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We have discovered mesoionic pyrido[1,2-a]pyrimidinones as a novel class of insecticides and identified compounds such as dicloromezotiaz for development. During optimization of this area, we also discovered that mesoionic pyrido[1,2-a]pyrimidinones containing 3-biaryl groups at the 3-position of the core ring possess potent biological activity against Lepidoptera species. In this chapter, we will present the discovery, preparation, and optimization of this class of compounds. Biological activity of representative analogs will also be presented.

The ryanodine receptor (RyR) is an intracellular calcium channel critical to the regulation of insect muscle contraction and the target site of diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide. To-date, diamides are the only known class of synthetic molecules with high potency against insect RyRs. Target-based screening of an informer library led to discovery of a novel class of RyR activators, pyrrole-2-carboxamides. Efforts to optimize receptor activity resulted in analogs with potency comparable to that of commercial diamides when tested against RyR of the fruit fly, Drosophila melanogaster. Surprisingly, testing of pyrrole-2-carboxamides in whole-insect screens showed poor insecticidal activity, which is partially attributed to differential selectivity among insect receptors and rapid detoxification. Among various lepidopteran species field resistance to diamide insecticides has been well documented and in many cases has been attributed to a single point mutation, G4946E, of the RyR gene. As with diamide insecticides, the G4946E mutation confers greatly reduced sensitivity to pyrrole-2-carboxamides. This, coupled with findings from radioligand binding studies, indicates a shared binding domain between anthranilic diamides and pyrrole-2-carboxamides.

BACKGROUND As the world population grows towards 9 billion by 2050, it is projected that food production will need to increase by 60%. A critical part of this growth includes the safe and effective use of insecticides to reduce the estimated 20–49% loss of global crop yields owing to pests. The development of new insecticides will help to sustain this protection and overcome insecticide resistance. RESULTS A novel class of mesoionic compounds has been discovered, with exceptional insecticidal activity on a range of Hemiptera and Lepidoptera. These compounds bind to the orthosteric site of the nicotinic acetylcholine receptor and result in a highly potent inhibitory action at the receptor with minimal agonism. The synthesis, biological activity, optimization and mode of action will be discussed. CONCLUSION Triflumezopyrim insect control will provide a powerful tool for control of hopper species in rice throughout Asia. Dicloromezotiaz can provide a useful control tool for lepidopteran pests, with an underexploited mode of action among these pests. © 2016 Society of Chemical Industry

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program that led to the identification of dicloromezotiaz as a potent insecticide to control a broad range of lepidoptera. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program which led to the discovery of triflumezopyrim as a highly potent insecticide controlling various hopper species. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.

Anthranilic diamides are an important commercial synthetic class of insecticides (IRAC Group 28) that bind to the ryanodine receptor with selective potency against insect versus mammalian forms of the receptor. The first commercialized diamide, chlorantraniliprole, has exceptional activity against lepidopteran pests. The second anthranilamide product, cyantraniliprole, has excellent cross-spectrum activity against a range of insect orders, including both lepidopteran and hemipteran pests. Here, a retrospective look is presented on the discovery of the class, along with chemistry highlights of the lead evolution to both products. © 2016 Society of Chemical Industry.

Cobaltosic oxide/nickel oxide (Co3O4/NiO) composite nanofibers were synthesized via an electrospinning technique and their electrocatalytic activities toward non-enzymatic glucose sensors were evaluated in detail. The Co3O4/NiO composite exhibited the homogeneously distributed nanofibers with high porosity, effective inter connectivity and an extended number of conducting channels with an average diameter of 160 nm. The diffraction patterns depicted the face centred cubic crystalline structure of Co3O4/NiO nanofibers and the purity of the composite nanofibers was further ensured by using FT-IR and UV-vis spectroscopic analyses. The electrocatalytic performances of prepared nanofibers toward the oxidation of glucose was determined by cyclic voltammetry and amperometry techniques and the experimental results showed that the Co3O4/NiO composite nanofibers exhibited a maximum electrooxidation toward glucose, owing to the synergistic effect of Co3O4 and NiO. The electrospun Co3O4/NiO nanofibers exhibited a detection limit of 0.17 μM, a wide linear range of 1 μM to 9.055 mM and a high sensitivity of 2477 μA mM−1 cm−2. The nanofibers have also exhibited favorable properties such as good selectivity, reproducibility, durability and real sample analysis, which ensured its potential applications in the clinical diagnosis of diabetes.

