Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects.

10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (Cmax ) and area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-t ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA-10. Adverse events (AEs) were dose-related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA-10 was safe and well-tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA-10 75-300 mg once daily.

Efficacy and safety of an octreotide implant in the treatment of patients with acromegaly.

CONTEXT: Acromegaly is caused by excessive GH secretion and IGF-I overproduction. The goals of treatment are to reduce GH and IGF-I values to normal and relieve the associated symptoms. OBJECTIVE: The purpose of this article was to demonstrate that an octreotide implant (84 mg) is safe and efficacious in patients with acromegaly who were responsive to prior monthly octreotide long-acting release (LAR) injections. DESIGN: This was a phase 3, open-label study. Before treatment, subjects received a stable monthly dose of octreotide LAR injections (10-40 mg) for ≥ 3 months. Randomization was in a 3:1 ratio to either a 6-month octreotide implant or monthly octreotide LAR injections. SETTING: This was a multicenter, international study conducted in private or institutional practices. SUBJECTS: Enrollment included 163 subjects (aged ≥ 18 years) with acromegaly. MAIN OUTCOME MEASURE: The efficacy, safety, and tolerability of the octreotide implant during 24 weeks of treatment was evaluated. RESULTS: After 24 weeks, the success rate of the implant for maintenance of IGF-I and GH levels was 86% (95% confidence interval, 80.3%) compared with a rate of 84% (95% confidence interval, 73.8%) for octreotide LAR. Serum octreotide concentrations after implant insertion increased within 8 days and peaked between days 14 and 28. The overall safety of the octreotide implant and octreotide LAR were similar. Diarrhea and headache were more frequent with the implant, whereas cholecystitis and hypertension were more frequent with octreotide LAR. CONCLUSIONS: In this pivotal phase 3 study, the octreotide implant maintained reduced blood levels of GH and IGF-I with continuous octreotide release over 6 months, which was well tolerated.

A subcutaneous octreotide hydrogel implant for the treatment of acromegaly.

OBJECTIVE: To evaluate the pharmacokinetics, efficacy, and safety of a subcutaneous octreotide hydrogel implant in patients with acromegaly. METHODS: In 2 phase II open-label randomized studies, patients aged ≥ 18 years with confirmed acromegaly and octreotide responsiveness received one or two 52 mg hydrated implants (52 mg study) or a hydrated or nonhydrated 84 mg implant (84 mg study) inserted subcutaneously in the upper arm. Implants were removed after 6 months. The 84 mg study assessed pharmacokinetics in patients with undetectable baseline octreotide concentrations. Both studies assessed efficacy (serum growth hormone [GH], insulin-like growth factor 1 [IGF-1]) and safety (adverse events, physical examination, clinical chemistry). RESULTS: Eleven patients received 1 (n = 5) or 2 (n = 6) 52 mg implants; 34 received a hydrated (n = 17 [safety]; n = 16 [efficacy analysis]) or nonhydrated (n = 17) 84 mg implant. With the nonhydrated versus hydrated 84 mg implant, mean maximum serum concentration (Cmax) and mean area under the drug concentration versus time curve from time 0 to 6 months were decreased (P = 0.002 and P = 0.03, respectively) and mean time to Cmax was increased (P = 0.002). In both studies, IGF-1 and GH declined in month 1 and were significantly suppressed during the 6-month treatment versus baseline (P<0.001). With the 52 mg and 84 mg implants, respectively, 3 of 11 patients (27%) and 17 of 33 patients (52%) achieved IGF-1 normalization and 8 of 11 patients (73%) and 13 of 33 patients (39%) exhibited GH <2.5 ng/mL; 9 of 11 patients (82%) and 11 of 34 patients (32%) experienced treatment-related adverse events, which were mainly gastrointestinal. CONCLUSION: Octreotide hydrogel implants were well tolerated and maintained stable octreotide release and suppression of IGF-1 and GH over 6 months.

Trends in gender, employment, salary, and debt of graduates of US veterinary medical schools and colleges.

OBJECTIVE: To characterize trends in gender, employment, starting salaries, and educational debt of graduates of US veterinary medical schools and colleges from 1988 to 2007. DESIGN: Meta-analysis. Sample Population-Veterinary medical graduates from 26 or 27 of 27 US veterinary schools and colleges from 1988 through 2007. PROCEDURES: Data were obtained from surveys published in the JAVMA. A chi2 test for trend was used to analyze trends in choices of employment and educational indebtedness for the veterinary graduate populations over time. RESULTS: The greatest changes in employment occurred in predominantly large animal practice, which attracted 10.7% of new graduates in 1989 but only 2.2% in 2007, and in advanced study, which attracted 15.2% of new graduates in 1989 and 36.8% in 2007. In 2007, 75% of graduates were women, but this gender shift was not associated with the decline in the percentage of graduates entering rural practice. From 1989 through 2007, starting salaries in private practice increased at a rate of 4.60%/y. During the same period, educational debt increased at an annual rate of 7.36%, or 60% higher than the rate of increases for starting salaries. As a result, debt at graduation increased from 1.1 times the starting salary in 1989 to 2.0 times the starting salary in 2007. CONCLUSIONS AND CLINICAL RELEVANCE: Veterinary students are now more in debt than they have ever been. This trend together with a substantial increase in the rate of interest charged for government-backed education loans create conditions for new graduates that appear unsustainable.