Pharmacokinetics of 2 Formulations of Buprenorphine in Macaques (Macaca mulatta and Macaca fascicularis)

Buprenorphine is the cornerstone of pain management in nonhuman primates, but the pharmacokinetics of this widely used drug are unknown. The purpose of this study was to evaluate the pharmacokinetic profiles of buprenorphine (0.01 and 0.03 mg/kg IM) and sustained-release buprenorphine (0.2 mg/kg SC) in 2 macaque species (M. mulatta and M. fascicularis) by using mass spectrometry. The pharmacokinetics did not differ significantly between species, and buprenorphine was dose-proportional at the tested doses. The low and high doses of buprenorphine had elimination half-lives of 2.6 ± 0.7 and 5.3 ± 2.0 h, respectively, but the low-dose data were constrained by the sensitivity of the analytical method. Sustained-release buprenorphine had an elimination half-life of 42.6 ± 26.2 h. The AUC_0-Tlast of buprenorphine were 9.1 ± 4.3 and 39.0 ± 25.1 ng×h/mL for the low and high doses, respectively, and sustained-release buprenorphine had an AUC_0-Tlast of 177 ± 74 ng×h/mL. Assuming a hypothesized therapeutic buprenorphine plasma concentration threshold of 0.1 ng/mL in macaques, these results suggest that buprenorphine doses of 0.01 mg/kg IM should be administered every 6 to 8 h, whereas doses of 0.03 mg/kg IM can be administered every 12 h. These results further demonstrate that a single 0.2-mg/kg SC injection of sustained-release buprenorphine maintains plasma concentrations above 0.1 ng/mL for 5 d in macaques. These findings support a new dosing strategy using sustained-release buprenorphine to improve pain management, decrease animal stress, improve animal welfare, and simplify the postoperative management of nonhuman primates in laboratory animal and zoological settings.Abbreviation: λ_z, elimination constant; C_max, maximal observed plasma concentration; HDB, high-dose buprenorphine; LDB, low-dose buprenorphine; MRT, mean residence time; SRB, sustained-release buprenorphine; T_last, time of last quantifiable plasma analyte concentration; T_max, time to C_max; V, volume of distributionBuprenorphine is a key component of veterinary multimodal pain management, especially in nonhuman primates. The long duration of action, low risk of respiratory depression, and negligible cardiovascular effects in healthy animals make it an advantageous opioid analgesic agent.⁴³ The widely accepted dosage range for buprenorphine in nonhuman primates is 0.01 to 0.03 mg/kg IM twice daily.^13,14,20 This dosage is based on the canine dose and anecdotal evidence, because few studies in the primary literature address therapeutic dosages in laboratory animal species.^24,38,42 The premise that the current recommended dosing regimen of buprenorphine provides appropriate analgesia is unsubstantiated, introducing the possibility that nonhuman primates do not gain sufficient pain control from the opioid component of the pain management plan.A new formulation of buprenorphine is reported to have analgesic activity for up to 72 h in cats and rats.^7,15 The manufacturer reports that, when administered at 0.27 mg/kg SC, this sustained-release buprenorphine (SRB; ZooPharm, Fort Collins, CO) reaches maximal plasma concentration within 1 h and remains above 1.0 ng/mL for 72 h after injection in dogs. In light of the prolonged duration attained in dogs, this new formulation warrants further evaluation in nonhuman primates.Drugs with prolonged durations of action are preferred in veterinary medicine and are typically developed for either production or companion animals rather than laboratory animal species. Recently, 2 studies evaluated cefovecin sodium in nonhuman primates, with the expectation that this third-generation cephalosporin antibiotic would have an extended duration of activity in nonhuman primates as it does in dogs and cats. Unfortunately, both studies concluded that the plasma clearance of the antibiotic was 20-fold higher in nonhuman primates than in dogs, providing only 12 to 24 h of antibiotic activity and therefore no dosing advantage over other cephalosporin antibiotics in nonhuman primates.^37,39 One study further demonstrated differences in the metabolism of the drug between nonhuman primates species.³⁹ Collectively, these findings highlight the importance of determining optimal dosing strategies for any drug in targeted nonhuman primates species, rather than simply using a published dose for a different species without further evaluation.The purpose of this study was to evaluate the plasma concentrations and elimination kinetics of buprenorphine and SRB at clinically relevant dosages and administration routes in the 2 most common Old World nonhuman primate species used in research. Specifically, we used liquid chromatography–electrospray ionization–tandem mass spectrometry to confirm that buprenorphine and SRB achieved quantifiable plasma concentrations after injection and to verify how long buprenorphine and individual metabolites remained detectable in the plasma.     

Growth monitoring: testing the new guidelines

OBJECTIVE: To assess the impact of recent guidelines from the UK joint working party of child health surveillance recommending that all children be measured at age 5 and again between 7 and 9 years of age to determine how many normal school age children are likely to be referred for specialist assessment. METHODS: The longitudinal data of 486 children measured by school nurses in a community setting were examined and compared with measurements made in a research setting by a single, skilled observer. MAIN OUTCOME MEASURES: Number of children identified as having abnormal stature (< 0.4th or > 99.6th centile) and abnormal growth rate height standard deviation score (HSDS) change > 0.67). RESULTS: The community survey identified seven (1.4%) children as having abnormal stature (four short, three tall), 11 (2.3%) were identified as "slow growing", and nine (1.9%) increased their HSDS by more than 0.67. These results were comparable to data collected in ideal research conditions. CONCLUSIONS: Following the recommendations would not result in an excess number of inappropriate referrals. However, this study highlights several unresolved issues such as interobserver variability and time interval between measurements. A large scale prospective study should be considered to establish realistic and cost-effective criteria before implementation of a national screening programme.     

Factors causing malnutrition in patients with chronic uremia

There is abundant evidence that patients with chronic renal failure (CRF), including those treated by hemodialysis or peritoneal dialysis, have evidence of malnutrition with decreased body weight and subnormal values of serum proteins (suggesting a loss of visceral protein stores). Potential causes of an abnormal nutritional status that have been identified include an inadequate intake of protein or calories, an inability to activate the metabolic responses that are needed to achieve nitrogen and protein balance, or the presence of a disease that prevents activation of these metabolic responses or acts to stimulate the breakdown of body protein stores. Three critical metabolic responses to a limited protein intake have been identified: a reduction in the irreversible degradation of amino acids and the degradation of protein breakdown and an increase in protein synthesis in response to a meal. Metabolic acidosis blocks the first two responses and hence contributes to malnutrition in patients with chronic uremia. Other factors that could contribute to malnutrition include an inadequate intake because of anorexia or hormonal imbalances that impair protein turnover. In evaluating CRF patients with malnutrition, the first task is to ensure an adequate intake and to eliminate factors that impair the ability to achieve nitrogen balance.     

How pediatricians can respond to the psychosocial implications of disasters. American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health, 1998-1999

Natural and human-caused disasters, violence with weapons, and terrorist acts have touched directly the lives of thousands of families with children in the United States.1 Media coverage of disasters has brought images of floods, hurricanes, and airplane crashes into the living rooms of most American families, with limited censorship for vulnerable young children. Therefore, children may be exposed to disastrous events in ways that previous generations never or rarely experienced. Pediatricians should serve as important resources to the community in preparing for disasters, as well as acting in its behalf during and after such events.