Further, following exercise-induced dehydration, the primary stimulus of thirst was an increase in plasma tonicity rather than hypovolemia.

Objective: To determine whether the composition of electrolyte pastes formulated for oral administration influences voluntary water intake (WI) by horses recovering from furosemide-induced dehydration., Animals: 6 horses., Procedures: Voluntary WI, body weight, and blood and urine constituents were measured before and after induction of dehydration by furosemide administration and overnight withholding of water; these same variables also were measured during a 36-hour rehydration period. Each horse was evaluated 4 times with random application of 4 treatments (electrolyte pastes) that provided 0.5 g of KCl/kg of body weight, 0.5 g of NaCl/kg, 0.25 g of NaCl and 0.25 g of KCl/kg, or no electrolytes (control treatment). Electrolyte pastes were administered 3 times (4, 8, and 12 hours after start of the rehydration period)., Results: Administration of all electrolyte pastes resulted in significantly greater voluntarily WI, compared with the control treatment, and was accompanied by significantly greater recovery of body weight when NaCl was a component of the paste. Administration of NaCl and NaCl-KCl pastes tended to produce a state of transient hyperhydration; however, electrolyte administration also resulted in significantly greater urine production and electrolyte excretion during the final 24 hours of the rehydration period. Adverse effects of oral administration of hypertonic electrolyte pastes were not observed., Conclusions and Clinical Relevance: Oral administration of electrolyte pastes to dehydrated horses increases voluntary WI and improves rehydration during the rehydration period. Rehydration is more rapid and complete when NaCl is a component of the electrolyte paste.

The murine monoclonal antibody K-1-21 with specificity for free but not heavy chain-associated kappa chains was used to develop an inhibition enzyme immunoassay for quantitation of free kappa chains in serum and urine. The assay utilizes a biotin conjugate of the monoclonal antibody and has an effective working concentration range of 0.5-50 micrograms/ml free kappa chain. Normal serum and urine yielded mean values of 1.2 and 4.9 micrograms/ml respectively using this assay system. Serum levels in patients with kappa chain myelomatosis ranged from 2 to 1700 micrograms/ml while serum from patients with lambda chain malignancies exhibited normal free kappa chain levels. The importance of the ability to readily quantitate light chains in serum was demonstrated by the finding in one patient of an absence of free kappa chains in the urine despite elevated levels of serum kappa chains. A significant drop in serum-free kappa chain levels was observed in this patient following a course of chemotherapy. The assay should prove valuable in the diagnosis, prognosis and monitoring of B cell neoplasias characterized by free kappa light chain secretion.

L-CM is a conditioned medium prepared from cultures of L-929 cells, a murine fibroblast line. It will promote the growth and antibody secretion of B cell hybridomas after fusion as well as facilitating cloning at limit dilution and the growth of cloned B cell lines in bulk culture. The medium is easy to prepare and stores well at 4 degrees C. It thus provides a convenient alternative to the use of feeder cells in the production of monoclonal antibodies.

Monoclonal antibody (MoAb) fragments are known to have advantages over intact immunoglobulins for radioimmunoscintigraphy. It is less clear whether they are as effective in the delivery of radioimmunotherapy. The imaging and dosimetric properties of an intact MoAb, K-1-21, reactive against human kappa light chains (LC) were compared with that of its F(ab')2 and Fab fragments using a normal rat model system. Two days after injection of 131I-K-1-21 into rats bearing antigen-sepharose implants, gamma camera images showed specific localization of the MoAb to the target (kappa LC) but not to the control (lambda LC) implant. Better images were obtained with K-1-21 F(ab')2 than with Fab or intact antibody. Mean kappa implant: blood ratios were 8.6 +/- 3.9 for Fab, 7.9 +/- 1.8 for F(ab')2 and 2.0 +/- 0.3 for intact K-1-21. The improvement associated with the use of 131I-K-1-21 fragments was, however, achieved at the expense of lower absolute values of activity at the target site. Thus the absorbed dose delivered to the implant by the intact K-1-21 was double that delivered with F(ab')2 and six times that delivered with Fab. As intact K-1-21 also delivered a greater radiation dose to normal tissues, F(ab')2 fragments may have the greatest overall advantages for therapy with radionuclide MoAb conjugates.

A novel experimental model was established in normal rats for studying the localisation and tissue distribution of a murine monoclonal antibody directed against kappa light chain B cell malignancies. The antibody, K-1-21 was raised against human kappa Bence Jones Proteins and reacts with a cell membrane antigen KMA which is restricted to some kappa myeloma and lymphoma cells. In the rat model, kappa or lambda Bence Jones protein-conjugated sepharose was implanted subcutaneously on either flank 24 h before the injection of 131I-labelled K-1-21 or its F(ab')2 fragment. Gamma camera imaging and tissue distribution studies showed specific localisation of the K-1-21 antibody in the kappa sepharose. Injection of F(ab')2 antibody fragments resulted in faster background clearance, earlier delineation of the specific image and significantly higher target to blood ratios than those obtained with the intact antibody. These results suggest that the model may provide an alternative system to tumour xenograft bearing nude mice for studying localisation of antibodies with therapeutic potential.