Pharmacokinetics of liposomal encapsulated buprenorphine suspension following subcutaneous administration to cats.

We investigated the effects of liposome encapsulation at prolonging the systemic exposure of buprenorphine following subcutaneous administration in cats. Seven healthy male cats were dosed intravenously with 0.02 mg/kg buprenorphine solution (STD-BUP), followed 14 days later by a subcutaneous injection of 0.2 mg/kg buprenorphine as a liposomal suspension (SUS-BUP) containing drug molecules both in liposomes and the suspending vehicle. Buprenorphine time plasma concentration data for both dosing routes were analyzed simultaneously with four compartmental models. Goodness of fit was assessed both graphically and with the Akaike information criterion. The time-course of intravenous STD-BUP was biphasic, with a 4.39 h average terminal half-life. The subcutaneous SUS-BUP produced plasma buprenorphine concentrations above 0.5 µg/L for more than 96 h, with three distinct peaks in the first 15 h. The model with best fit comprised a central and a peripheral compartment, plus three subcutaneous absorption compartments: one of dissolved drug molecules that were absorbed through a first-order process, and two of liposome-encapsulated drug molecules that were transferred to the solution compartment through separate zero-order processes. Liposomes effectively prolonged the systemic exposure of buprenorphine in cats.

Effect of synthetic colloid administration on coagulation in healthy dogs and dogs with systemic inflammation.

BACKGROUND: Synthetic colloids are often used during fluid resuscitation and affect coagulation. OBJECTIVE: To compare the effects of an isotonic crystalloid and synthetic colloid on coagulation in healthy dogs and dogs with systemic inflammation. ANIMALS: Sixteen adult purpose-bred Beagles. METHODS: Randomized, placebo-controlled, blinded study. Dogs were randomized into one of two groups receiving fluid resuscitation with either 40 mL/kg IV 0.9% NaCl or tetrastarch after administration of lipopolysaccharide or an equal volume of placebo. After a 14-day washout period, the study was repeated such that dogs received the opposite treatment (LPS or placebo) but the same resuscitation fluid. Blood samples were collected at 0, 1, 2, 4, and 24 hours for measurement of coagulation variables. RESULTS: Administration of either fluid to healthy dogs and dogs with systemic inflammation resulted in similar increases in prothrombin time and activated clotting time. In comparison to saline administration, tetrastarch administration resulted in significantly decreased R (P = .017) in healthy dogs, as well as significantly increased activated partial thromboplastin time (P ≤ .016), CL30% (P ≤ .016), and K (P < .001) and significantly decreased platelet count (P = .019), α (P ≤ .001), MA (P < .001), and von Willebrand factor antigen (P < .001) and collagen binding activity (P ≤ .003) in both healthy dogs and dogs with systemic inflammation. CONCLUSIONS AND CLINICAL IMPORTANCE: Tetrastarch bolus administration to dogs with systemic inflammation resulted in a transient hypocoagulability characterized by a prolonged activated partial thromboplastin time, decreased clot formation speed and clot strength, and acquired type 1 von Willebrand disease.

Effects of high-frequency oscillation on endogenous surfactant in an acute lung injury model.

This study evaluated the effects of high-frequency oscillation (HFO) and conventional mechanical ventilation (CMV) on gas exchange and the pulmonary surfactant system in an acute lung injury model. Following induction of lung injury with N-nitroso-n-methylurethane, adult rabbits were anesthetized and randomized to one of the following ventilatory strategies: HFO for 120 min, CMV for 120 min, HFO for 60 min, followed by CMV for 60 min, CMV for 60 min followed by HFO for 60 min or CMV for 60 min. Separate animals were ventilated using CMV with a lower tidal volume and a positive end-expiratory pressure level that was increased throughout the experimental period. Oxygenation was significantly greater in animals ventilated with HFO compared with animals ventilated with CMV. The proportion of surfactant in large aggregate forms was significantly greater following ventilatory support with HFO compared with CMV. Surfactant aggregate conversion was also significantly lower during HFO compared with CMV. We conclude that in our model of acute lung injury, HFO was a superior mode of ventilation and reduced the conversion of alveolar surfactant large aggregates into small aggregate forms, resulting in a greater percentage of large aggregate forms in the alveolar space.

Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant.

