Switchable Oxidative Reactions of N-allyl-2-Aminophenols: Palladium-Catalyzed Alkoxyacyloxylation vs an Intramolecular Diels-Alder Reaction.

The Pd(II)-catalyzed reaction of N-allyl-2-aminophenols in the presence of PhI(OCOR)2 as the oxidant resulted in an alkoxyacyloxylation process, with the formation of functionalized dihydro-1,4-benzoxazines. The reaction performed in the absence of palladium catalyst switched to an intramolecular Diels-Alder reaction (IMDA) pathway, which was the result of an oxidative dearomatization of the 2-aminophenol, nucleophilic addition, and Diels-Alder reaction cascade, highlighting the role of the oxidant as both a nucleophilic donor and an oxidizing agent.

Syntheses of Thailandepsin†B Pseudo-Natural Products: Access to New Highly Potent HDAC Inhibitors via Late-Stage Modification.

New Thailandepsin B pseudo-natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium-catalyzed hydrooxycarbonylation. The newly developed pseudo-natural products are extremely potent and selective HDAC inhibitors. The non-proteinogenic amino acid d-norleucine was obtained enantioselectively by a recently developed method of rhodium-catalyzed hydroamination.

Real-life inhaler adherence and technique: Time to get smarter!

Smart inhalers, connected to smartphones, can provide real-life objective information about the patterns of a patient's adherence and their inhaler technique during routine use. The e-modules contain the battery and measuring sensors. Many of these are add-on modules attached externally whilst others are integrated inside the inhaler. Smart inhalers that identify a dose has either been actuated or prepared do not confirm the dose was inhaled but they can send missed dose reminders and clinical studies have highlighted their potential to improve adherence and outcomes. The e-modules that measure an inhalation profile confirm a dose has been inhaled together with providing useful information about the inhaler technique. Studies confirm that the sensors are accurate and confirm their usefulness to provide information about real-life inhaler use. Add-on e-modules are generic whereas integrated smart inhalers can be approved containing active agents and, therefore, prescribed and instructed under healthcare guidance. Real-life studies need to be carried out to demonstrate their potential to improve disease control and prevent exacerbations to justifying their increased cost.

Synthesis of Modified Nucleoside Oligophosphates Simplified: Fast, Pure, and Protecting Group Free.

Phosphoramidite analogues of modified cyclotriphosphates provide a general and step-economical synthesis of nucleoside triphosphates and analogues on scale without the need for protecting groups. These reagents enable rapid access to pure nucleoside oligophosphates and a range of other analogues that were previously difficult to obtain (e.g., NH, CH2, CCl2, and CF2 replacements for O, phosphono- and phosphoimidazolides, -morpholidates, -azidates, and -fluoridates). DFT calculations demonstrate that the selectivity of the cyclotriphosphate opening reactions proceeds via an in-line substitution mechanism that displaces the least charged leaving group.

A Phosphoramidite Analogue of Cyclotriphosphate Enables Iterative Polyphosphorylations.

An iterative polyphosphorylation approach is described, which is based on a phosphoramidite (P-amidite) derived reagent (c-PyPA) obtained from the cyclization of pyrophosphate with a reactive diisopropylaminodichlorophosphine. This type of reagent is unprecedented as it represents a reactive P-amidite without protecting groups. The reagent proved to be stable in solution over several weeks. Its utility is described in the context of iterative monodirectional and bidirectional polyphosphorylations. The ensuing functionalized cyclotriphosphate can be opened with a variety of nucleophiles providing ready access to diverse functionalized polyphosphate chains of defined length with several tags, including both P-N and P-O labels. Their interaction with exo- and endopolyphosphatases is described.

Gallium Complexation, Stability, and Bioconjugation of 1,4,7-Triazacyclononane Derived Chelators with Azaheterocyclic Arms.

