Oxidative Syntheses of N,N-Dialkylhydroxylamines.

Despite the wide utility of hydroxylamines in organic synthesis, relatively few are commercially available, and there is a need for direct, efficient, and selective methods for their synthesis. Herein, we report two complementary methods to accomplish direct oxidation of secondary amines using UHP as an oxidant. The first method uses 2,2,2-trifluoroethanol (TFE) and a large excess of amine. Isolation of hydroxylamine products is enabled by selective salt formation, and recovery of excess amine is demonstrated. The second method uses hexafluoroacetone as an additive and is highlighted by the 1:1 stoichiometry between the oxidant and amine.

Synthesis of 1,2,4-Triazinones Exploiting the Reactivity of Diazadiene and N-Isocyanate Intermediates.

1,2,4-Triazinones are useful compounds, but their synthesis can be challenging. Herein, we report a strategy to build 1,2,4-triazinones using α-bromohydrazones to access diazadienes and exploiting their ability to undergo facile substitution with nitrogen nucleophiles. The N-isocyanate intermediate formed in situ can then undergo cyclization to give the desired triazinones. This provides access to products with various substituents at the 4-position, and with suitable hydrazone precursors (R2 = Ph), the cascade reaction yields 1,2,4-triazin-3(2H)-ones at room temperature.

Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model.

BACKGROUND: We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS. METHODS: Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 µg kg-1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg-1) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). RESULTS: Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco2 (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min-1; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg-1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg-1; ED90CNS: 86.1 mg kg-1), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. CONCLUSIONS: Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.

Development of Palladium-Catalyzed Decarboxylative Allylation of Electron-Deficient Sulfones and Identification of Unusual Side Products.

The use of sulfones as electron-withdrawing groups in substrates for palladium-catalyzed decarboxylative allylation was explored. A previously published trifluoromethanesulfonyl-based substrate was highly reactive and selective under mild conditions, but the substrate scope was not readily expanded. Instead, 3,5-bis(trifluoromethyl)phenyl sulfones were employed, thereby simultaneously retaining most of the electron deficiency and providing facile synthetic access. Optimization of the catalytic conditions to maximize the product distribution to a synthetically useful level of the allylation product over the protonation side product proved extremely challenging, with inconsistent and irreproducible results afforded with Pd2(dba)3 as the palladium source. A variety of substrates were subjected to the optimized catalytic conditions of PdCp(1-cinnamyl) and Xantphos in tetrahydrofuran at 50 °C for 30 min. These conditions were applicable to all substrates with the exception of the α,α-dimethyl allyl ester, which required more forcing conditions and afforded four products: the allylation and protonation products, as expected, along with a cyclopropylation product and an unprecedented pseudodimeric product. The mechanism for the formation of these unusual side products is considered.

Rapid strep testing in children with recently treated streptococcal pharyngitis.

IMPORTANCE: The use of the rapid antigen-detection test (RADT) has become the standard of care in the early diagnosis of group A beta-hemolytic Streptococcus (GAS) pharyngitis. Concern has been expressed over increased false positives when the child had been treated recently for GAS pharyngitis, resulting in over use of antibiotics. OBJECTIVE: To determine if the false positive rate for RADT is increased in children recently treated for GAS pharyngitis. METHODS: We conducted a prospective study to evaluate 300 children from a private practice with acute pharyngitis who were treated for GAS pharyngitis within the preceding 28 days (study group) compared to 306 children of comparable age who had not been previously treated (control group). RADT and throat culture were performed on all children presenting with signs and symptoms of acute pharyngitis. The false positive and false negative rates were determined and compared in both groups. RESULTS: The false positive rate of 11.5% (23/200) in the study group was significantly higher than the false positive rate of 0 in the control group. False positives were more likely to occur in younger children. INTERPRETATION: These data would indicate that while RADT is reliable in most children, it can lead to over treatment in children who have been recently treated for GAS. In children treated in the preceding 28 days for GAS pharyngitis, the presence of infection should be determined with a throat culture only. Treatment based on a positive RADT should be reserved for children not recently treated for GAS pharyngitis.

