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Study Objective To provide estimates of the costs and health outcomes implications of the excess risk of unexpected disposition for nurse anesthetist (NA) procedures. Design A projection model was used to apply estimates of costs and health outcomes associated with the excess risk of unexpected disposition for NAs reported in a recent study. Setting Ambulatory and inpatient surgery. Patients Base-case model parameters were based on estimates taken from peer-reviewed publications when available, or from other sources including data for all hospital stays in the United States in 2013 from the Healthcare Cost and Utilization Project Web site. The impact of parameter uncertainty was assessed using 1-way and 2-way sensitivity analyses. Interventions Not applicable. Measurements Major complication rates, relative risks of complications, anesthesia costs, costs of complications, and cost-effectiveness ratios. Main Results In the base-case model, there were on average 2.3 fewer unexpected dispositions for physician anesthesiologists compared with NAs. Overall, anesthesia-related costs (including the cost of managing unexpected dispositions) were estimated to be about $31 higher per procedure for physician anesthesiologists compared with NAs. Alternative model scenarios in the sensitivity analysis produced estimates of smaller additional costs associated with physician anesthesia administration, to the point of cost savings in some scenarios. Conclusions Provision of anesthesia for ambulatory knee and shoulder procedures by physician anesthesiologists results in better health outcomes, at a reasonable additional cost, compared with procedures with NA-administered anesthesia, at least when using updated cost-effectiveness willingness-to-pay benchmarks.

Study objective The perioperative surgical home (PSH) is a recent innovation in perioperative care delivery that coordinates the pre-, intra-, and post-operative elements of surgical care under one organizational umbrella. Although significant research supports the efficacy of individual elements of the PSH in improving outcomes, there is not a published systematic review of the efficacy of entire PSH programs in improving patient outcomes. This article summarizes descriptions of PSH programs available in the literature and examines outcomes of original studies of PSH implementation. Design We conducted a systematic literature review to identify relevant articles on PSH implementation and synthesize our findings. Setting The studies included in our review took place at multiple academic and community hospitals in the United States. Patients Patients involved in the PSH studies included surgical patients of various ages and ASA classifications in various surgical specialties. Interventions All studies included in our review involved the implementation of a PSH program. Measurements Outcomes examined include length of stay, postoperative recovery, readmission rates, and patient discharge destination, among others. Main results We identified 11 studies of PSH implementation that met our inclusion and exclusion criteria. Most PSH programs described in these studies included an emphasis on preoperative education, standardization of care protocols in all phases of surgery, use of opioid-sparing multimodal analgesia, and collaborative staffing models. PSH program implementation was often associated with decreased length of stay, decreased utilization of postoperative opioids, decreased utilization of the ICU, and increased probability of discharge to home. PSH implementation was not meaningfully associated with reductions in readmission rates. Findings for cost reductions following PSH implementation were mixed. Conclusions Early evidence indicates that through elements that emphasize care coordination, standardization, and patient-centeredness, PSH programs can improve patient postoperative recovery outcomes and decrease hospital utilization.

Background: Medicaid Personal Care Services (PCS) help families meet children’s needs for assistance with functional tasks. However, PCS may have other effects on a child’s well-being, but research has not yet established the existence of such effects. Objectives: To investigate the relationship between the number of PCS hours a child receives with subsequent visits to physicians for evaluation and management (E&M) services. Methods: Assessment data for 2058 CSHCN receiving PCS were collected in 2008 and 2009. Assessment data were matched with Medicaid claims data for the period of 1 year after the assessment. Zero-inflated negative binomial and generalized linear multivariate regression models were used in the analyses. These models included patient demographics, health status, household resources, and use of other medical services. Results: For every 10 additional PCS hours authorized for a child, the odds of having an E&M physician visit in the next year were reduced by 25%. However, the number of PCS hours did not have a significant effect on the number of visits by those children who did have a subsequent E&M visit. A variety of demographic and health status measures also affect physician use. Conclusions: Medicaid PCS for CSHCN may be associated with reduced physician usage because of benefits realized by continuity of care, the early identification of potential health threats, or family and patient education. PCS services may contribute to a child’s well-being by providing continuous relationships with the care team that promote good chronic disease management, education, and support for the

The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.

Three novel heterocyclic benzofurans A-688057 ( 1 ), A-687136 ( 2 ), and A-698418 ( 3 ) were profiled for their in vitro and in vivo properties as a new series of histamine H 3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H 3 receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2–19 nM, possessed other favorable features, including high selectivity for H 3 receptors (H 3 , K i = 1.5 nM) versus off-target receptors and channels (including the hERG K + channel, K i > 9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD pH7.4 = 2.05), and good CNS penetration (blood/brain 3.4×). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP 450 inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration ( t 1/2 in rat of 2.9 h, 1.7 h in dog, 1.8 h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.

Further SAR studies on novel histamine H(3) receptor antagonists are presented. Compound 14bb is a potent antagonist of both the rat cortical and human clone receptors, and is demonstrated to act functionally as an antagonist in an in vivo mouse dipsogenia model.

SAR studies for novel non-imidazole containing H 3 receptor antagonists with high potency and selectivity for rat H 3 receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.

The selective H(3) receptor agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]imidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model. Water intake increased over baseline in a dose-related manner following intraperitoneal administration of 80, 160 or 240 micromol/kg (R)-alpha-MeHA, but this effect was dependent on age (P30P60P80=P120). [3H]-N-alpha-methylhistamine binding studies showed no change in H(3) receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 micromol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 micromol/kg), thioperamide (0.01-10 micromol/kg), clobenpropit (0.1-30 micromol/kg) and GT-2331 (0.03-10 micromol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 micromol/kg) only partially attenuated drinking elicited by (R)-alpha-MeHA: coadministration of proxyfan and ciproxifan resulted in an attenuation of ciproxifan's effects. This new dipsogenia model provides the first in vivo behavioral evidence for possible pharmacological differences between three putative H(3) receptor inverse agonists, GT-2331 and proxyfan.