A series of quinoline and isoquinoline isoxazolines have been designed as pesticides for crop protection. Herein we reported the chemical synthesis, biological activity and structure–activity relationships. The isoquinoline derivative, such as 3i , is discovered as potent new class of isoxazoline insecticide which is competitive with commercial insecticide Indoxacarb .

Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide range of pests from multiple insect orders. Here we report on the chemistry, biology and structure-activity trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial development.

Isoxazoline insecticides have been shown to be potent blockers of insect GABA receptors with excellent activity on a broad pest range, including Lepidoptera and Hemiptera. Herein we report on the synthesis, biological activity and mode-of-action for a class of 4-heterocyclic aryl isoxazoline insecticides.

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure–activity relationship elucidation and biological activity evaluation are also presented.

Diamide insecticides have emerged as one of the most promising new classes of insecticide chemistry owing to their excellent insecticidal efficacy and high margins of mammalian safety. Chlorantraniliprole and flubendiamide, the first two insecticides from this class, demonstrate exceptional activity across a broad range of pests in the order Lepidoptera. This chemistry has been confirmed to control insects via activation of ryanodine receptors which leads to uncontrolled calcium release in muscle. The high levels of mammalian safety are attributed to a strong selectivity for insect over mammalian receptors.

A series of highly active fluorinated anthranilic diamide insecticides have been prepared and their biological activity assessed on two aphid species in the search for systemically active compounds that control Hemiptera. In addition, we have demonstrated a new synthesis of N-aryl 3-fluoropyrazoles.

Background: The Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) trial demonstrated that montelukast added to budesonide (MNT + BD) was as efficacious as double the dose of budesonide (dBD) in improving morning peak expiratory flow (AM PEF) in adult asthmatics. Recent studies have demonstrated that montelukast is also effective in treating daytime and nighttime allergic rhinitis (AR) symptoms in asthmatic patients. This analysis was designed to examine whether asthmatic patients with comorbid AR respond differently than patients without comorbid AR in terms of asthma control (lung function). Methods: There were 216 asthmatic patients in the MNT + BD group and 184 patients in the dBD group with AR. Treatment differences in the change from baseline in AM PEF were compared. Least square (LS) mean and 95% confidence interval (CI) were derived from an anova model adjusting for baseline and study site. Results: There was a 9.2% increase in AM PEF from baseline in the MNT + BD group compared with a 6% increase in the dBD group. The LS mean difference [(MNT + BD) ) dBD] was 14.2 l/min (P ¼ 0.028). Other secondary endpoints were similar between groups. Conclusion: In the subgroup of asthmatic patients with AR, a combined treatment approach that included montelukast and budesonide provided significantly greater efficacy in reducing airflow obstruction compared with doubling the dose of budesonide. These results support recommendations by the Allergic Rhinitis and its Impact on Asthma initiative that suggest a unified approach aimed at treating the airway inflammation common to both diseases is beneficial for the large proportion of asthmatics who also suffer from AR.

Development of insecticides with unique modes of action is necessary to combat widespread insecticide resistance. A new class of insecticides has been discovered, the anthranilic diamides, that provides exceptional control through action on a novel target, the ryanodine receptor. Anthranilic diamides potently activate this receptor, releasing stored calcium from the sarcoendoplasmic reticulum causing impaired regulation of muscle contraction. Expression of a recombinant Drosophila ryanodine receptor in a lepidopteran cell line confers sensitivity to anthranilic diamides similar to that observed with native receptors. Ligand-binding studies with radiolabeled ryanodine and radiolabeled anthranilic diamide in Periplaneta americana reveal a single, saturable binding site for this chemistry distinct from that of ryanodine. Further, calcium mobilization studies using mammalian cell lines indicate anthranilic diamides exhibit >500-fold differential selectivity toward insect, over mammalian, receptors. Consequently, anthranilic diamides offer a novel pharmacological tool for calcium signaling research in addition to a unique alternative to existing pest-management strategies.

Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure.To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR.Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients.Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P.001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P.01) and -0.15 (95% CI, -0.24 to -0.06; P.001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment.Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

A novel class of anthranilic diamides has been discovered with exceptional insecticidal activity on a range of Lepidoptera. These compounds have been found to exhibit their action by release of intracellular Ca2+ stores mediated by the ryanodine receptor. The discovery, synthesis, structure-activity, and biological results are presented.

Montelukast, a potent leukotriene receptor antagonist, is an effective therapy for symptoms of seasonal allergic rhinitis, a disease governed by patients' individual sensitivity and exposure to relevant allergens.To evaluate the relationship of montelukast treatment effect vs pollen exposure in studies conducted during 3 consecutive fall allergy seasons.A combined analysis of these multicenter, randomized, double-blind, parallel-group studies was performed; 1 of the 3 studies is presented for the first time in this article. After a placebo run-in period, 1,862 symptomatic patients were randomly assigned to receive either a 10-mg montelukast tablet (n = 929) or placebo (n = 933) once daily for 2 weeks. Pollen exposure was summarized by mean daily weed pollen count. The interaction between treatment effect and pollen exposure was evaluated on the primary efficacy endpoint and daytime nasal symptom score, as rated by patients; also evaluated was the influence of the timing of the 2-week treatment period relative to the peak of the weed pollen season.Montelukast significantly improved daytime nasal symptoms score and individual scores of congestion, rhinorrhea, itching, and sneezing compared with placebo. There was a significant interaction (P.043) between treatment effect and weed pollen exposure; a larger treatment effect was noted in patients exposed to higher pollen counts. An interaction between treatment effect and timing of treatment in relation to peak pollen season was suggested.Montelukast significantly improved daytime nasal symptoms score in patients with seasonal allergic rhinitis, and the effect was greater in patients exposed to higher pollen levels.

Summary Background Cysteinyl leukotrienes (CysLTs) are bioactive lipids that have been shown to contribute to allergic and inflammatory diseases. Eosinophils and mast cells have the capacity to produce large amounts of CysLTs after allergic or non-allergic stimulation. Molecular identification of both the synthetic and signalling proteins in the CysLT pathway allows the investigation of expression of the CysLT enzymes and receptors in active allergic rhinitis. Objective We examined the expression of the proteins involved in the synthesis of CysLTs and the cysteinyl leukotriene-1 (CysLT1) and cysteinyl leukotriene-2 (CysLT2) receptors in inflammatory cells from patients with active seasonal allergic rhinitis. Methods Nasal lavage samples were obtained from patients during active seasonal allergic rhinitis. Specific cellular immunocytochemical techniques were used to detect the cysteinyl leukotriene synthetic proteins, namely 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and leukotriene C4 synthase (LTC4S). In situ hybridization and immunocytochemical techniques were used to identify the mRNA and proteins for the CysLT1 and CysLT2 receptors. Results 5-LO, FLAP and LTC4S, and the CysLT1 and CysLT2 receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells. 5-LO, FLAP and the CysLT1 receptor, but not LTC4S or the CysLT2 receptor, were expressed in a subset of nasal neutrophils. Conclusions Our study demonstrates the presence of CysLT pathway proteins in key allergic and inflammatory cells from the upper airway of patients with active seasonal allergic rhinitis. Our expression data highlight the potential of CysLT-modifying agents to treat both upper and lower airway symptoms in patients suffering from allergic rhinitis and asthma.

Gadolinium (Gd) doped Bismuth ferrite (BFO) nanofibers (Bi1-xGdxFeO3 (x=0.0, 0.05, 0.10, 0.15 and 0.20)) were synthesized via electrospinning. Scanning Electron Microscope (SEM) analysis showed that the diameter of the nanofibers ranged from 150 to 250 nm. X-Ray Diffraction (XRD) analysis revealed a structural phase transition with varying 'x', the compositions with x≤0.10 have crystal structures with space group R3c, while the compositions with x > 0.10 have crystal structures with space group Pnma. Vibrating Sample Magnetometer (VSM) analysis exhibited the weak ferromagnetic nature of the BFO nanofibers. However an increase in the saturated magnetic moment with increase in Gd dopant concentration was observed. The Photoluminescence (PL) spectra of the Bi:1-x :x nanofibers show enhanced Near Band Emission (NBE) intensity at x=0.10 due to the passivation of oxygen vacancies by Gd doping. © 2015 Elsevier Ltd and Techna Group S.r.l. All rights reserved.

