Evaluation of nanoparticle delivered cisplatin in beagles.

Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg(-1) or 2 mg kg(-1) or 2.2 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs. At all doses over the 14-day period, no neurotoxicity was observed based upon periodic neurological examinations and cerebrospinal fluid analysis. These studies demonstrated the translational nature of T-Platin-M-NPs for applications in the treatment of brain tumors.

Correlation of near-infrared spectroscopy and direct pressure monitoring in an acute porcine compartmental syndrome model.

OBJECTIVE: To correlate near-infrared spectroscopy (NIRS) and the tibial intracompartmental perfusion pressure (TIPP) in an acute limb compartmental syndrome. METHODS: Landrace swine were subdivided into 2 groups: plasma infusion (n = 16) and blunt trauma plus plasma infusion (n = 15). NIRS sensors were placed over the craniolateral muscle compartment of proximal both tibiae. Albumin infusion elevated tibial intracompartmental pressures (TICP). Time-synchronized measures of systolic, diastolic, and mean arterial pressures, TICP, and percent oxygenation from each leg were collected. For the blunt trauma group, trauma was induced by dropping a 2-kg weight 30 times from 100 cm directly on the muscle compartment. For each group, a repeated-measures analysis of variance model was used to test differences in the TICP, TIPP, and oxygenation values. Pearson correlations were calculated between TICP and oxygenation and between TIPP and oxygenation. RESULTS: Both models created reproducible increases in TICP and decreases in TIPP. Trauma did not alter TICP, TIPP, or percent oxygenation in the model. NIRS was able to detect significant changes in tissue oxygenation at all the same time points. NIRS was able to detect decreased oxygenation at every TIPP decrease and subsequent increase after fasciotomies. An increase in percent oxygenation was seen in all cases once fasciotomy was performed and TICP was reduced. CONCLUSIONS: NIRS provided a sensitive measure correlating to both an increase and decrease in TICP and TIPP, respectively, in this infusion model. The addition of blunt trauma to the model did not alter the correlations of NIRS values with TICP and TIPP. Fasciotomy produced a rebound in oxygenation values.

Evaluation of a rapid pressor response test in healthy cats.

OBJECTIVE: To evaluate angiotensin I and angiotensin II rapid pressor response tests in healthy cats. ANIMALS: 6 purpose-bred sexually intact male cats. PROCEDURES: Telemetric blood pressure (BP) implants were placed in all cats. After 2 weeks, cats were anesthetized for challenge with exogenous angiotensin I or angiotensin II. Continuous direct arterial BP was recorded during and immediately after IV administration of boluses of angiotensin I or angiotensin II at increasing doses. Blood pressure responses were evaluated for change in systolic BP (SBP), change in diastolic BP (DBP), and rate of increase of SBP by 4 observers. RESULTS: Following IV angiotensin I and angiotensin II administration, transient, dose-dependent increases in BP (mean ± SEM change in SBP, 25.7 ± 5.2 and 45.0 ± 9.1; change in DBP, 23.4 ± 4.7 mm Hg and 36.4 ± 7.8 mm Hg; for 100 ng of angiotensin I/kg and angiotensin II/kg, respectively) and rate of increase of SBP were detected. At angiotensin I and II doses < 2.0 ng/kg, minimal responses were detected, with greater responses at doses ranging from 20 to 1,000 ng/kg. A significant effect of observer was not found. No adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The rapid pressor response test elicited dose-dependent, transient increases in SBP and DBP. The test has potential as a means of objectively evaluating the efficacy of various modifiers of the renin-angiotensin-aldosterone system in cats. Ranges of response values are provided for reference in future studies.

In vitro effects of meloxicam on metabolism in articular chondrocytes from dogs with naturally occurring osteoarthritis.

OBJECTIVE: To assess effects of in vitro meloxicam exposure on metabolism in articular chondrocytes from dogs with naturally occurring osteoarthritis. SAMPLE: Femoral head cartilage from 16 dogs undergoing total hip replacement. PROCEDURES: Articular cartilage samples were obtained. Tissue sulfated glycosaminoglycan (SGAG), collagen, and DNA concentrations were measured. Collagen, SGAG, chondroitin sulfate 846, NO, prostaglandin E2 (PGE2), and matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and MMP-13 concentrations in culture medium were analyzed. Aggrecan, collagen II, MMP-2, MMP-3, MMP-9, MMP-13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)-4, ADAMTS-5, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, interleukin-1ß, tumor necrosis factor-α, cyclooxygenase-1, cyclooxygenase-2, and inducible nitric oxide synthase gene expression were evaluated. Comparisons between tissues cultured without (control) and with meloxicam at concentrations of 0.3, 3.0, and 30.0 µg/mL for up to 30 days were performed by means of repeated-measures analysis. RESULTS: Meloxicam had no effect on chondrocyte SGAG, collagen, or DNA concentrations. Expression of ADAMTS-5 was significantly decreased in all groups on all days, compared with the day 0 value. On day 3, culture medium PGE2 concentrations were significantly lower in all meloxicam-treated groups, compared with values for controls, and values remained low. Culture medium MMP-3 concentrations were significantly lower on day 30 than on day 3 in all meloxicam-treated groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that in vitro meloxicam treatment of osteoarthritic canine cartilage for up to 30 days did not induce matrix degradation or stimulate MMP production. Meloxicam lowered PGE2 release from this tissue, and effects on tissue chondrocyte content and matrix composition were neutral.