Veterinary Clinical Trial Research Articles

Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)

Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

Topical treatment of Pseudomonas aeruginosa otitis of dogs with a bacteriophage mixture: A before/after clinical trial

In an evaluation of a bacteriophage treatment for infection, ten dogs were included with chronic Pseudomonas aeruginosa otitis. Each received, directly into the auditory canal of one ear, a single dose of a topical preparation containing approximately 1 × 10 5 plaque forming units (PFU) of each of 6 bacteriophage strains, active against P. aeruginosa. At the time of bacteriophage administration and 48 h later each dog's core temperature was taken, its ear was assigned a clinical score (higher = worse condition) and aural swabs were taken for bacteriophage and P. aeruginosa counts. Forty eight hours after treatment the clinical score and P. aeruginosa count of all ears had fallen (mean score fall: 30.1%, range 7.7–56.3%, p < 0.0001; mean count fall: 67%, range 29.4–96.8%, p < 0.001). The bacteriophage counts had risen from the administered dose (mean rise: 99.1-fold, range 2.8–433.3-fold). No treatment related inflammation or other adverse events were detected during the trial period. This is the first report of a veterinary clinical trial of a bacteriophage treatment of infection. The results show that administration of this topical bacteriophage mixture leads to lysis of P. aeruginosa in the ear without apparent toxicity and that it has potential to be a convenient and effective treatment for P. aeruginosa otitis in dogs.

Influence of carboplatin infusion on osteosarcoma blood flow

Herein we report that carboplatin infusion influenced tumor blood flow signal independent of the mechanical decompression induced by the artificial lymphatics system technology that was being evaluated as part of a randomized veterinary clinical trial, treating spontaneously occurring canine appendicular osteosarcoma, a tumor very similar to its human counterpart. Blood flow within the central region of the tumor was recorded continuously using laser Doppler flowmetry, a real-time measurement technology. Time-averaged flow values were computed from segments taken from the recordings immediately before starting carboplatin infusion, and during infusion. Carboplatin increased the tumor blood flow signal by an additional 59 +/- 26% (mean +/- SEM; p = 0.06) over the increase induced by the decompression. The increase started within 49 +/- 46 s after the start of infusion, had a response time constant of 19 +/- 21 s and persisted throughout the infusion, ending shortly after infusion ended. The rapidity of the flow signal increase suggests that carboplatin may have an autonomic effect on circulation, either local or systemic. The observations identify a new action of this drug and suggest a possible mechanism to exploit therapeutically.

Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices

A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was explored for effective incorporation and long-term retention into fibrin ingrowth matrices. The solubility of native BMP-2 is greatly dependent on its glycosylation. To enhance retention of BMP-2 in fibrin matrices, a nonglycosylated form (nglBMP-2), which is less soluble than the native glycosylated protein, was produced recombinantly and evaluated in critical-size defects in the rat calvarium (group n=6). When 1 or 20 μg nglBMP-2 was incorporated by precipitation within the matrix, 74 ± 4% and 98 ± 2% healing was observed in the rat calvarium, respectively, as judged radiographically by closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls, induced less healing, demonstrating a positive correlation between low solubility, retention in vitro, and healing in vivo. Subsequently, the utility of nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal fusion in dogs, replacing the standard-of-care, namely autologous cancellous autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients, fibrin with 600 μg/ml nglBMP-2 performed better than autograft in the first weeks of bone healing and comparably thereafter. Furthermore, a greater fraction of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each of the treated joints at both 12 and 17 weeks than in animals treated with autograft. These results suggest that evaluation in a human clinical setting of nonglycosylated BMP-2 in fibrin matrices might be fruitful.

Echinacea powder: Treatment for canine chronic and seasonal upper respiratory tract infections

An open multi-centered veterinary clinical trial, comparing conditions before and after treatment with a herbal preparation, containing the powdered root of Echinacea purpurea, was conducted by 6 practicing veterinarians in Switzerland. The plant-based immune stimulant was administered to 41 dogs with manifestations of chronic and seasonal upper respiratory tract infections, including pharyngitis/tonsillitis, bronchitis and kennel cough. Each animal was at an individual stage of the disease, with various symptoms and different severity scores, at start of treatment. There was no control group. Echinacea powder (1:3) was administered with the food at a dose of 1.0 g/10 kg body weight once daily for 8 weeks. Overall efficacy showed significant improvement for 92% of 39 dogs after 4 weeks of treatment and this was confirmed after 8 weeks. Significant reductions of severity and resolution of typical clinical symptoms, of clear nasal secretions, enlargement of lymph nodes, dry cough, dyspnea and dry lung sounds, were evident after 4 weeks. Only two adverse effects, not suspected to be attributable to the study drug, were recorded. Because quality and stability of the Echinacea powder were defined, using an analytical standard and purity tests, these data suggest, that the Echinacea preparation can be recommended as a well tolerated alternative treatment of canine upper respiratory tract infections.

Standards for veterinary clinical trials

This chapter discusses standards for veterinary clinical trials. A clinical trial is a prospective study that compares the effect(s) and value(s) of an intervention. Although the clinical trial is the most effective method for establishing the effects (efficacy or safety) of an intervention, proper planning and execution are paramount to its success and validity. The groundwork for high-quality clinical trials is laid by observational studies that focus on new or existing interventions and provide the baseline data for these trials. Unlike human clinical trials, the subject of a veterinary clinical trial may be owned by the research facility (experimental) or may be a client-owned patient. It is important to distinguish the source of experimental subjects for a veterinary clinical trial as certain types of bias can be more easily minimized when using experimental animals. Because subject variability (for example, differences due to age, breed, sex, diet, environment, or disease) can be more easily standardized, some investigators do not consider studies that use experimental animals as clinical trials.

An image-directed robotic system for precise orthopaedic surgery

The authors have developed an image-directed robotic system to augment the performance of human surgeons in precise bone machining procedures in orthopaedic surgery, initially targeted at cementless total hip replacement surgery. The total system consists of an interactive CT-based presurgical planning component and a surgical system consisting of a robot, redundant motion monitoring, and man-machine interface components. In vitro experiments conducted with this system have demonstrated an order-of-magnitude improvement in implant fit and placement accuracy, compared to standard manual preparation techniques. The first generation system described in this paper was used in a successful veterinary clinical trial on 26 dogs needing hip replacement surgery. It was the basis for subsequent development of a second-generation system that is now in human clinical trials.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>