Pharmacokinetics of hydromorphone after intravenous and intramuscular administration in male rhesus macaques (Macaca mulatta).

This study reports the pharmacokinetics of hydromorphone after intravenous and intramuscular administration to rhesus macaques (Macaca mulatta). Hydromorphone (0.075 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions to healthy, socially housed, socially reared, adult, intact male rhesus macaques (n = 4). Blood samples were collected prior to and until 10 h after administration. Serum hydromorphone concentrations were analyzed with liquid chromatography-mass spectrometry. Compartment models were fit to time-concentration data. A 3-compartment model with input in and elimination from the central compartment best fit intravenous data, whereas a 1-comparment model best fit intramuscular data. After intravenous administration, the median clearance and terminal half-life were 37.7 (range, 33.7 to 47.1) mL/kg/min and 142 (range, 131 to 218) min, respectively. The median (range) elimination half-life after intramuscular administration was 81.5 (77.2 to 92.5) min. Median intramuscular bioavailability was 92% (range, 75% to 104%). Rhesus macaques maintained concentrations greater than or equal to 4.0 ng/mL for at least 2 h after intravenous and intramuscular administration. The disposition of hydromorphone was characterized by a large volume of distribution and moderate clearance. Intramuscular administration resulted in rapid and almost complete drug absorption. Whole-body pruritus, sedation, and decreased appetite were observed in all macaques after initial drug administration

Ketamine-induced neuromuscular reactivity is associated with aging in female rhesus macaques.

Rhesus macaques represent an important species for translational and pre-clinical research studies across a multitude of disease and injury models, including aging. Ketamine anesthesia is used in humans and non-human primates but may be associated with adverse effects, including neuromuscular reactions. The effects of aging on ketamine adverse effects is not well characterized. Urodynamic recordings and electromyography (EMG) studies were performed in aged (>20 years old) and adult (3.9-14.9 years old) female rhesus macaques under an equal and light plane of sedation by constant rate infusion (CRI) of ketamine. A total of 4 of 41 adult subjects (9.7%) showed clinical signs of ketamine-induced abnormal neuromuscular reactivity, whereas a larger portion of 14 of 26 aged subjects showed similar ketamine-induced neuromuscular reactivity (53.8%; P< 0.001). The ketamine CRI rate was 19.8±0.9 mg/kg/h in adults and lower in aged subjects at 16.5±1.4 mg/kg/h (P<0.05). The ketamine CRI rate was negatively correlated with age (r = -0.30, P<0.05, n = 64). The incidence of ketamine reactivity or CRI rate was not different between aged pre-and post-menopausal females. EMG recordings during neuromuscular reactivity showed coordinated activation of multiple muscles, suggesting a central nervous system (CNS) mechanism for ketamine-associated neuromuscular reactivity. The incidence of ketamine-induced neuromuscular reactivity is age related but not affected by the estrous cycle in female rhesus macaques. A coordinated activation of multiple muscles, innervated by different peripheral nerves, suggests that ketamine-induced neuromuscular reactivity originates in the CNS

Rotavirus is associated with decompensated diarrhea among young rhesus macaques (Macaca mulatta)

Diarrhea with secondary decompensation is the main cause of morbidity and mortality in captive young rhesus macaque (Macaca mulatta) colonies. Approximately 25% of diarrhea cases with secondary decompensation are considered to be idiopathic chronic diarrhea. The purpose of this study was to investigate the suspected but not systematically examined association between rotavirus infection and diarrhea with secondary decompensation among young rhesus macaques at the California National Primate Research Center (CNPRC). Blood and stool samples were collected from 89 randomly selected young animals (age range: 6 months to 1.5 years) and were tested for the presence of rotavirus antibody, and rotavirus antigen, respectively, using enzyme-linked immunosorbent assays (ELISA's). Test and clinical data were analyzed using Fisher's exact tests and multivariate logistic regression model. Our analysis indicates that rotavirus is endemic among young outdoor-housed rhesus macaques at the CNPRC. Although the relationship between detectable rotavirus antigen in stool and symptomatic diarrhea with secondary decompensation was not significant, there was a significant association between rotavirus seropositivity and a history of diarrhea with secondary decompensation within the past 6 months. While our cross-sectional and case-control study suggests an association between rotavirus infection and diarrhea with secondary decompensation among captive rhesus macaques, more extensive longitudinal studies on larger cohorts and with more intensive sample collection are needed to confirm these findings

Pharmacokinetics of a Long-lasting, Highly Concentrated Buprenorphine Solution after Subcutaneous Administration in Rhesus Macaques (Macaca mulatta).

