A comparison of the effects of hydromorphone HCl and a novel extended release hydromorphone on arterial blood gas values in conscious healthy dogs.

The purpose of this study was to evaluate arterial blood gases in dogs that were given hydromorphone or extended release liposome-encapsulated hydromorphone (LEH). Dogs were randomly administered LEH, n=6, (2.0 mg kg(-1)), hydromorphone, n=6, (0.2 mg kg(-1)) or a placebo of blank liposomes, n=3, subcutaneously on separate occasions. Arterial blood samples were drawn at serial time points over a 6-h time period for blood gas analysis. There was no change from baseline values in P(a)CO(2), P(a)O(2), (HCO(3)-), pH, and SBEc in the dogs that received the placebo. Administration of hydromorphone resulted in significant increases in P(a)CO(2) (maximum (mean+SD] 44.4+1.1mm of Hg) and significant decreases in P(a)O(2) (minimum (mean+SD) 82.4+4.7 mm of Hg) and pH (minimum (mean+SD) 7.31+0.01) compared with baseline. Administration of LEH resulted in significant increases in P(a)CO(2) (maximum (mean+SD) 44.6+0.9 mm of Hg) and significant decreases in P(a)O(2) (minimum (mean+SD) 84.8+2.6mm of Hg) and pH (minimum (mean+SD) 7.34+0.02) compared with baseline. There was no significant difference between these two groups at any time point. The changes observed in P(a)CO(2), P(a)O(2), and pH, however, were within clinically acceptable limits for healthy dogs. LEH was determined to cause moderate changes in arterial blood gas values similar to those caused by hydromorphone.

Pharmacokinetics of a controlled-release liposome-encapsulated hydromorphone administered to healthy dogs.

The purpose of the study was to assess the pharmacokinetics of liposome-encapsulated (DPPC-C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14-28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC-C formulation (half-life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half-life of hydromorphone after SC administration of DPPC-C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C(MAX)/D) ranged between 19.41-24.96 ng/mL occurring at 0.18-0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6-72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC-C hydromorphone. Liposome-encapsulated hydromorphone (DPPC-C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.

Chronic myelocytic leukemia in a juvenile rhesus macaque (Macaca mulatta).

Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating myelocytic cells, including 1% blasts, and normocytic normochromic anemia on a blood sample obtained for monthly health monitoring. The animal was treated with hydroxyurea, blood transfusion, and recombinant human erythropoietin to reduce the leukocytosis and correct the anemia. The disease had a relatively indolent course for 3 months, when it progressed to blast crisis. After the onset of blast crisis, the animal was euthanized because of bleeding problems, anemia, and a progressive decline in her health. The animal was negative by serology, polymerase chain reaction (PCR) assays, and/or culture for simian retrovirus (SRV), simian T-lymphotropic virus type I (STLV-I), and simian immunodeficiency virus (SIV). PCR assay for the bcr-ABL chromosomal translocation using primers made for the human gene was negative. Serology for Epstein-Barr virus (EBV)-like viruses was positive for IgG directed against the viral nucleocapsid antigen, but epidemiologic factors make it unlikely that the leukemia was associated with EBV-induced viral transformation. Lead exposure has been associated with neoplasia in human beings, and the possible role of neonatal lead exposure in hematologic neoplasias deserves further scrutiny.

A comparison of two opioid analgesics for relief of visceral pain induced by intestinal resection in rats.

While developing a rat model for human short bowel syndrome, we noted that untreated rats as well as rats administered buprenorphine after intestinal resection exhibited behavior and appearance consistent with visceral pain and distress. To provide appropriate analgesics, we developed criteria to assess pain-related behavioral changes and conducted an experiment to evaluate the effectiveness of buprenorphine versus oxymorphone to alleviate the pain induced by intestinal resection. Rats underwent either small-bowel resection or transection surgery; in addition, animals received jugular catheterization for the delivery of total parenteral nutrition (TPN). Rats treated with buprenorphine received 0.5 mg/kg every 6 h subcutaneously, and rats treated with oxymorphone received 0.03 mg/kg hourly for 32 h via continuous intravenous (i.v.) infusion with TPN solution. Rats treated with buprenorphine exhibited behavior and appearance consistent with pain and distress for as long as 32 h postoperatively, whereas animals treated with oxymorphone exhibited behavior and appearance similar to their preoperative state. Thus, oxymorphone alleviated the pain-related behavioral changes after intestinal resection far better than did buprenorphine. Of interest, we observed that the buprenorphine was associated with a decrease in the volume of urine collected, whereas oxymorphone was associated with urine volumes similar to those of nonresected rats maintained with TPN. Because oxymorphone appeared to be a superior analgesic, we also evaluated three routes for administering this drug. Pain-related behavior changes were alleviated by the administration of oxymorphone by either Alzet mini-pump, bolus i.v. injection, or continuous i.v. infusion. We conclude that compared with buprenorphine, oxymorphone is a superior analgesic for the alleviation of visceral pain due to intestinal resection.

Primary cultures of rhesus placental syncytiotrophoblasts are permissive for SIV infection.

Primary cultures of rhesus syncytiotrophoblasts incubated with SIVdeltaB670, SIVmac251, or SIVmac239 produced readily detectable virus in the supernatant for up to three weeks after infection. At four weeks, cells generally failed to release virus but placental cell lysates and placental cells cocultured for 24 hours with uninfected CEM x 174 cells were able to transmit infection. The presence of virus was confirmed by electron microscopy and PCR amplification of viral sequences from trophoblast genomic DNA. SIV p27 antigen was localized by immunostaining primarily in syncytiotrophoblasts.