Primary care-based intervention to reduce at-risk drinking in older adults: a randomized controlled trial.

AIMS: To examine whether a multi-faceted intervention among older at-risk drinking primary care patients reduced at-risk drinking and alcohol consumption at 3 and 12 months. DESIGN: Randomized controlled trial. SETTING: Three primary care sites in southern California. PARTICIPANTS: Six hundred and thirty-one adults aged ≥ 55 years who were at-risk drinkers identified by the Comorbidity Alcohol Risk Evaluation Tool (CARET) were assigned randomly between October 2004 and April 2007 during an office visit to receive a booklet on healthy behaviors or an intervention including a personalized report, booklet on alcohol and aging, drinking diary, advice from the primary care provider and telephone counseling from a health educator at 2, 4 and 8 weeks. MEASUREMENTS: The primary outcome was the proportion of participants meeting at-risk criteria, and secondary outcomes were number of drinks in past 7 days, heavy drinking (four or more drinks in a day) in the past 7 days and risk score. FINDINGS: At 3 months, relative to controls, fewer intervention group participants were at-risk drinkers [odds ratio (OR) 0.41; 95% confidence interval (CI) 0.22-0.75]; they reported drinking fewer drinks in the past 7 days [rate ratio (RR) 0.79; 95% CI 0.70-0.90], less heavy drinking (OR 0.46; 95% CI 0.22-0.99) and had lower risk scores (RR 0.77 95% CI 0.63-0.94). At 12 months, only the difference in number of drinks remained statistically significant (RR 0.87; 95% CI 0.76-0.99). CONCLUSIONS: A multi-faceted intervention among older at-risk drinkers in primary care does not reduce the proportions of at-risk or heavy drinkers, but does reduce amount of drinking at 12 months.

Inhibitory role of Ser-425 of the alpha1 2.2 subunit in the enhancement of Cav 2.2 currents by phorbol-12-myristate, 13-acetate.

Voltage-gated calcium channels (Ca(v)) 2.2 currents are potentiated by phorbol-12-myristate, 13-acetate (PMA), whereas Ca(v) 2.3 currents are increased by both PMA and acetyl-beta-methylcholine (MCh). MCh-selective sites were identified in the alpha(1) 2.3 subunit, whereas the identified PMA sites responded to both PMA and MCh (Kamatchi, G. L., Franke, R., Lynch, C., III, and Sando, J. J. (2004) J. Biol. Chem. 279, 4102-4109; Fang, H., Franke, R., Patanavanich, S., Lalvani, A., Powell, N. K., Sando, J. J., and Kamatchi, G. L. (2005) J. Biol. Chem. 280, 23559-23565). The hypothesis that PMA sites in the alpha(1) 2.2 subunit are homologous to the PMA-responsive sites in alpha(1) 2.3 subunit was tested with Ser/Thr --> Ala mutations in the alpha(1) 2.2 subunit. WT alpha(1) 2.2 or mutants were expressed in Xenopus oocytes in combination with beta1b and alpha2/delta subunits. Inward current (I(Ba)) was recorded using Ba(2+) as the charge carrier. T422A, S1757A, S2108A, or S2132A decreased the PMA response. In contrast, S425A increased the response to PMA, and thus, it was considered an inhibitory site. Replacement of each of the identified stimulatory Ser/Thr sites with Asp increased the basal current and decreased the PMA-induced enhancement, consistent with regulation by phosphorylation at these sites. Multiple mutant combinations showed (i) greater inhibition than that caused by the single Ala mutations; (ii) that enhancement observed when Thr-422 and Ser-2108 are available may be inhibited by the presence of Ser-425; and (iii) that the combination of Thr-422, Ser-2108, and either Ser-1757 or Ser-2132 can provide a greater response to PMA when Ser-425 is replaced with Ala. The homologous sites in alpha(1) 2.2 and alpha(1) 2.3 subunits seem to be functionally different. The existence of an inhibitory phosphorylation site in the I-II linker seems to be unique to the alpha(1) 2.2 subunit.