The effects of both surfactant distribution patterns and ventilation strategies utilized after surfactant administration were assessed in lung-injured adult rabbits. Animals received 50 mg/kg surfactant via intratracheal instillation in volumes of either 4 or 2 ml/kg. A subset of animals from each treatment group was euthanized for evaluation of the exogenous surfactant distribution. The remaining animals were randomized into one of three ventilatory groups: group 1 [tidal volume (VT) of 10 ml/kg with 5 cmH2O positive end-expiratory pressure (PEEP)]; group 2 (VT of 5 ml/kg with 5 cmH2O PEEP); or group 3 (VT of 5 ml/kg with 9 cmH2O PEEP). Animals were ventilated and monitored for 3 h. Distribution of the surfactant was more uniform when it was delivered in the 4 ml/kg volume. When the distribution of surfactant was less uniform, arterial PO2 values were greater in groups 2 and 3 compared with group 1. Oxygenation differences among the different ventilation strategies were less marked in animals with the more uniform distribution pattern of surfactant (4 ml/kg). In both surfactant treatment groups, a high mortality was observed with the ventilation strategy used for group 3. We conclude that the distribution of exogenous surfactant affects the response to different ventilatory strategies in this model of acute lung injury.

Effects of ventilation strategies on the efficacy of exogenous surfactant therapy in a rabbit model of acute lung injury.

We evaluated the effects of various ventilation strategies on the efficacy of exogenous surfactant therapy in lung-injured adult rabbits. Lung injury was induced by repetitive whole-lung saline lavage followed by mechanical ventilation. Three hours after the final lavage, 100 mg lipid/kg bovine lipid extract surfactant was instilled. After confirmation of similar responses to exogenous surfactant, animals were then randomized to one of four ventilation groups; (1) Normal tidal volume (VT) (5 cm H2O): VT = 10 ml/kg, respiratory rate (RR) = 30/min, positive end-expiratory pressure (PEEP) = 5 cm H2O; (2) Normal VT (9 cm H2O): VT = 10 ml/kg, RR = 30/min, PEEP = 9 cm H2O; (3) Low VT (5 cm H2O): VT = 5 ml/kg, RR = 60/min, PEEP = 5 cm H2O; (4) Low VT (9 cm H2O): VT = 5 ml/kg, RR = 60/min, PEEP = 9 cm H2O. Animals were ventilated for an additional 3 h and then killed, and lung lavage fluid was analyzed. Animals ventilated with the low-VT modes (Low VT [5 cm H2O] and Low VT [9 cm H2O]) had higher PaO2 values (430 +/- 7 mm Hg and 425 +/- 18 mm Hg versus 328 +/- 13 mm Hg) and higher percentages of surfactant in large aggregate forms (83 +/- 2% and 82 +/- 2% versus 67 +/- 4%) at 3 h after treatment than did the Normal VT (5 cm H2O) group (p < 0.05). Increasing the PEEP level was beneficial for a short period after surfactant administration to maintain oxygenation, but did not affect exogenous surfactant aggregate conversion. We speculate that ventilation strategies resulting in low exogenous surfactant aggregate conversion will result in superior physiologic responses to exogenous surfactant.

Reporting of medication regimen in applied studies of persons with mental retardation and ADHD.

The present survey determined whether articles describing attempts to alter behavior in people with mental retardation and Attention-Deficit/Hyperactivity Disorder (ADHD) (a) reported whether or not participants were receiving medications, (b) evaluated drugs as independent variables, and (c) evaluated (or discussed) interactions between pharmacological and nonpharmacological treatments. All behavior-change articles published from 1991 through 1995 in 10 major journals were evaluated. In contrast to the results of earlier surveys, nearly 40% of studies involving participants with mental retardation provided information about medication. This change appears to represent a significant methodological improvement. Nearly 60% of articles involving persons with ADHD provided information about medication. Studies of drugs were common when participants were people with ADHD, but not when they were people with mental retardation. The psychopharmacology of mental retardation continues to be a small, but important, research area. Studies examining treatment interactions were rare, regardless of participants' characteristics. Given that pharmacological treatments may alter participants' sensitivity to nonpharmacological interventions, further research in this area is sorely needed.

Baylisascariasis in raccoons from southern coastal Texas.

Two hundred and two Baylisascaris procyonis were collected from 23 (70%) of 33 raccoons (Procyon lotor) at three localities in southern coastal Texas (USA). Abundances of B. procyonis were similar among collection localities. The presence of B. procyonis in Texas is confirmed, and this record considerably extends the potential range of baylisascariasis larval migrans in North America.

A comparison of romifidine and xylazine when used with diazepam/ketamine for short duration anesthesia in the horse.

