Recently, tramadol and its active metabolite, O-desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g., dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post-tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4-32.7) mL/min/kg. Terminal half-life of tramadol was 111 (106-127) min IV and 133 (84.9-198) min PO. Bioavailability of tramadol was poor [3.47% (2.14-5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88-2.73) ng/mL IV and 11.2 (9.37-14.9) ng/mL PO. Sedation and pruritus were observed after IV administration.

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (i.v.) and intramuscular (i.m.) administration. Four healthy, opioid-naïve, socially housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, postadministration. Serum buprenorphine concentrations were analyzed with liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the i.v. study as compared to the i.m. study was 177 (159-189) vs. 185 (174-214) min, respectively [median (range)]. In the i.v. study, concentration back-extrapolated to time zero was found to be 33.0 (16.8-57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the i.m. study was 11.8 (6.30-14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations >0.10 ng/mL for over 24 h in the i.v. study and over 12 h in the i.m. study. Bioavailability was found to be 68.1 (59.3-71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.

p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy.This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128.