Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates.

Thyrotropin-releasing hormone (TRH) and TRH-like peptides carry a therapeutic potential for neurological conditions. Nanoparticles (NP) made of the biodegradable polymer, Poly(Sebacic Anhydride) (PSA), have been developed to carry TRH, intended for intranasal administration to patients. There is limited information on the safety of biodegradable polymers when given intranasally, and therefore, we have performed two preclinical safety and toxicity studies in cynomolgus monkeys and rats using TRH-PSA nanoparticles. The rats and monkeys were dosed intranasally for 42 days or 28 days, respectively, and several animals were followed for additional 14 days. Animals received either placebo, vehicle (PSA), or different concentrations of TRH-PSA. No systemic adverse effects were seen. Changes in T3 or T4 concentrations were observed in some TRH-PSA-treated animals, which did not have clinical or microscopic correlates. No effect was seen on TSH or prolactin concentrations. In the monkey study, microscopic changes in the nasal turbinates were observed, which were attributed to incidental mechanical trauma caused during administration. Taken together, the TRH-loaded PSA NPs have proven to be safe, with no local or systemic adverse effects attributed to the drug loaded nanoparticles. These findings provide additional support to the growing evidence of the safety of peptide-loaded NPs for intranasal delivery and pave the way for future clinical trials in humans.

Retrospective characterization of canine coagulopathies using the turbidimetric ACL-TOP 300 analyzer (2014-2015): Forty-seven dogs.

OBJECTIVE: To characterize disseminated intravascular coagulation (DIC), liver failure (LF), post-hepatic cholestasis (PHC), and anticoagulant rodenticide intoxication (ROD) in dogs using an immunoturbidimetric coagulation analyzer and to characterize the relationship between clinical bleeding and bleeding parameters. DESIGN: Retrospective study (August 2014-July 2015). SETTING: University teaching hospital. ANIMALS: Forty-seven client-owned dogs diagnosed with DIC (n = 24), LF (n = 9), PHC (n = 5), or ROD (n = 9) based on history, clinical pathology, cytology, histopathology. or exploratory surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Median prothrombin time (PT), activated partial thromboplastin time (aPTT), and quantitative fribrinogen assay (QFA) were above the reference interval for DIC, LF, PHC and ROD with the exception of a normal QFA for LF. Clot curve analysis for DIC was characterized by elevated PT Delta, PT first derivative, and aPTT Delta, and normal for aPTT second derivative; all LF parameters were within the RI; all PHC parameters were above the RI; and ROD had elevated aPTT delta, but low aPTT second derivative. Coagulopathic bleeding recognized within the DIC group was characterized by median PT delta in mABS (milliabsorbance), first derivative and aPTT delta values in mABS within the RI at 35.0, 55.5 and 38, respectively. The nonbleeding DIC group median values of these same parameters were 189.5, 586.5 and 288, respectively. CONCLUSIONS: The classically utilized indicators of secondary hemostasis, PT and aPTT, were prolonged within all 4 groups; DIC, LF, PHC and ROD as expected. Fibrinogen concentration was increased in both PHC and ROD, decreased in LF and increased but with a bimodal distribution in DIC that correlated with clinical bleeding. The degree of PT and aPTT prolongation did not correlate with clinical bleeding in the DIC group, however clot curve analysis, did reveal an association.

Performance characteristics of the turbidimetric ACL-TOP CTS 300 coagulation analyzer in dogs and cats.

OBJECTIVE: To evaluate the technical performance of the turbidimetric ACL-TOP CTS 300 coagulation analyzer (IL) in dogs and cats and to create reference intervals for standard and novel parameters. DESIGN: Coagulation testing results from dogs and cats generated by the IL were prospectively compared with another mechanical clot detection system. Precision was documented and reference intervals were created for prothrombin time, activated partial thromboplastin time, and Clauss fibrinogen and D-dimer values, as well as for the quantitative clot curve parameters (high and low amplitude, delta, and first and second derivative curves). Clot curve signatures containing common artifacts due to lipemia, hemolysis, or preactivation were demonstrated. ANIMALS: Residual frozen plasma from 20 dogs and 10 cats was used for method comparison; prospectively recruited healthy dogs (n = 48) and cats (n = 45) were used for reference interval and precision studies. MEASUREMENTS AND MAIN RESULTS: Bland-Altman analysis showed a proportional positive bias in the IL compared with mechanical clot detection in dogs and a suggestion of a similar pattern in cats. Precision was good and met manufacturer's recommendations for all assays. Reference intervals are reported. Clot curve artifacts were similar in animals to those reported in people. CONCLUSIONS: The turbidimetric system had a slight high proportional positive bias compared with mechanical clot detection. Thus, new reference intervals were generated including for novel parameters generated by clot curve analysis. Some preanalytical errors can be identified by inspection of clot curves. This robust novel technology compares favorably with mechanical endpoint detection methods and can be used in dogs and cats.

Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas.

BACKGROUND: There are no known effective therapies for distantly metastatic, rapidly progressive thyroid carcinomas unresponsive to radioiodine. OBJECTIVE: Since thyroid carcinomas are hypervascular and thalidomide is antiangiogenic, we assessed thalidomide's tumoristatic effects and toxicity in a phase II trial. DESIGN: Thirty-six patients with follicular, papillary, insular, or medullary thyroid carcinomas and distant, radioiodine-unresponsive metastases (volumes increasing >or= 30% per year before entry) were accrued between July 2001 and December 2002. Daily thalidomide started at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Toxicities and responses were assessed at 8-week intervals with tumor volume assessments. MAIN OUTCOMES: Twenty-eight of 36 patients were evaluable, 5 with partial responses (PR: 18%; 95% confidence interval [95% CI]: 6-37%) and 9 patients with stable disease (SD: 32%; 95% CI: 12-42%) for overall 50% response (95% CI: 31-69%). Median PR duration was 4 months (range: 2-6 months), and SD duration was 6 months (range: 2-14 months). Median survival was 23.5 months for responders (PR + SD) and 11 months for nonresponders. Most frequent toxicity was fatigue (69% grade 1-2, 8% grade 3-4). Four patients had grade 3-4 infections (without neutropenia), one had pericardial effusion, and one had pulmonary embolus. CONCLUSIONS: Thalidomide confers therapeutic benefit in subsets of thyroid cancer patients with rapidly progressive, distantly metastatic disease.