Opioids are essential for use in rhesus macaques (Macaca mulatta) that require multimodal analgesia or those unable to receive NSAID as part of their pain management plan. The current opioid epidemic has universally limited the availability of these vital analgesics, compelling clinicians to investigate other options including novel opioid formulations. A commercially available injectable, long-lasting, highly concentrated buprenorphine solution (HCBS) provides therapeutic plasma concentrations lasting 24 h after a single dose in cats ( Felis catus). We hypothesized that this same HCBS would achieve therapeutic concentrations (≥0.1 ng/mL) for at least 24 h in rhesus macaques. In the current study, 6 healthy, adult rhesus macaques were included in a randomized, 2-period, 2-treatment crossover study. The low dose (0.24 mg/kg SC) achieved a peak plasma concentration of 19.1 ± 5.68 ng/mL at 0.308 ± 0.077 h, with an AUC of 236.4 ± 22.5 h/ng/mL and terminal elimination half-life of 19.6 ± 4.02 h; for the high dose (0.72 mg/kg SC), these parameters were 65.2 ± 14.7 ng/mL, 0.034 ± 0.004 h, 641.3 ± 79.4 h/ng/mL, and 20.6 ± 2.30 h, respectively. The mean plasma concentrations for the low and high doses in rhesus macaques significantly exceeded the therapeutic threshold for 48 and 72 h, respectively. One macaque showed mild somnolence at both doses, and another showed mild pruritus at both doses. These findings show that subcutaneous administration of HCBS provides prolonged and long-lasting therapeutic plasma levels for 48 to 72 h dosing without problematic adverse effects and thus represents a potential new analgesic alternative

Identifying Cardiac Diseases using Cardiac Biomarkers in Rhesus Macaques (Macaca mulatta).

Cardiac biomarkers are an important tool for diagnosing cardiac diseases in both human and veterinary patients. Serum concentrations of N-terminal probrain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) have been used to indicate the presence of various cardiac diseases including hypertrophic cardiomyopathy (HCM) in various species including humans. However, these cardiac biomarkers have not been established as a diagnostic tool for detecting cardiac disease in rhesus macaques. In the rhesus macaque colony at the California National Primate Research Center, naturally occurring HCM and various other cardiac diseases have been identified. In this study, commercially available assays were used to measure serum cTnI and NT-proBNP concentrations to evaluate their utility as a diagnostic screening tool for cardiac diseases in rhesus macaques. This study revealed that the serum cTnI concentration was significantly higher in animals with echocardiographically apparent cardiac disease as compared with the animals that had no cardiac structural and functional changes (the control group). However, no significant differences were detected between animals with HCM and non-HCM cardiac disease. Because the area under the receiver operating characteristic curve was 0.81 when the serum cTnI was compared between the control and cardiac disease groups, serum cTnI was considered a moderately accurate test to predict the presence of cardiac disease. The optimal cut-off value of serum cTnI concentration for diagnosis of cardiac disease was 0.0085 ng/mL, with a sensitivity of 0.68 and specificity of 0.94. Significant but weak correlations were noted between the serum cTnI concentration and several echocardiographic parameters. Conversely, no significant differences in NT-proBNP concentrations were detected between animals with and without cardiac diseases. In conclusion, measurement of serum cTnI can be used to aid in diagnosing cardiac diseases in rhesus macaques. However, cTnI measurement does not replace echocardiographic evaluation to diagnose cardiac diseases in rhesus macaques due to the poor sensitivity of the assay and the weak correlation to with more established echocardiographic markers for cardiac disease

Pharmacokinetics of Ceftiofur Crystalline Free Acid in Male Rhesus Macaques (Macaca mulatta) after Subcutaneous Administration.

