Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Discriminative stimulus effects of etorphine in rhesus monkeys

Two rhesus monkeys were trained to discriminate the IM injection of etorphine (0.001 mg/kg) from saline in a task in which 20 consecutive responses on one of two levers resulted in food delivery. In both monkeys, etorphine (0.0001–0.0018), meperidine (0.1–1.0 mg/kg), morphine (0.1–3.2 mg/kg), and codeine (0.3–3.2) produced dose-related increases in the percentage of total session responses that occurred on the etorphine-appropriate lever. In contrast, ethylketazocine, SKF-10047, and pentazocine, at doses up to and including those that suppressed response rates, produced responses primarily on the saline-appropriate lever. Thus, etorphine-like narcotics, including morphine, have discriminative stimulus effects in rhesus monkeys which can be distinguished from those produced by narcotics with nonmorphine-like actions such as ethylketazocine, SKF-10047, and pentazocine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46422/1/213_2004_Article_BF00431828.pd

Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon

Separate groups of pigeons were trained to discriminate the IM injection of ketamine, cyclazocine, or dextrorphan from saline. Each of the training drugs and phencyclidine produced dose-related, drug-appropriate responding in each group of birds. In contrast, ethylketazocine and nalorphine generally produced responding appropriate for saline. These results indicate that common elements of discriminable effects exist among ketamine, cyclazocine, and dextrorphan, structurally dissimilar compounds that are generally considered to belong to distinct pharmacological classes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46423/1/213_2004_Article_BF00422419.pd

Impact of computerized physician order entry (CPOE) system on the outcome of critically ill adult patients: a before-after study

<p>Abstract</p> <p>Background</p> <p>Computerized physician order entry (CPOE) systems are recommended to improve patient safety and outcomes. However, their effectiveness has been questioned. Our objective was to evaluate the impact of CPOE implementation on the outcome of critically ill patients.</p> <p>Methods</p> <p>This was an observational before-after study carried out in a 21-bed medical and surgical intensive care unit (ICU) of a tertiary care center. It included all patients admitted to the ICU in the 24 months pre- and 12 months post-CPOE (Misys^®) implementation. Data were extracted from a prospectively collected ICU database and included: demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, admission diagnosis and comorbid conditions. Outcomes compared in different pre- and post-CPOE periods included: ICU and hospital mortality, duration of mechanical ventilation, and ICU and hospital length of stay. These outcomes were also compared in selected high risk subgroups of patients (age 12-17 years, traumatic brain injury, admission diagnosis of sepsis and admission APACHE II > 23). Multivariate analysis was used to adjust for imbalances in baseline characteristics and selected clinically relevant variables.</p> <p>Results</p> <p>There were 1638 and 898 patients admitted to the ICU in the specified pre- and post-CPOE periods, respectively (age = 52 ± 22 vs. 52 ± 21 years, p = 0.74; APACHE II = 24 ± 9 vs. 24 ± 10, p = 0.83). During these periods, there were no differences in ICU (adjusted odds ratio (aOR) 0.98, 95% confidence interval [CI] 0.7-1.3) and in hospital mortality (aOR 1.00, 95% CI 0.8-1.3). CPOE implementation was associated with similar duration of mechanical ventilation and of stay in the ICU and hospital. There was no increased mortality or stay in the high risk subgroups after CPOE implementation.</p> <p>Conclusions</p> <p>The implementation of CPOE in an adult medical surgical ICU resulted in no improvement in patient outcomes in the immediate phase and up to 12 months after implementation.</p

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46416/1/213_2004_Article_BF00433247.pd

A Phase 1 Trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion

BackgroundThe selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.MethodsTwelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained.ResultsSelegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline.ConclusionNo pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions

Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals