A new method for determining levels of sedation in dogs: A pilot study with propofol and a novel neuroactive steroid anesthetic.

BACKGROUND: Different levels of consciousness are required in order to perform different medical procedures. Sedation scales established to objectively define various levels of sedation in humans have not been thoroughly characterized in non-human species. Postural changes in rats or dogs are useful as gross measures of sedation but are inadequate for quantitative assessment since graded levels of sedation are difficult to delineate and obscured by movement abnormalities. NEW METHOD: A new canine sedation scoring (CSS) method was developed based on the modified observer's assessment of alertness and sedation score (MOAA/S) used in humans. The method employed a combination of physical, auditory and somatosensory stimuli of increasing intensity. Cardiovascular, respiratory, and a neurophysiological measure of sedation (bispectral index: BIS) data were recorded. Validation studies were performed following intravenous loading and constant rate infusion of propofol or a novel synthetic neuroactive steroid (SGE-746). RESULTS: Four levels of consciousness were identified: 1) Awake, 2) Moderate Sedation (MS), 3) Deep Sedation (DS) and 4) General Anesthesia (GA). Cardiorespiratory measurements obtained after bolus administration of propofol and SGE-746 and at the end of each CRI remained within normal limits. Canine sedation scores correlated with BIS for SGE-746. SGE-746 exhibited a more gradual exposure-response relationship than propofol. Larger increases in the plasma concentration from awake values were required to achieve different levels of sedation with SGE-746 compared to propofol. COMPARISON WITH EXISTING METHODS: No other canine sedation scoring methods are widely accepted. CONCLUSION: A CSS method, based on the human MOAA/S scale defined four levels of consciousness in dogs and provided better resolution of sedation depth than BIS alone.

Efficacy of a mephentermine-based product as a vasopressor and a cardiac performance enhancer when given intramuscularly to cattle.

The goal of this study was to confirm the vasopressor and cardiac effects of POTENAY® INJETÁVEL (POT), a mephentermine-based product, given to cattle with induced vascular/cardiac depression. Ten healthy Holstein cattle (206 ± 13 kg) followed a randomized-complete-block design (RCBD) utilizing crossover study design. Each animal randomly received (1 ml/25 kg, IM) of either POT (n = 10) or volume-matched placebo control (0.9%NaCl, CP, n = 10). A subset of animals (n = 5) received POT first (day 0) while the remaining (n = 5) received CP; after a six-day washout period, cattle received the opposite compound. Animals were anesthetized and catheterized for systemic/left ventricular hemodynamic monitoring. Myocardial dysfunction/hypotension was induced by increasing the end-tidal isoflurane concentration until arterial blood pressure was 20% lower than at baseline and remained stable. Once the animal was determined to be hypotensive and hemodynamically stable, steady-state hypotensive baseline data (BL2) were acquired, and treatment with either POT or CP was given. Data were acquired post-treatment at every 15 min for 90 min. POT improved cardiac output (+68 L/min, ±14%, p < 0.05), MAP (+14 mmHg, ±4%, p < 0.05), HR (+22 bpm, ±8%, p < 0.05), and peak rates of ventricular pressure change during both systole (dP/dtmax : +37 mmHg/s ±13%, p < 0.05) and diastole (dP/dtmin : +31 mmHg/s, ±7%, p < 0.05). No improvements were noted following placebo-control administration. Results indicate that POT improves cardiac performance and systemic hemodynamics in cattle with induced cardiovascular depression when given as single intramuscular injection.

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.

NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.

CIITA promoter I CARD-deficient mice express functional MHC class II genes in myeloid and lymphoid compartments.

Three distinct promoters control the master regulator of major histocompatibility complex (MHC) class II expression, class II transactivator (CIITA), in a cell type-specific manner. Promoter I (pI) CIITA, expressed primarily by dendritic cells (DCs) and macrophages, expresses a unique isoform that contains a caspase-recruitment domain (CARD). The activity and function of this isoform are not understood, but are believed to enhance the function of CIITA in antigen-presenting cells. To determine whether isoform I of CIITA has specific functions, CIITA mutant mice were created in which isoform I was replaced with isoform III sequences. Mice in which pI and the CARD-encoding exon were deleted were also created. No defect in the formation of CD4 T cells, the ability to respond to a model antigen or bacterial or viral challenge was observed in mice lacking CIITA isoform I. Although CIITA and MHC-II expression was decreased in splenic DCs, pI knockout animals expressed CIITA from downstream promoters, suggesting that control of pI activity is mediated by unknown distal elements that could act at pIII, the B-cell promoter. Thus, no critical function is linked to the CARD domain of CIITA isoform I with respect to basic immune system development, function and challenge.

