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.     

Quantitative Accuracy of the Simplified Strong Ion Equation to Predict Serum pH in Dogs

Background

Electrochemical approach to the assessment of acid‐base states should provide a better mechanistic explanation of the metabolic component than methods that consider only pH and carbon dioxide.

Hypothesis/Objectives

Simplified strong ion equation (SSIE), using published dog‐specific values, would predict the measured serum pH of diseased dogs.

Animals

Ten dogs, hospitalized for various reasons.

Methods

Prospective study of a convenience sample of a consecutive series of dogs admitted to the Massey University Veterinary Teaching Hospital (MUVTH), from which serum biochemistry and blood gas analyses were performed at the same time. Serum pH was calculated (Hcal+) using the SSIE, and published values for the concentration and dissociation constant for the nonvolatile weak acids (A_tot and K _a), and subsequently Hcal+ was compared with the dog''s actual pH (Hmeasured+). To determine the source of discordance between Hcal+ and Hmeasured+, the calculations were repeated using a series of substituted values for A_tot and K _a.

Results

The Hcal+ did not approximate the Hmeasured+ for any dog (P = 0.499, r ² = 0.068), and was consistently more basic. Substituted values A_tot and K _a did not significantly improve the accuracy (r ² = 0.169 to <0.001). Substituting the effective SID (Atot−[HCO3−]) produced a strong association between Hcal+ and Hmeasured+ (r ² = 0.977).

Conclusions and clinical importance

Using the simplified strong ion equation and the published values for A_tot and K _a does not appear to provide a quantitative explanation for the acid‐base status of dogs. Efficacy of substituting the effective SID in the simplified strong ion equation suggests the error lies in calculating the SID.     

Sound Pressure Levels in 2 Veterinary Intensive Care Units

Background

Intensive care units (ICUs) in human hospitals are consistently noisy environments with sound levels sufficient to substantially decrease sleep quality. Sound levels in veterinary ICUs have not been studied previously, but environmental sound has been shown to alter activity in healthy dogs.

Hypothesis

Veterinary ICUs, like those in human medicine, will exceed international guidelines for hospital noise.

Animals

NA.

Methods

Prospective, observational study performed consecutively and simultaneously over 4 weeks in 2 veterinary ICUs. Conventional A‐weighted sound pressure levels (equivalent continuous level [a reflection of average sound], the sound level that is exceeded 90% of the recording period time [reflective of background noise], and maximum sound levels) were continuously recorded and the number of spikes in sound >80 dBA were manually counted.

Results

Noise levels were comparable to ICUs in human hospitals. The equivalent continuous sound level was higher in ICU1 than in ICU2 at every time point compared, with greatest differences observed on week day (ICU1, 60.1 ± 3.7 dBA; ICU2, 55.9 ± 2.5 dBA, P < .001) and weekend nights (ICU1, 59.9 ± 2.4 dBA; ICU2, 53.4 ± 1.7 dBA, P < .0001) reflecting a 50% difference in loudness. Similar patterns were observed for the maximum and background noise levels. The number of sound spikes was up to 4 times higher in ICU1 (162.3 ± 84.9 spikes) than in ICU2 (40.4 ± 12.2 spikes, P = .001).

Conclusions and Clinical Importance

These findings show that sound in veterinary ICUs is loud enough to potentially disrupt sleep in critically ill veterinary patients.     

Effect of Chronic Administration of Phenobarbital,or Bromide,on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy

Background

Levetiracetam (LEV) is a common add‐on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs.

Hypothesis/Objectives

To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs.

Animals

Eighteen client‐owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB–BR group, n = 6).

Methods

Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high‐pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area‐under‐the‐curve (AUC) calculated to the last measured time point.

Results

Compared to the PB and PB–BR groups, the BR group had significantly higher peak concentration (C _max) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028).

Conclusions and Clinical Importance

Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add‐on treatment with phenobarbital in dogs.