Summary Background Cysteinyl leukotrienes are important proinflammatory mediators believed to have a role in allergic rhinitis. Objective This multicentre, randomized, double-blind, placebo- and active-controlled trial evaluated the effectiveness and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, for treating patients with seasonal allergic rhinitis. Methods After a 3- to 5-day, single-blind placebo run-in period, 1302 male and female patients (aged 15–81 years) with active allergic rhinitis symptoms were randomly assigned to receive montelukast 10 mg (n = 348), loratadine 10 mg (n = 602), or placebo (n = 352) administered once daily at bedtime for 2 weeks during the spring allergy season. Results Mean patient characteristics and symptom scores at baseline were similar for the three treatment groups. The primary end-point, daytime nasal symptoms score (mean of nasal congestion, rhinorrhea, nasal pruritus, and sneezing scores; 0–3 scale), improved from baseline during treatment by (least squares mean, 95% confidence interval) − 0.37 (− 0.43, − 0.31), − 0.47 (− 0.52, − 0.43), and − 0.24 (− 0.29, − 0.18) in the montelukast, loratadine, and placebo groups, respectively (P ≤ 0.001 comparing each active treatment with placebo). Mean changes from baseline in all other diary-based scores, including night-time and eye symptom scores, were significantly greater for each active treatment than for placebo. The rhinoconjunctivitis quality of life overall score improved significantly with montelukast and with loratadine as compared with placebo. Montelukast and loratadine showed a safety profile comparable to that of placebo. Conclusion Montelukast is well tolerated and provides improvements in daytime and night-time symptoms, as well as quality of life parameters, for patients with seasonal allergic rhinitis.

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1–0.2 μg/ml to be effective against both fleas ( Ctenocephalides felis ) and ticks ( Dermacentor variabilis ). Pharmacokinetic profiles in dogs following a 2.5 mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5 mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

The evolution of the insecticidal pyrazoline moiety that was originally discovered in 1972 has led to the discovery of a new crop insecticide, indoxacarb, which is the first commercialized pyrazoline-type sodium-channel blocker. Both monocyclic and fused-tricyclic pyrazolines and pyridazines, as well as structurally related semicarbazones were examined prior to the discovery of analogous tricyclic oxadiazines which had similarly high activity as well as favorable environmental dissipation rates and low toxicity to non-target organisms. The eventual leading candidate, DPX-JW062, was originally obtained as a racemic molecule, but a chiral synthesis was developed which produces material that is 50% ee in the insecticidal (+)-S-enantiomer (DPX-MP062, indoxacarb).

Airway sensory nerves play a role in reactions to inhaled allergens, irritants, and physical stimuli. Capsaicin, the pungent principle of hot peppers, stimulates a subcategory of sensory nerves. To study the consequences of selective activation of airway sensory nerves in the human nose, we administered capsaicin nasal challenges to eight volunteers (four normal subjects and four subjects with perennial allergic rhinitis). Capsaicin (20 mumol/L), when sprayed into the nose, induced burning, rhinorrhea, and lacrimation. Capsaicin also induced a significant increase in total protein content of nasal lavage fluid after challenge compared with vehicle (increase from before challenge to 1 minute after challenge, 172 +/- 55 vs 46 +/- 29 micrograms/ml, p < 0.001). In contrast to many animal studies, capsaicin did not increase vascular permeability in the airway, because albumin content of nasal lavage fluid was not increased (p = 0.86). On the other hand, lactoferrin, a marker of glandular secretion, was increased (p < 0.005). Repetitive capsaicin challenge every 10 minutes led to tachyphylaxis of symptoms, total protein secretion, and lactoferrin secretion. Compared with vehicle, unilateral capsaicin (6 mmol/L) disk challenge induced significant secretion both ipsilateral (21.3 +/- 4.2 vs 4.9 +/- 2.1 mg, p < 0.01) and contralateral (18.2 +/- 4.4 vs 7.4 +/- 1.9 mg, p < 0.04) to challenge. Thus we have shown that capsaicin challenge to the human nose leads to airway sensory nerve activation. Further, we have demonstrated that capsaicin stimulates a predominantly central neuronal response and that the induced secretory response is of glandular rather than vascular origin.

