A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs

Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol^® for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase‐anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.     

Single‐ and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT‐116 (a TRPV1 antagonist) in dogs

Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT‐116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT‐116. Results showed a half‐life of 6.9 h, k_el of 0.1/h, AUC of 56.5 μg·h/mL, T_max of 3.7 h, and C_max of 3.8 μg/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT‐116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 μg/mL previously determined for rodents) for analgesia during the 24‐h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT‐116 following oral delivery in dogs.     

B‐Mode and Doppler Sonography of the Mammary Glands in Dairy Goats for Mastitis Diagnosis

This study aimed to evaluate the sonographic characteristics of the udder and teats and to determine the Doppler indexes of mammary artery in healthy and undergoing subclinical and clinical mastitis goats. Thirty animals among Saanen and Alpine Brown goats were arranged in three groups, healthy goats (HG), goats with subclinical mastitis (SMG) and goats with clinical mastitis (CMG). Using the B‐mode, the sonographic characteristics (echotexture and echogenicity) and biometry (diameter and area of the udder cistern, diameter and area of the teat cistern and thickness of the teat wall) were evaluated. Using Doppler ultrasonography, the vascular indexes of the mammary artery were obtained. It was observed hyperechogenicity with solid component in the gland cistern when comparing animals with clinical mastitis and healthy mammary tissue. Regarding the echotexture of the breast tissue, there was heterogeneity in the mammary parenchyma on the three groups, for the milk, it was observed homogeneity for animals on HG and SMG and heterogeneity for animals on CMG. Grey‐scale quantitative assessment revealed increase in echogenicity (mean value) for all the structures when comparing the three groups. Biometry did not reveal statistical difference between groups, for none of the evaluated structures. Doppler examination of the mammary artery showed the decrease of end diastolic velocity and raise of pulsatility index between groups. The association of B‐mode and Doppler ultrasonography is useful for the evaluation of the udder of dairy goats with mastitis. It is a sensitive and specific method for the study of this disease. Doppler mode was unable to establish reliable criteria for diagnosis of subclinical mastitis. Moreover, the quantification of echogenicity is a useful technique for the evaluation of the milk in animals with mastitis; therefore, it is suggested that it can be used as complementary technique for the diagnosis of mastitis in goats.     

The ventricles of the brain in the N. American mink (Mustela vison (Brisson, 1756))

Using anatomical as well as radiographic and tomographic methods, sixty brains of the N. American mink were examined. It was found that the brain consists of four ventricles. Also, it was noted that the posterior horn was missing and that there was the olfactory recess present in the lateral ventricle, a large-size interthalamic connection present in the third ventricle, and a flat, necklace-like bottom in the fourth ventricle. Only recently, the ins and outs of the mink's anatomical structure have begun to absorb anatomists. Apparently, it is related to the fact that furry animals, among them the mink, are being domesticated as if "before our eyes". For this reason and because of the easy access to material, examining of the brain ventricles in the mink was taken up.     

Comparison of direct and indirect blood pressure measurements in anesthetized dogs.

The precision and accuracy of an indirect oscillometric blood pressure measurement technique (Dinamap 8100) was assessed in 11 anesthetized Beagle dogs weighing 8 to 11.5 kg. Direct blood pressure measurements were made by catheterization of the lingual artery, and simultaneous indirect measurements were determined by placing a cuff over the median artery (midradial area). Blood pressure measurements at 2 different planes of anesthesia (light and deep) were recorded in triplicate. At a light plane of anesthesia, the Dinamap 8100 underestimated diastolic and mean arterial pressure, and at a deep anesthetic plane overestimated systolic pressure. The indirect technique had good repeatability of systolic pressures. Regression analysis for the 2 techniques showed excellent correlation (r = 0.93). The results indicate that the indirect oscillometric blood pressure measurement technique provides a good estimate of systolic, diastolic, and mean arterial pressure in dogs weighing 8-11.5 kg.     

Central Venous Pressure Measurements in the Caudal Vena Cava of Sedated Cats

The caudla vena cava (CVA) was evaluated as an laternative site for the measurement of central venous pressure (CPV) in six healthy, sedated (ketamine 10 mg/km, midazolam 0.1 mg/kg, and atropine 0.04 mg/kg IM) cats. The CVC was cathererized via medial saphenous puncture, and estimates of CPV from this site compared to those obtained via a jugular catheter. Simulataneous CPV values were recorded electronically (mmgh), via calibrated pressure transducer positioned at the level of the manubrium in cats in lateral recumbency. Five readings, performed at 1 minute intervals, were collected from the jugular and CVC catheters at rest (baseline) and following a rapid fluid bolus. Twenty-four hours later, cats were resedated, baseline measurements repeated, and CVPs recorded following a rapid, 25% whole-blood volume bleed. CVP measurements from the jugular and CVC were statistically compared using repeated measures ANOVA (p<0.05). There were no significant differences between the two sites in the baseline and bleed trials. Significant defferences between jugular and CVC CVPs were noted at 1 and 2 minutes following the fluid bolus. It was concluded that CVC is an alternative site for measurement of CPV in sedated cats.