ATP-sensitive K+ (K(ATP)) channels in the human medulloblastoma TE671 cell line were characterized by membrane potential assays utilizing a potentiometric fluorescent probe, bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)), and by mRNA analysis. Membrane potential assays showed concentration-dependent and glyburide-sensitive changes in fluorescence upon addition of (-)-cromakalim, pinacidil, diazoxide and P1075. The rank order of potency for these openers was P1075 > (-)-cromakalim approximately = pinacidil > diazoxide. Additionally, glyburide and glipizide inhibited P1075-evoked responses in TE671 cells with half-maximal inhibitory concentrations of 0.22 and 14 microM, respectively. The rank order potencies of both openers and inhibitors were similar to those observed in the rat smooth muscle A-10 cell line. In contrast, in the rat pancreatic insulinoma RIN-m5F cell line, only diazoxide was effective as an opener. Reverse transcription-polymerase chain reaction (RT-PCR) studies detected sulfonylurea receptors SUR2B and SUR1 mRNA in TE671 cells whereas only SUR2B and SUR1 mRNA were, respectively, detected in A-10 and RIN-m5F cells. The inward rectifier Kir6.2 mRNA was detected in all three cell types whereas Kir6.1 was detected only in A-10 cells. Collectively, the molecular and pharmacologic studies suggest that K(ATP) channels endogenously expressed in TE671 medulloblastoma resemble those present in the smooth muscle.

The development of a novel series of carbamoylamino acid benzoylpiperidides as CCK B ligands is described. Selected members of the series antagonized CCK 8 -induced calcium mobilization and showed efficacy in the mouse elevated-plus maze, a measure of potential anxiolytic activity.

New and existing methodologies were used to prepare a series of modified CCK analogs in which each amide bond was replaced by a trans-alkene unit. The data indicate that every amide linkage at C-terminal tetrapeptide (CCK-4) region is crucial for biological activity. While the amide bond beyond the Trp residue in the N-terminal direction can be replaced by a trans-alkene and still retain most of the binding potency and functional activity.

The backbone amide bonds in two series of tetrapeptide-based CCK-A receptor agonists were systematically replaced with the methylene amino isostere. Potent and selective pseudopeptides were identified that will facilitate our understanding of how these peptides interact with the CCK receptor and their structural correlations with other CCK ligands. This information will aid in the eventual development of peptidomimetics.

The disposition kinetics of cyclohexanone, a commonly used industrial solvent, was studied in beagle dogs following intravenous administration of a 284 mg/kg dose at various rates for 18 or 21 days. The major metabolite of cyclohexanone was identified as cyclohexanol. Plasma and urine concentrations of the compound and the metabolite were determined using a newly developed gas chromatographic procedure. A two-compartment open model was used to analyze plasma concentration-time data of cyclohexanone. The distribution half-life, biological half-life, and clearance values for cyclohexanone were 6.6 ± 3.6 min, 81.0 ± 22.5 min, and 27.4 ± 4.3 ml/kg/min, respectively. Between 74 and 100% of the administered dose of cyclohexanone was converted to cyclohexanol and approximately 60% of the dose was excreted in the urine as the glucuronide conjugate of cyclohexanol. Peak cyclohexanol concentrations in plasma following intravenous bolus administrations of 284 mg/kg of cyclohexanone ranged from 140 to 220 μg/ml and occurred between 5 and 30 min after cyclohexanone administration. Apparent plasma elimination half-life of the metabolite was 99 min. Urinary excretion data suggested that less than 1% of the dose was excreted as cyclohexanol and cyclohexanone. Under the dosage schedule employed in the present study, there was neither any accumulation of cyclohexanone nor any evidence of enzyme induction on repeated administrations. The data gathered in the present investigation are useftul in calculations of cyclohexanone peak or steady-state levels during comparative toxicological studies involving different dosage regimens.

The importance of concentration and rate of intravenous administration in affecting the toxicity of cyclohexanone was investigated. Four groups (I–IV) comprised of three male dogs each received a dosage of 284 mg/kg/day for 18–21 days as follows: 6% ( v v ) solution at 75 (I) or 5 ml/min (II); or 0.75% solution at 75 (III) or 5 ml/min (IV). Signs of toxicity observed included vocalization, lacrimation, scleral vasodilation, mydriasis, salivation, urination, defecation, restlessness, stupor, ataxia, occasional convulsive movements, hyperpnea, and/or dyspnea. Also, regimen I produced a metabolic acidosis with an apparent respiratory component. The severity of the responses correlated well to the maximal plasma concentrations of cyclohexanone attained, which ranged from 80 to 320 μg/ml, and to the conditions of administration as follows: I > II > III > IV. This distinction became even more apparent with repeated administrations and affected the prognosis for recovery. The concentration of cyclohexanone given was more critical than the rate of injection in producing localized tissue inflammation at injection sites, hemolysis, and secondary responses, e.g., bone marrow hyperplasia and extramedullary hematopoiesis. The rate of administration was also important since, at either concentration of cyclohexanone employed, the group receiving the compound at a faster rate had a greater response. Thus, the influence of iv administration factors on cyclohexanone toxicity was great, showing the importance of taking such factors into account in any safety evaluation study.