Background Prostaglandin D 2 is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D 2 receptor type 1 (DP1) gene (PTGDR) have been suggested to be associated with asthma susceptibility. Objectives We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity. Methods For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV 1 . For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score. Results For asthma, no significant differences in FEV 1 or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P ≤ .001). No clear association was seen between haplotype pair (ie, diplotype) and asthma severity. For AR, although cetirizine (vs placebo) demonstrated an improvement in the Daytime Nasal Symptoms Score ( P Conclusion Laropiprant did not demonstrate efficacy in asthmatic patients or patients with AR. Variations in PTGDR did not appear related to baseline asthma severity or treatment response (NCT00533208; NCT00783601).

Rynaxypyr™ is a highly potent and selective activator of insect ryanodine receptors with exceptional activity on a broad range of Lepidoptera. A strong correlation between insecticidal activity and ryanodine receptor activation is observed along with selective activity against insect over mammalian receptors. The synthesis and biological results are presented.

ackground and objective: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls. Methods: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV1 following exercise (ΔFEV1). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 μg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum ΔFEV1 at 2 h postdose. Secondary end points included maximum ΔFEV1 at the two later time points, and other measures (including recovery time and need for β-agonist rescue) at all time points. Results: The maximum ΔFEV1 magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [± SE], 13.2 ± 1.2%, 11.7 ± 1.2%, and 10.0 ± 1.1% vs 21.8 ± 1.2%, 16.8 ± 1.3%, and 14.0 ± 1.1%, respectively; p ≤ 0.001, < 0.01, and < 0.05). All secondary end point results supported the primary end point. Montelukast and salmeterol had similar efficacy at 2 and 8.5 h, but only montelukast was effective at 24 h. Conclusion: Montelukast provided significant protection against EIB having an onset within 2 h following a single oral dose and lasting for at least 24 h.

Background Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing. Objective To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist. Methods In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (≥20% postexercise decrease in forced expiratory volume in 1 second [FEV 1 ]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV 1 from preexercise baseline during 60 minutes after the 2-hour challenge. Results At 2, 12, and 24 hours after dosing, the maximum decrease in FEV 1 was 10.8% ± 7.9%, 8.4% ± 7.5%, and 8.3% ± 7.3% for montelukast and 22.3% ± 13.1%, 16.1% ± 10.2%, and 16.9% ± 11.7% for placebo, respectively ( P ≤ .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo ( P ≤ .001); mean (95% confidence interval) differences were −26.8 minutes (−35.1 to −18.4 minutes), −16.0 minutes (−22.9 to −9.2 minutes), and −17.4 minutes (−24.9 to −9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV 1 during 60 minutes after exercise was smaller after montelukast ( P ≤ .001); montelukast protected more patients against EIB ( P ≤ .001). Fewer patients required postexercise β-agonist rescue at 2 hours after dosing with montelukast ( P = .03). Conclusion Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

The radiolabelling of isoxazoline insecticide 1a employing a Lindlar catalyst tritium dehalogenation of a bromo precursor is described. Copyright © 2009 John Wiley & Sons, Ltd.

We investigated whether hyperosmolar saline (HS), applied via paper disk onto the septum of one nostril, induces a nasal secretory response. Furthermore, we examined whether this response is accentuated in patients with active allergic rhinitis (AR) compared with healthy volunteers. Unilateral HS produced significant nasal secretions both ipsilateral and contralateral to the site of challenge in the AR group and only ipsilaterally in the healthy group. The HS-induced nasal secretions were significantly greater in the AR vs. the healthy subjects. In a separate study, we ascertained that the nasal response to HS is neurally mediated and found that ipsilateral nerve blockade with lidocaine significantly attenuates the HS-induced secretions bilaterally. In another group of AR subjects, we determined whether nociceptive fibers were involved in this response and found that sensory nerve desensitization with repeated application of capsaicin attenuated the HS-induced nasal secretions. Finally, we determined whether the secretory hyperresponsiveness in AR is attributable to increased reactivity of submucosal glands rather than of nerves. We found that the dose response to methacholine, which directly stimulates the glands, was identical among AR and healthy subjects. We conclude that, in AR, nasal challenge with HS induces significantly greater reflex secretions involving capsaicin-sensitive nerve fibers, consistent with the notion of neural hyperresponsiveness in this disease.