Emergence from anesthesia in the prone versus supine position in patients undergoing lumbar surgery.

BACKGROUND: Conventional supine emergence in patients undergoing prone lumbar surgery frequently results in tachycardia, hypertension, coughing, and loss of monitoring as the patient is rolled supine. The prone position might facilitate a smoother emergence because the patient is not disturbed. No data describe this technique. METHODS: Fifty patients were anesthetized with fentanyl, nitrous oxide, isoflurane, and rocuronium. By the conclusion of surgery, all patients achieved spontaneous ventilation and full reversal of neuromuscular blockade in the prone position, as the volatile anesthetic level was reduced. Baseline heart rate and mean arterial pressure were recorded. Patients were then randomized at time 0 to the supine (n = 24) or prone (n = 21) position as 100% oxygen was administered. Patients in the supine position were then rolled over, while those in the prone position remained undisturbed. Heart rate, mean arterial pressure, and coughs were recorded until extubation. Tracheas were extubated on eye opening or purposeful behavior. RESULTS: When compared with the supine group, prone patients had significantly less increase in heart rate (P = 0.0003, maximum increase 9.3 vs. 25 beats/min), less increase in mean arterial pressure (P = 0.0063, maximum increase 4.8 vs. 19 mmHg), less coughing (P = 0.0004, 7.0 vs. 23 coughs), and fewer monitor disconnections (P < 0.0001). Time to extubation from time 0 was similar (4.0 vs. 3.7 min, prone vs. supine). No one required airway rescue. There was no significant difference in need for restraint (three prone, four supine). CONCLUSIONS: Prone emergence and extubation is associated with less hemodynamic stimulation, less coughing, and less disruption of monitors, without specifically observed adverse effects, when compared with conventional supine techniques.

The effects of paradoxical sleep deprivation and valine on spatial learning and brain 5-HT metabolism.

We have previously reported that rapid eye movement sleep deprivation (REMSD), induced by the flower pot technique, causes a deficit in reference spatial memory and increases rates of serotonin (5-HT) metabolism in the brain. In this study we used increased concentrations of dietary valine to inhibit tryptophan (TRP) transport across the blood-brain barrier in an attempt to modify the REMSD-induced increase of 5-HT metabolism. Rats were fed either a control diet or the same diet supplemented to 2% by weight valine, and were allocated to one of three experimental groups: cage control (CC), stress tank control (TC), or REMSD. Reference and working spatial memory of all rats was tested in a Morris water maze on Days 2, 3, and 4. REMSD produced a significant decrement in reference memory on Days 2 and 4, independent of dietary condition. The valine diet had a detrimental effect on the reference memory of TC rats on Day 2 but not Day 4. Measurements made on Day 4 indicated that the valine diet decreased brain TRP only in the CC rats. In contrast, the valine diet did not prevent increases in brain TRP or 5-HT metabolism in REMSD rats, and increased hypothalamic and brain stem TRP concentrations and the hippocampal 5-HIAA/5-HT ratio in TC rats. These results indicate that dietary valine does not prevent REMSD-induced changes in spatial memory or serotonin metabolism, although it does reduce brain TRP in nonstressed rats.

Peritoneal dialysis adequacy: a model to assess feasibility with various modalities.

BACKGROUND: The current standard of adequacy for peritoneal dialysis (PD) is to provide a weekly normalized urea clearance (Kt/V) of 2.0 or more and a creatinine clearance (CCr) of 60 liter/1.73 m2 or more. As native renal function is lost, it is important to determine the effectiveness of the available therapeutic modalities in achieving these goals. METHODS: A model to assess our ability to provide a weekly Kt/Vurea of 2.0 or more and a CCr of 60 liter/1.73 m2 or more to anuric patients undergoing continuous ambulatory PD (CAPD) and automated PD (PD Plus) was developed. The body surface area (BSA) distribution was obtained from 38,768 patients undergoing dialysis during January 1997. The distribution of peritoneal transport rates (PTRs) was obtained from 2531 peritoneal equilibration tests performed during 1996. The weekly Kpt/Vurea was calculated for the various PTR groups and the range of BSA with four PD prescriptions: CAPD 8 liters, CAPD 10 liters, PD Plus 12 liters, and PD Plus 15 liters, using a previously validated kinetic program (PackPD). RESULTS: The predicted percentage of patients capable of achieving the adequacy goals for Kt/V and CCr, respectively, were 24.8 and 11. 2 for CAPD 8 liters, 54.2 and 33.0 for CAPD 10 liters, 77.8 and 54.9 for PD Plus 12 liters, and 93.2 and 72.9 for PD Plus 15 liters. CONCLUSIONS: Most patients can attain the current adequacy standards of therapy with automated PD, but few (less than 25%) can do so with standard CAPD in the absence of residual renal function.

The effects of restraint stress on intake of preferred and nonpreferred solutions in rodents.

In these experiments we determined whether stress influenced intake of different flavored test solutions or only those that were preferred. In a series of studies, rats or hamsters were exposed to acute (1 h) or repeated (3 h/day for 3 days) restraint stress immediately followed by access to one of four tastants (saccharin, salt, citric acid, or quinine solutions) paired with water in a 24-h preference test. As rats prefer salt and hamsters do not, both species were used to test the effects of stress on preferred vs. nonpreferred solutions using the same stimulus. Acute restraint inhibited intake of saccharin in rats but had no effect on preference, indicating that suppression of intake was not due to changes in hedonic response. Restraint had no effect on saccharin intake of hamsters but significantly increased salt intake. However, as the preference ratio remained low for the solution (0.26), the stress-induced increase in salt intake was probably associated with a disturbance of sodium and fluid balance rather than a change in sensory perception. This was supported by stress having no effect on intake of nonpreferred solutions in rats or hamsters. Repeated restraint had no effect on salt or saccharin intake of rats when test solutions were presented after stress, but rats showed no preference for saccharin in a subsequent study in which the solution was associated with onset of stress. These results indicate that stress has specific effects on saccharin and salt intake that are not limited to preferred solutions.

Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets.

Exposure to the moderate stressor of 3-h restraint for 3 consecutive days causes a temporary drop in food intake but a permanent reduction in body weight in adult rats. Young rats did not show the same response. Food intake of adult rats exposed to repeated restraint was significantly lower than that of controls for 4 days after the end of stress, and there was no rebound hyperphagia. Body weight remained significantly lower for at least 40 days after stress. When the rats were fed a high-fat diet of 80% chow and 20% vegetable shortening (48% kcal fat, 16% protein), lean body mass accounted for all of the weight loss in stressed rats. When the experiment was repeated with a purified high-fat diet containing corn oil and coconut oil as the source of fat (41% kcal fat, 16% protein), weight loss consisted of both lean and fat tissue. There were no sustained changes in single time point measures of corticosterone, insulin, or leptin that could account for the reduced body weight in these rats.

Delivered dialysis dose with PD Plus therapy. A multicenter study.

AIM: To evaluate the effect of PD Plus on weekly Kt/Vurea and creatinine clearance (Kcr) among patients undergoing CAPD/CCPD (continuous ambulatory peritoneal dialysis/continuous cyclic peritoneal dialysis). METHODS: The kinetic studies of 92 CAPD and 18 CCPD patients who transferred to PD Plus were analyzed. All patients underwent CAPD/CCPD and PD Plus for a minimum of 3 months. Standard collection methods were used and kinetic indices calculated with the Pack PD Kinetic Modeling program. 57 patients had transport data and were modeled for a target weekly Kt/Vurea >/=2.1 using PD Plus with /=2.1 and 47% a Kcr >/=60 liters/1.73 m2 with PD Plus, but only 20% did so with CAPD/CCPD. A close correlation between the supervised patients and modeled therapy was observed. CONCLUSIONS: Adequate dialysis is possible by using higher fill volumes, the supine position, and optimal dwell times (PD Plus) in most patients. The discrepancy between modeled and achieved dose is likely due to poor compliance with therapy, inadequate training, or poor specimen collection.

Failure to change exploration or saccharin preference in rats exposed to chronic mild stress.

