Pharmacokinetic and Phase I Evaluation of Carboplatin in Dogs

Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD₅₀) or a 5% incidence of severe toxicity (SEV₅). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD₅₀ and SEV₅ for the first treatment course were 340 and 278 mg/M², respectively. MOD₅₀ and SEV₅ values for the first plus second treatment courses were 327 and 231 mg/M², respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541/μL and 62,600/μL, respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T_1/2), area-under-the-curve and total body clearance (CL_b) were not dose dependent. Volume of distribution (VD_ss) significantly increased with dose only between 100 and 150 mg/M², not between 150 and 300 mg/M². Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity. (Journal of Veterinary Internal Medicine 1993; 7:235–240. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

In vivo kinetic study on uptake and distribution of intramuscular tritium-labeled polysulfated glycosaminoglycan in equine body fluid compartments and articular cartilage in an osteochondrial defect model

The uptake and distribution of intramuscularly (IM) administered tritium-labeled polysulfated glycosaminoglycan (³H-PSGAG) in serum, synovial fluid, and articular cartilage of eight horses was quantitated, and hyaluronic acid (HA) concentration of the middle carpal joint was evaluated in a pharmacokinetic study. A full-thickness articular cartilage defect, created on the distal articular surface of the left radial carpal bone of each horse served as an osteochondral defect model. ³H-PSGAG (500 mg) was injected IM, between 14 and 35 days after creation of the defects. Scintillation analysis of serum and synovial fluid, collected from both middle carpal joints at specific predetermined times up to 96 hours post-injection, revealed mean ³H-PSGAG concentrations peaked at 2 hours post-injection. ³H-PSGAG was detected in cartilage and subchondral bone 96 hours post-injection in samples from all eight horses. There were no statistically significant differences in ³H-PSGAG concentration of synovial fluid or cartilage between cartilage defect and control (right middle carpal) joints.

HA assay of synovial fluid revealed concentrations significantly increased at 24, 48, and 96 hours post-injection in both joints. The concentration nearly doubled 48 hours post-injection. However, no statistically significant differences were found between synovial concentrations of HA in cartilage defect and control joints.

³H-PSGAG administered IM to horses, was distributed in the blood, synovial fluid, and articular cartilage. HA concentrations in synovial fluid increased after IM administration of polysulfated glycosaminoglycan.     

Coagulopathic Effects and Therapy of Brodifacoum Toxicosis in Dogs

The clinical signs and laboratory changes of brodifacoum (BDF) intoxicated dogs and their response to vitamin K1 treatment were examined. Brodifacoum, a second-generation anticoagulant rodenticide, was fed to four dogs for 3 consecutive days producing a cumulative dose of 1.1 mg BDF/kg body weight. Clinical observations of the animals were made daily throughout the study. Monitored laboratory parameters included: one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), activated coagulation time (ACT), complete blood counts, thrombocyte counts, and serum chemistry values. Response to vitamin K1 therapy was evaluated clinically and by laboratory tests. Serum BDF concentrations were monitored. Inappetence and hemorrhagic tendencies were exhibited by day 5 postrodenticide exposure. One-stage prothrombin time, APTT, and ACT were 25% greater than time zero values at 24, 24, and 72 hours postdosing, respectively. All laboratory parameters returned to normal within 48 hours of initiating vitamin K1 therapy (0.83 mg/kg orally, TID for 5 days). Serum brodifacoum concentrations were highest (1065-1215 ng/mL) during the 3 days after BDF dosing and were detectable (3.0-7.5 ng/mL) until day 24 postexposure. A mean BDF elimination half-life of 6 +/- 4 days was observed.     

MAGNETIC RESONANCE IMAGING OF THE EQUINE STIFLE

The purpose of this study was to define normal gross anatomic structures in the equine stifle with magnetic resonance images. Magnetic resonance (MR) images were made in sagittal, 15° supinated, transverse, and dorsal planes of two equine stifles. The MR images were scrutinized by comparing MR images to dissection specimens and frozen cross sections of stifle joints. Sagittal and 15° supinated images were the most valuable in assessing articular cartilage, subchondral bone, and soft tissue structures within the joint. Cranial and caudal cruciate ligaments, medial and lateral menisci, meniscotibial and meniscofemoral ligaments, long digital extensor tendon, and patellar ligaments were easily evaluated. MR images provided substantially more gross anatomical information than the currently available imaging modalities.     

A Comparison of the Cutaneous Trunci Myocutaneous Flap and Latissimus Dorsi Myocutaneous Flap in the Dog

Latissimus dorsi and cutaneous trunci myocutaneous flaps of equal dimension and location were randomly elevated on opposite sides of the thorax in 10 dogs (group 1) and resutured to their respective bed. The procedure was repeated in four additional dogs (group 2); however, the short perforating branches of the thoracodorsal artery and vein were divided at the base of each cutaneous trunci myocutaneous flap, whereas the cutaneous pedicle and underlying cutaneous trunci muscle were divided in the latissimus dorsi myocutaneous flaps to determine subsequent skin survivability and the major source of circulation of each myocutaneous flap. There was little difference in the percentage of skin survival between the latissimus dorsi and cutaneous trunci myocutaneous flaps in group 1 dogs. Circulation to the "skin island" of group 2 latissimus dorsi myocutaneous flaps originated from intramuscular anastomotic connections between the major branch of the thoracodorsal artery entering the latissimus dorsi muscle and the proximal lateral intercostal arteries perforating the muscle. Ligation of the short perforating branches of the thoracodorsal artery resulted in partial skin necrosis in all group 2 cutaneous trunci myocutaneous flaps. Results from this study indicate that it is unnecessary to elevate the latissimus dorsi muscle for major skin flap elevation and survival. The thicker latissimus dorsi myocutaneous flap is more difficult to develop surgically and appears to have no clinical major advantage over the more mobile cutaneous trunci myocutaneous flap or the adjacent thoracodorsal axial pattern flap for closure of large skin defects within the radius of flap rotation.     

Ultrastructural analysis of platelets and megakaryocytes from a dog with probable essential thrombocythemia

Blood platelets and bone marrow megakaryocytes from a dog with essential thrombocythemia were analyzed by transmission electron microscopy and compared with those of control dogs. Platelets varied in size and shape and contained enlarged and dilated open canalicular systems. Megakaryocytes were dysmorphic and had evidence of abnormal maturation, with large numbers of megakaryoblasts containing alpha granules and poorly organized and reduplicated demarcation membranes. The fewer, more mature megakaryocytes lacked normal cytoplasmic organization. Most notable was the absence of well-demarcated "platelet fields," due to the excessive and disorderly array of demarcation membranes.