Capsaicin is a specific activator of sensory nerve endings. In rodents, mucosal application of capsaicin causes cells to infiltrate the tissue. To examine whether inflammatory-cell influx follows sensory-nerve activation in human airways, we delivered capsaicin (200 microM) nasal spray into the nares of 20 subjects (10 with allergic rhinitis and 10 normal), and measured the total leukocyte content of nasal lavage fluid obtained from 10 min to 4 h after the capsaicin challenge. Vehicle spray (1% EtOH in 0.9% saline) served as a control. Capsaicin challenge caused significant increases from prechallenge leukocyte counts at 10 min (p0.03), 30 min (p0.01), and 4 h (p0.03) after challenge, but not at 1 h after challenge (p = 0.68). Vehicle challenge did not increase leukocyte counts. Differential counts (performed on the 13 of 20 subjects from whom adequate specimens for differential counts were obtained) showed that neutrophils, eosinophils, and mononuclear cells increased at 10 min, 30 min, and 4 h (all p0.04), but not at 1 h after capsaicin challenge. Comparing the rhinitic to the normal subjects, we found no significant differences in the cellular response to capsaicin. These data support a nonspecific inflammatory effect of sensory nerve activation in the human nose. Consequently, this work provides evidence that neurogenic inflammation can be induced in the human airway in vivo.

An oxygen saturation sensor, for the purpose of chronically controlling the heart rhythm produced by a pacemaker, should be specific to oxygen saturation and should be minimally affected by the harsh blood environment. For the sensor type we tested we found: (1) one sensor failure in 205.5 canine-months of chronic implantation (n = 11, range 4 to 50 months); (2) hematocrit-induced error of less than 5 percentage points of SvO2 over the range of 50% to 80% SvO2 and 15% to 45% hematocrit; (3) carboxyhemoglobin (HbCO)-induced error of less than 4 percentage points of SvO2 with HbCO up to 20%; (4) a fibrotic sheath-induced error of less than 3 percentage points of SvO2 in the range of 50% to 80% SvO2 due to fibrotic sheath thicknesses up to 0.22 mm; (5) no significant error induced by velocity variations local to the sensor; (6) no significant error due to temperature in the range of 30 degrees to 42 degrees C; and (7) that the sensor could be as close as 0.3mm to the ventricular wall and still only produce an error of 5% SvO2.

Rabbit muscle glycogen phosphorylase b (1,4-α- d -glucan: orthophosphate α-glucosyltransferase, EC 2.4.1.1) was found to be inhibited by a wide variety of soluble aromatic compounds. The effectiveness of the inhibitors appeared to be controlled by steric factors and was not a function of the electron density of the benzene ring or charges per se on the aromatic molecules. In the presence of p -nitrophenol the glucose 1-phosphate sites became cooperative and the cooperativity of the AMP sites increased, showing that a compound structurally unrelated to the feed-back inhibitors could influence allosteric transitions. The existence of a specific site for aromatic compounds on phosphorylase is shown to explain the contradictory properties of chemically modified enzyme derivatives.

α-Glucan phosphorylase b (1,4-α- d -glucan:orthophosphate α-glucosyltransferase, EC 2.4.1.1) isolated and purified from a deep-sea fish, Indocibium guttattam (a variety of butter fish), showed lack of cooperativity between glucose 1-phosphate sites in the presence of allosteric inhibitors such as glucose, glucose 6-phosphate and ATP. These inhibitors exhibited competitive kinetics for glucose 1-phosphate. Cooperativity of AMP sites was not induced in the presence of glucose but slightly induced in the presence of glucose 6-phosphate. In all these respects this enzyme differs from phosphorylase from other sources. The results indicate that the allosteric properties of phosphorylase from all animal sources need conform to a general pattern.

The usual bargaining model used to analyze the interaction of foreign companies and developing countries is inadequate because its political assumptions are usually misleading and tend to abstract from a highly complex reality. The case of the International Petroleum Company in Peru is used to illustrate how political parties there were constrained by the presence of a large foreign firm to act in certain ways which could not have been predicted by a ‘rational’ model of bargaining.