Trauma is a common sequela to agonistic social encounters in rhesus macaques (Macaca mulatta), and veterinarians often prescribe antibiotics as part of a balanced treatment plan. Long-acting, single-dose, injectable antibiotics for use in rhesus macaques are unavailable currently. Ceftiofur crystalline free acid (CCFA) is a long-acting, single-dose, injectable third-generation cephalosporin that provides at least 7 d of ceftiofur therapeutic plasma concentrations in swine (Sus scrofa domesticus). We hypothesized that CCFA would achieve similar therapeutic concentrations (≥ 0.2 μg/mL) in rhesus macaques. We describe the pharmacokinetic profile of CCFA in healthy, adult male rhesus macaques ( n = 6) in this 2-period, 2-treatment crossover study of 5 and 20 mg/kg SC administered once. Plasma ceftiofur metabolite concentrations were determined prior to and for a maximum of 21 d after administration. Noncompartmental pharmacokinetic analysis was performed. The 5-mg dose achieved a maximal plasma concentration of 2.24 ± 0.525 μg/mL at 2.59 ± 1.63 h, an AUC of 46.9 ± 17.6 h/μg/mL, and a terminal elimination half-life of 56.5 ± 21.7 h; for the 20-mg/kg dose, these parameters were 9.18 ± 4.90 μg/mL at 1.82 ± 1.30 h, 331 ± 84.4 h/μg/mL, and 69.7 ± 8.86 h, respectively. No adverse effects were noted after either dose. Macaques maintained plasma ceftiofur concentrations of 0.2 μg/mL or greater for at least 2 d after 5 mg/kg SC and at least 7 d after 20 mg/kg SC

Pharmacokinetics of a Novel, Transdermal Fentanyl Solution in Rhesus Macaques (Macaca mulatta).

Rhesus macaques (Macaca mulatta) are the most commonly used NHP biomedical model and experience both research and clinical procedures requiring analgesia. Opioids are a mainstay of analgesic therapy. A novel, transdermal fentanyl solution (TFS) has been developed as a long-acting, single-administration topical opioid and was reported to provide at least 4 d of effective plasma concentrations in beagles (Canis familiaris). To evaluate the pharmacokinetic profile of TFS in healthy adult rhesus macaques, we used a 2-period, 2-treatment crossover study of a single topical administration of 1.3 (25) and 2.6 mg/kg (50 μL/kg) TFS. TFS was applied to the clipped dorsal skin of adult rhesus macaques (n = 6; 3 male, 3 female) under ketamine sedation (10 mg/kg IM). We hypothesized that TFS in rhesus macaques would provide at least 4 d of effective plasma concentrations (assumed to be ≥ 0.2 ng/mL, based on human studies). Plasma fentanyl concentrations were determined by liquid chromatography-tandem mass spectrometry before drug administration and at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 240, 336, 408, and 504 h afterward. Noncompartmental pharmacokinetic analysis was performed. For each dose (1.3 and 2.6 mg/kg), respectively, the maximal plasma concentration was 1.95 ± 0.40 and 4.19 ± 0.69 ng/mL, occurring at 21.3 ± 4.1 and 30.7 ± 8.7 h; the AUC was 227.3 ± 31.7 and 447.0 ± 49.1 h/ng/mL, and the terminal elimination half-life was 93.7 ± 7.1 and 98.8 ± 5.4 h. No adverse effects were noted after drug administration at either dose. Macaques maintained plasma fentanyl concentrations of 0.2 ng/mL or greater for at least 7 d after 1.3 mg/kg and at least 10 d after 2.6 mg/kg topical administration of TFS. A single TFS dose may provide efficacious analgesia to rhesus macaques and reduce stress, discomfort, and risk to animals and personnel

Sexual dimorphism of detrusor function demonstrated by urodynamic studies in rhesus macaques

The lower urinary tract (LUT) and micturition reflexes are sexually dimorphic across mammals. Sex as a biological variable is also of critical importance for the development and translation of new medical treatments and therapeutics interventions affecting pelvic organs, including the LUT. However, studies of LUT function with comparisons between the sexes have remained sparse, especially for larger mammals. Detrusor function was investigated by filling cystometry and pressure flow studies in 16 male and 22 female rhesus macaques. By filling cystometry, male subjects exhibited a significantly larger bladder capacity and compliance compared to females. Pressure flow studies showed a significantly higher bladder pressure at voiding onset, peak pressure, and elevation in detrusor-activated bladder pressure from the end of bladder filling to peak pressure in the male subjects. The activation of reflex micturition, with associated detrusor contractions, resulted in voiding in a significantly larger proportion of female compared to male subjects. A higher urethral outlet resistance is suggested in the male subjects. We conclude that sexual dimorphism of detrusor function is prominent in rhesus macaques, shares many features with the human, and merits consideration in translational and pre-clinical research studies of micturition and LUT function in non-human primates