Chronic mild stress (CMS) exposes animals to unpredictable stressors. Reduced consumption of sucrose or saccharin solutions by CMS rats has been used as a putative measure of anhedonia, typical of depression. Our objective was to determine whether saccharin consumption and preference and suppression of exploratory and rearing behaviors in the open field were reliable indicators of CMS-induced behavioral depression. In Experiment 1, male Wistar rats subjected to 6 weeks of CMS consumed significantly less food and gained less weight than controls. CMS did not effect saccharin intake, or preference, measured in a two-bottle test with water. CMS rats exposed to a novel open field showed increased exploration and rearing. In a second test, performed immediately after a novel stress of restraint, there were no differences in exploratory or rearing behavior of CMS and control rats. In Experiment 2, CMS was reduced to 3 weeks and rats were single or group housed in their home cages. Open field activity of CMS rats was similar to that in Experiment 1. Saccharin preference of CMS rats was significantly suppressed when tested after 24 hours of water deprivation, but was not different from controls after 5 hours of water deprivation. In the final experiment Sprague Dawley rats behaved the same as Wistar rats in the CMS paradigm. Therefore, the CMS protocol used in these experiments did not induce behaviors indicative of depression but did cause a mild anorexia and weight loss. Saccharin intake of CMS rats was dependent upon their dehydration state and could not be attributed to stress-induced anhedonia.

Appetitive operant behavior and free-feeding in rats exposed to acute stress.

This study investigated whether appetitive operant food reinforcement or free-feeding behavior in rats, food-restricted to 85% of body weight, was disrupted by exposures to 3 h of restraint stress or by 3 h of restraint plus water immersion stress (RWI). Rats were trained under a 3-cycle 10-min time-out-10-min time-in fixed-ratio 15 (FR15) schedule of food reinforcement. Free-feeding was measured in a 3-cycle 10-min food jar-out-10-min food jar-in test conducted in the operant chambers. Three hours of restraint stress did not significantly affect response rate or food reinforcement in the operant FR15 task or in the free-feeding condition. In contrast, 3 h of RWI completely abolished operant food reinforcement and suppressed response rate, whereas free-feeding was significantly reduced but not abolished in food-restricted, hungry rats. We conclude that acute restraint stress in food-restricted, hungry rats does not affect their appetite or motor ability to lever-press for food nor did it affect their ability to feed in a free-feeding situation. In contrast, RWI stress may have induced a motor impairment, or some other aspect of motivation independent of hunger, that disrupted their performance in the operant FR15 task.

Sleep deprivation by the "flower pot" technique and spatial reference memory.

This study investigated whether paradoxical, or rapid eye movement (REM), sleep deprivation (SD) affected spatial memory. SD was induced in male Wistar rats by housing them on small platforms over water. They fell into the water if they lost muscle tone. Controls were either housed in tanks with large platforms (TC) or in normal cages (CC). All rats had free access to food and water. Each day they were tested in a place-learning set task using a Morris water maze. The rats were released from 6 different starting points (sets) and allowed 2 min to find a submerged platform. Two trials were conducted from each starting point. SD caused a significant decrement in performance in Trial 1 from Day 2. By Day 4, when distance swum to find the platform was plotted against set, area under the curve was doubled in SD compared to that in TC and CC rats, indicating a significant impairment in reference spatial memory. There was no consistent effect on working memory, indicated by Trial 2. SD caused weight loss and increased serum corticosterone compared to that in CC rats. There were no differences in concentrations of hypothalamic, hippocampal, or cortical catecholamines or their metabolites. Serotonin metabolism was elevated in the hypothalamus and hippocampus in SD rats. These results indicate that SD induced in rats housed on small platforms causes a substantial impairment of reference memory. The memory deficit may not be specific to SD because the rats are physically stressed and lose some nonREM sleep when housed in these conditions.

The University of Texas Medical Branch--Texas Department of Criminal Justice Telemedicine Project: findings from the first year of operation.

BACKGROUND: The University of Texas Medical Branch (UTMB) and Texas Tech Health Science Center (TTHSC) are responsible for providing health care for approximately 130,000 inmates of the Texas Department of Criminal Justice through a health maintenance organization (HMO). Telemedicine was considered a way to solve some of the problems presented. OBJECTIVES: To develop approaches to patient care, technology, support systems, evaluation, and uses of the system for applications other than patient care as part of the first stage of implementation. METHODS: Four prison delivery unit models were utilized. After a pilot study, the first patients were seen from October 1994 to November 1995, when 1715 consults were conducted in 18 scheduled specialty telemedicine clinics. Patients and providers were surveyed by interviews and questionnaires for their views on this form of providing care. RESULTS: Ninety-five per cent of the telemedicine consults saved one or more trips to UTMB for outpatient specialty appointments. User surveys indicated a high degree of satisfaction on the part of patients, presenters, and specialty consultants. CONCLUSIONS: Preliminary review of the data indicated favorable care outcomes, and initial economic analyses suggested that telemedicine is likely to be cost-effective in this environment. The project will be continued.

