Organocatalytic aldol approach for the protecting group-free asymmetric synthesis of (7R')-parabenzlactone, (-)-hinokinin, (-)-yatein, (-)-bursehernin, (-)-pluviatolide, (+)-isostegane and allied lignans.

A short and efficient catalytic asymmetric protection-free synthesis of dibenzylbutyrolactone lignans, such as (-)-hinokinin, (-)-yatein, (-)-bursehernin, (-)-pluviatolide, and their 7'-hydroxylignans - (7'R)-parabenzlactone, (7'R)-hydroxyyatein, (7'R)-hydroxybursehernin, and (7'R)-hydroxy pluviatolide, respectively, is described. The syntheses of (+)-isostegane and the formal synthesis of (-)-podophyllotoxin and bicubebins are also described. Organocatalytic aldol-reduction-lactonization and Pd/C-catalyzed hydrogenative debromination are two-pot sequential reactions for the enantioselective synthesis of hydroxybutyrolactone 13b with excellent diastereo- and enantioselectivity (dr 33 : 1 and >99% ee). The protecting group-free chemoselective α-alkylation of 13b directly led to 7'-hydroxydibenzylbutyrolactone lignans, followed by hydrogenative dehydroxylation, which led to their (deoxy) dibenzylbutyrolactone lignans, and the syntheses were completed in three to five steps from 6-bromopiperonal.

Efficacy, Safety, and Systemic Exposure of Once-Daily Indacaterol Acetate in Pediatric Asthma: A Randomized, Double-Blind, Controlled Dose-Finding Study.

BACKGROUND: Indacaterol acetate (IND), a long-acting ß2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma. METHODS: In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment. RESULTS: In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 µg group and 25% patients in IND 150 µg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile. CONCLUSIONS: Once-daily IND 75 µg and IND 150 µg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 µg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02892019; 08-Sep-2016).

Asymmetric total synthesis of (+)-propolisbenzofuran B.

The first asymmetric total synthesis of (+)-propolisbenzofuran B is accomplished in 11 steps with an overall yield of 11.9%. The key steps are tandem deacetylative Sonogashira coupling-annulation reaction to synthesize the 2-substituted benzofuran core, stereoselective syn-aldol reaction and Friedel-Crafts cyclization to install the desired stereocenters & third-ring, and Stille coupling for C-acetylation.

Stereochemistry of the Benzylidene γ-Butyrolactone Dictates the Reductive Heck Cyclization Mode in the Asymmetric Synthesis of Aryltetralin Lignans: A Detailed Experimental and Theoretical Study.

The reductive Heck cyclization of nonracemic benzylidene γ-butyrolactone is studied toward the asymmetric synthesis of aryltetralin lignans, where the stereochemistry of the benzylidene lactone is found to control the mode of cyclization. The Z-isomer undergoes mostly 6-endo-cyclization and provides the desired (-)-isopodophyllotoxin along with a minor amount of 5-exo-cyclized product, but the E-isomer goes through exclusively 5-exo-cyclization, leading to the undesired dihydroindenolactone compound instead of (-)-podophyllotoxin. The experimental results are well-supported by the DFT studies.

Efficacy and safety of inhaled once-daily low-dose indacaterol acetate/mometasone furoate in patients with inadequately controlled asthma: Phase III randomised QUARTZ study findings.

BACKGROUND: Global initiative for asthma (GINA) 2019 recommends adding a long-acting ß2-agonist (LABA) to an inhaled corticosteroid (ICS) as a maintenance controller therapy in patients with inadequately controlled asthma. Indacaterol acetate (IND, a LABA) in combination with mometasone furoate (MF, an ICS) is under development for the treatment of these patients. OBJECTIVE: This phase III QUARTZ was a multicentre, randomised, double-blind, double-dummy and parallel-group study to assess the efficacy and safety of low-dose IND/MF 150/80 µg once daily (o.d.) versus MF 200 µg o.d. in adult and adolescent patients with inadequately controlled asthma. METHODS: Eligible patients (n = 802) were randomised (1:1) to receive either low-dose IND/MF 150/80 µg o.d. via Breezhaler® or MF 200 µg o.d. via Twisthaler® for 12 weeks. Primary endpoint was trough forced expiratory volume in 1 s (FEV1) and key secondary endpoint was Asthma Control Questionnaire (ACQ-7) treatment difference after 12-week treatment. Other secondary endpoints included ACQ-7 responder analysis, morning and evening peak expiratory flow, Asthma Quality of Life Questionnaire total score, rescue medication use, daily symptom score, nighttime awakenings and rate of exacerbations, evaluated over 12-week treatment. Safety was also assessed including serious asthma outcomes. RESULTS: Low-dose IND/MF significantly improved trough FEV1 (least squares mean treatment difference [LSMTD]: 0.182 L; p < 0.001) and ACQ-7 (LSMTD: -0.218; p < 0.001) versus MF at Week 12. Improvements in all other secondary endpoints favoured low-dose IND/MF. Safety was comparable. CONCLUSION: These results support the use of low-dose IND/MF 150/80 µg o.d. as a potential therapy for adult and adolescent patients with inadequately controlled asthma.

Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies.

PURPOSE: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 µg and once-daily UMEC/VI 62.5/25 µg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

Disseminated Emmonsia pasteuriana infection in India: a case report and a review.

We report here the first case of disseminated Emmonsia pasteuriana infection in a patient with AIDS in India. The patient presented with weight loss, dyspnoea, left-sided chest pain and multiple non-tender skin lesions over face and body for 3 months. Disseminated emmonsiosis was diagnosed on microscopic examination and fungal culture of skin biopsy and needle aspirate of lung consolidation. It was confirmed by sequencing internal transcribed spacer region of rDNA, beta tubulin, actin, and intein PRP8. The patient responded to amphotericin B and itraconazole therapy.