The purpose of this study was to compare and evaluate sedation with intravenous xylazine (1.1 mg/kg bodyweight [BW]) versus intravenous romifidine (100 micrograms/kg BW) followed by induction of anesthesia with intravenous diazepam (0.04 mg/kg BW) and ketamine (2.2 mg/kg BW). Twelve healthy horses were used in a blinded, randomized, cross-over design. Heart rate, presence of 2nd degree atrioventricular heart blocks (2 degrees AVB), respiratory rate, arterial blood pressures, blood gases, packed cell volume, total serum proteins, and duration of anesthesia and recumbency were recorded. Induction and recovery quality was evaluated using a 0 to 4 score. Response to stimulation with noise, pressure, and cutaneous electrical stimulation was assessed at 5 minute intervals during recumbency to evaluate the depth of anesthesia. Heart rate was lower and 2 degrees AVB more frequent in the romifidine group, while blood pressure was lower in the xylazine group. Duration of anesthesia was longer in the romifidine group (mean 20.8, s mean 2.3 min) versus the xylazine group (mean 15.8, s mean 1.6 min), while induction and recovery were excellent in both groups. Respiratory rates, blood gas values, packed cell volumes, and total protein levels did not differ between groups. The results indicate that romifidine premedication followed by diazepam and ketamine is a very satisfactory regime for short duration intravenous anesthesia in horses.

The phylogenetically predicted base-pairing interaction between alpha and alpha' is required for group II splicing in vitro.

The correct folding of group II introns apparently depends on multiple tertiary base-pairing interactions. Understanding the relationship between spliceosome and group II splicing systems ultimately requires a three-dimensional model for both structures. In turn, successful modeling depends at least in part on identifying tertiary base pairings. Sequence elements alpha and alpha' are partners in a potential interaction of approximately 6 base pairs that can be identified within domain 1 of most group II introns. In comparisons between related introns, alpha and alpha' maintain their potential for Watson-Crick base pairing, even though their primary sequences can vary [Michel, F., Umesono, K. & Ozeki, H. (1989) Gene 82, 5-30]. Substitutions were constructed at alpha and alpha' for a block of 6 bases each in the group II intron a5 gamma, the last intron of the COXI gene from the mitochondrial DNA of Saccharomyces cerevisiae. Each substitution was defective for self-splicing, while the compensatory double derivative was restored to active splicing. The alpha-alpha' interaction is required for the first step of splicing--that is, recognition of the 5' splice junction and transesterification with the branch site--since the derivative transcripts displayed little or no activity. The compensatory double derivative produced lariat introns and spliced exons with normal structures, showing that splicing activity and precise recognition were restored. We conclude that the alpha-alpha' base pairing is necessary for efficient self-splicing by intron a5 gamma under several conditions. This result also provides an additional constraint for any three-dimensional model of group II intron structure.

Combined effects of hyperthermia (to 45 degrees C) and ultrasound irradiation on the surface ultrastructure of HeLa cells.

Hyperthermic treatment of HeLa cells in suspension combined with ultrasound irradiation produced alterations to the cell surfaces. The changes induced were related to ultrasound intensity in the standing wave and to heat treatments between 37 and 45 degrees C. Two transducers were used, driven at resonant frequencies of 0.75 and 1.5 MHz, and producing peak intensities up to 7 W/cm2. These intensities produced a negligible rise in temperature of the cell suspension medium. Ultrastructural damage in standing wave fields, as seen by scanning electron microscopy, progressed through stages. The first stage was characterized by the loss of microvilli and smooth appearance of the cell surface, e.g. after insonation at 41.5 degrees C for 10 min; damage increased to a final stage where the surface appeared heavily pitted and porous, with the cells showing signs of disintegration, e.g. after insonation at 45 degrees C for 10 min. The monitoring of ultrasound-induced cavitation suggested that damage was caused by bubble oscillations, not collapse cavitation. Shearing stresses accentuated by hyperthermia were considered the probable cause of such damage. Coulter counter studies of cell size distribution showed that the extent of cell damage depended on the geometry of the vessel in which insonation was carried out.

Ultrasound-induced damage of veins in pig ears, as revealed by scanning electron microscopy.

Pig ear veins have been treated in situ with ultrasound at a frequency of 750 kHz and intensity of 1.5 W cm-2 (spatial average) during which the temperature in the surrounding tissues rose to 52-54 degrees C. The veins were examined by scanning electron microscopy. Gaps developed between the endothelial cells, which showed many fine perforations in their membranes. Extensive blood clots were observed in which erythrocytes had become more spherical and showed damaged membranes. Effects on membranes were also found with HeLa cells heated to 50 degrees C, and have been previously described by others in heat-treated blood vessels.

The effect of monensin on virion production and protein secretion in pseudorabies virus-infected cells.

The effects of monensin on cells infected with pseudorabies virus have been studied. Treatment with monensin (1 microM) prevented the secretion of the 89K pseudorabies virus-induced sulphated glycoprotein. A polypeptide with a mol. wt. of 78K was secreted into the medium from monensin-treated BSC-1 cells. Mannose labelling showed that initial glycosylation proceeded normally in the presence of monensin, although the absence of fucose label revealed that the later stages in processing were blocked. No intracellular accumulation of virus-induced proteins was found in monensin-treated cells. Infectivity assays, measurement of thymidine-labelled particles and electron microscopy showed that monensin blocked the release of virus particles from cells, although viral morphogenesis was unaffected.