Clinical evaluation of a peritoneal dialysis kinetic modeling set.

A closed system kinetic modeling set (KMS) has been fabricated which permits collection of a small 100-mL aliquot from each exchange. The KMS was used to collect aliquots from 65 exchanges in 13 patients. The concentrations of urea nitrogen (UN), creatinine (Cr), glucose (G), and total protein (TP) were measured in each individual aliquot (Cka) and drain bag (Cba), and all aliquots for each dialysis treatment were used to calculate the concentrations expected in total batched dialysate (BaC) for the treatment and were compared to the measured concentrations (BaM) in mixed total dialysate. The ratios Cka/Cba [mean+/- two times coefficient of variation (mean +/- 2CV)] were 1.00 +/- 5%, 1.00 +/- 5%, 1.01 +/- 10%, and 1.00 +/- 6%, respectively, for UN, Cr, G, and TP (each, n = 61). The ratios BaC/BaM (mean +/- 2CV) were 1.00 +/- 2%, 1.00 +/- 5%, 1.01 +/- 3%, and 0.99 +/- 5%, respectively, for UN, Cr, G, and TP (each, n = 15). We concluded that the KMS aliquots can be reliably used for kinetic and total clearance calculations without mixing and transporting large volumes of dialysate.

The discriminative stimulus properties of legal, over-the-counter stimulants administered singly and in binary and ternary combinations.

Ninety-six male Sprague-Dawley rats were trained in one of seven drug versus saline (SAL) discrimination (DD) tasks under a variable-ratio 5-15 schedule of food-motivated lever press responding. Three groups of rats (n = 12/group) were trained to discriminate between one of the legal over-the-counter (OTC) stimulants--caffeine (CAF), ephedrine (EPHED), phenylpropanolamine (PPA), and SAL. Three other groups (n = 12/group) were trained to discriminate between one of three binary stimulant combinations--CAF+EPHED, CAF+PPA, EPHED+PPA, and SAL. The seventh group of rats (n = 24) was trained to discriminate between SAL and a ternary combination of the OTC stimulants, CAF+EPHED+PPA. Generalization tests were conducted with each of the OTC stimulants and the controlled stimulants--amphetamine (AMPHET) and cocaine (COC). The data suggest: 1) there is cross-generalization between some OTC combinations and controlled stimulants; 2) full generalization between the OTC and controlled stimulants were demonstrated in rats trained to discriminate two of the binary stimulant combinations from SAL; 3) drug mixtures are not perceived as new entities distinct from their component elements; 4) training dose-ratio may influence the characteristics of mixture discriminations; 5) stimulus overshadowing may be a factor determining drug mixture cues, and 6) the DD properties of aggregate drug compounds may function within a euclidean metric space. We propose that some binary OTC stimulant combinations may effectively function as a methadone-like replacement therapy in cocaine dependence.

The discriminative stimulus properties of acute ethanol withdrawal (hangover) in rats.

Twenty male Sprague-Dawley rats were trained to discriminate pentylenetetrazole (PTZ, 15 mg/kg, intraperitoneally) from saline (SAL) under a drug discrimination procedure. Test sessions were conducted with 10 randomly selected subjects. Tests with various doses of PTZ resulted in a dose-dependent increase in the percentage of total session responses emitted on the PTZ-appropriate lever without a significant change in response rates across a wide range of test PTZ doses. Rats did not generalize the PTZ stimulus to ethanol (ETOH) up to ETOH test doses that completely suppressed responding. High acute ETOH doses (2, 3, and 4 g/kg) administered at various time points prior to discrimination test sessions engendered responding on the PTZ-appropriate level in a quantitative fashion, that was dose- and time-dependent. This acute ETOH delayed effect from these high doses replicates our previously published study using a Drug 1-Drug 2 discrimination task with Chlordiazepoxide and PTZ. More importantly, we suggest that the present behavioral assay may be a sensitive animal analogue of human "hangover" phenomena.