Reinforcing and adverse observable effects of nicotine and minor tobacco alkaloids in squirrel monkeys.

The most prevalent psychoactive chemical in tobacco smoke is nicotine, which has been shown to maintain tobacco consumption as well as cause acute adverse effects at high doses, like nausea and emesis. Recent studies in laboratory animals have suggested that many non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may also contribute to tobacco's overall reinforcing and adverse effects. Here, we used intravenous (IV) self-administration (n = 3) and observation (n = 4) procedures in squirrel monkeys to, respectively, compare the reinforcing and adverse observable effects of nicotine and three prominent minor tobacco alkaloids, nornicotine, anatabine, and myosmine. In self-administration studies, male squirrel monkeys were trained to respond under a second-order fixed-interval schedule of reinforcement and dose-effects functions for nicotine and each of the minor tobacco alkaloids nornicotine, anatabine, and mysomine were determined. Observation studies were conducted in a different group of male squirrel monkeys to quantify the ability of nicotine, nornicotine, anatabine, and mysomine to produce adverse overt effects, including hypersalivation, emesis, and tremors. Results show that nicotine and to a lesser extent nornicotine were readily self-administered, whereas anatabine and myosmine were not. In observation studies, all minor tobacco alkaloids produced adverse observable effects that were either comparable or more pronounced than nicotine. Collectively, the present results showing that nicotine and the minor tobacco alkaloids nornicotine, anatabine, and myosmine produce differential reinforcing and acute adverse observable effects in monkeys provides further evidence that these constituents may differently contribute to the psychopharmacological and adverse effects of tobacco consumption.

Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201.

The synthetic forms of delta-9-tetrahydrocannabinol (Δ9-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ9-THC. Here, we utilized drug discrimination methods to compare the interoceptive effects of CB ligands that vary in potency, efficacy, and selectivity at the CB receptors, including two ligands, AM411 and AM4089, that show CB1 partial agonist-like actions in vitro. Male rats were trained to discriminate 0.1 mg/kg AM2201 from saline under a fixed-ratio (FR) 10 response schedule of food reinforcement. After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB1 antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB1 full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ9-THC), and non-cannabinoids (fentanyl, atropine) were compared. The CBs either fully (AM2201, CP-55,940, JWH-018, AM8936, Δ9-THC) or partially (AM411, AM4089) substituted for AM2201, whereas fentanyl and atropine did not produce AM2201-like effects. All CB drugs were more potent than Δ9-THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB1 but not CB2 receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ9-THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally mediated via CB1 receptors.

Investigation of monoclonal antibody CSX-1004 for fentanyl overdose.

The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, we present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Moreover, toxicokinetic evaluation in a repeat-dose rat study and human tissue cross-reactivity study reveals a favorable pharmacokinetic profile of CSX-1004 with no safety-related issues. Using a highly translational non-human primate (NHP) model of respiratory depression, we demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3-4 weeks. Furthermore, treatment with CSX-1004 produces up to a 15-fold potency reduction of fentanyl in NHP respiration, antinociception and operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose.

Pediatric neck abscesses caused by methicillin-resistant Staphylococcus aureus: a retrospective study of incidence and susceptibilities over time.

Since the early 2000s, studies have shown that the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections in the pediatric population has been increasing. Moreover, studies also have indicated a trend toward increased resistance to commonly used antibiotics over time. However, few studies have specifically focused on such trends in pediatric neck abscesses. We undertook a retrospective study of 109 patients to compare the incidence of pediatric neck abscesses caused by MRSA during two separate 5-year periods at Children's Hospital of New Orleans in an attempt to determine if the incidence was indeed increasing. We also analyzed differences in MRSA susceptibility to various antibiotics over the same two time periods-January 1997 through December 2001 (n = 22) and January 2002 through December 2006 (n = 87). We found a statistically significant increase in the incidence of MRSA between the first 5-year period and the second-from 25 to 70.3% (p = 0.0388). We did not find any significant difference in antibiotic susceptibility patterns between the two 5-year periods.

Common agents used to unblock blood clots within tympanostomy tubes: an ex vivo study and review of literature.

OBJECTIVES: To determine the efficacy of common solutions used to dissolve blood clots blocking tympanostomy tubes (TTs) of differing lengths and diameters. STUDY DESIGN: An ex vivo experimental study. METHODS: Ear models were built by the study investigator. Tympanostomy tubes were inserted into the models and blocked with blood clots. Test solutions were applied to the blood clots, and time for clearance was recorded via microscopic visual confirmation. RESULTS: Richards T-tube had higher odds of unclogging than collar button tubes (odds ratio: 2.37, 95% confidence intervals 1.02-5.54, p=0.042). Vinegar and 3% hydrogen peroxide were most effective for Richards T-tubes and collar button tubes, respectively. CONCLUSION: Common solutions (vinegar and hydrogen peroxide) were more effective than antibiotic drops in clearing blood clot blocking TTs.

Hydroxyapatite cement cranioplasty in translabyrinthine acoustic neuroma surgery-update.

OBJECTIVE: To update the outcome of hydroxyapatite cement cranioplasty in translabyrinthine acoustic neuroma (TLAN) surgery. PATIENTS: One hundred eight previously reported patients undergoing abdominal fat graft reconstruction versus hydroxyapatite cement cranioplasty with additional 4-year follow up. Ninety additional patients undergoing a uniform technique of hydroxyapatite cement cranioplasty after TLAN. INTERVENTION(S): After TLAN, strips of abdominal fat are placed through the dural opening and medial to the level of the mastoid antrum, filling the lateral mastoid cavity. MAIN OUTCOME MEASURE(S): Cerebrospinal fluid (CSF) leaks and wound complications. RESULTS: No additional CSF leaks or wound complications were identified in the patients included in the previous report. In the new series of 90 consecutive patients, there was one CSF leak. CONCLUSION: Hydroxyapatite cranioplasty is a reliable method to avoid CSF leaks after TLAN surgery.