We have recently introduced a 1,4,7-triazacyclononane (TACN) based chelating system with additional five-membered azaheterocyclic substituents for complexation of radioactive Cu2+ ions. In this work, we investigated the complexation properties of these novel chelators with Ga3+. In labeling experiments, we could show that the penta- and hexadentate imidazole derivatives NODIA-Me 4 and NOTI-Me 1 can be labeled with 68Ga in specific activities up to ∼30 MBq nmol-1, while the corresponding thiazole derivative NOTThia 2 did not label satisfactorily under identical conditions. NMR studies on the Ga complexes of 1 and the model compound NODIA-Me-NH-Me 5 revealed formation of rigid 1:1 chelates with a slow macrocyclic interconversion and inert Ga-N bonds to the methylimidazole residues on the NMR time scale. The TACN-derived bifunctional chelator NODIA-Me was furthermore conjugated to a prostate-specific membrane antigen (PSMA) targeting moiety to give the corresponding bioconjugate NODIA-Me-PSMA 7. Serum stability and ligand challenge experiments of 68Ga-7 confirmed formation of a stable complex for up to 4 h. The remaining coordination site of five-coordinate Ga complexes was found to be occupied by monodentate ligands including hydroxide and chloride anions depending on the conditions. According to density functional theory calculations, coordination of monodentate ligands as well as of the amide group for the bioconjugated ligand are energetically plausible. Finally, the labeled bioconjugate 68Ga-7 exhibited rapid renal clearance in biodistribution studies performed by small animal PET imaging with no indication of transchelation/demetalation in vivo. Altogether, our results provide strong evidence for a stable Ga complexation of our novel TACN-based chelators bearing imidazole arms. Despite the formation of two complexes incorporating different monodentate ligands in vitro, the imidazole type ligands show promise as chelating agents for the future development of gallium based radiopharmaceuticals.

Direct conjugate alkylation of α,ß-unsaturated carbonyls by Ti(III)-catalysed reductive umpolung of simple activated alkenes.

The titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate ß-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.

The effects of theophylline on hospital admissions and exacerbations in COPD patients: audit data from the Bavarian disease management program.

BACKGROUND: Theophylline is often used to treat chronic obstructive pulmonary disease (COPD). Current evidence leaves the effectiveness and safety of this drug open to question. Thus, we evaluated the effectiveness of theophylline on the rate of hospitalizations and disease exacerbations by examining routine data from the ambulatory disease management program for COPD in the German state of Bavaria. METHOD: Data sets from a total of 30 330 patients were examined. Logistic regression models were used to calculate propensity scores that controlled for baseline characteristics. These propensity scores, in turn, were used to create comparable patient groups, which were observed for a median follow-up time of 9 quarters (the theophylline group) and 10 quarters (the control group). RESULTS: 1496 patients with first prescription of theophylline were matched with 1496 patients with no record of theophylline treatment. 1. The probability of suffering an exacerbation during the period of observation, was 33.5% for the control group and 43.4% for the theophylline group [hazard ratio (HR) 1.41; 95% confidence interval (CI) 1.24 to 1.60], yielding a number needed to harm (NNH) of 11 (95% CI 7.7 to 20.9). The probability for hospitalization was 11.4% for the control group and 17.4% of the theophylline group (HR 1.61; 95% CI 1.29 to 2.01), yielding a NNH of 17 (95%CI 11.0-34.5). CONCLUSION: Treatment with theophylline is associated with an elevated incidence of exacerbations and hospitalizations. The therapeutic value of this drug should be reconsidered and investigated in further studies.

A pharmacokinetics and safety comparison of a highly concentrated tobramycin solution with TOBI.

BACKGROUND: Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. METHODS: In a randomized, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow(®) nebulizer and TOBI(®) (300 mg/5 mL) nebulized with a PARI LC PLUS(®) nebulizer in 78 CF patients. RESULTS: Noninferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulization time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination. CONCLUSION: Inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics.

Disease management programs for patients with asthma in Germany: a longitudinal population-based study.

BACKGROUND: The primary aim of the disease management program (DMP) for patients with asthma is to improve health outcomes and to reduce costs. Five years after its introduction in Germany, no consensus has yet been reached as to whether DMP has been effective in reaching these goals. OBJECTIVE: To evaluate the DMP for asthma in Bavaria using routinely collected subject medical records. METHODS: A longitudinal population-based study encompassing over 100,000 DMP participants between 2006 (when the program began) and 2010. RESULTS: The prescription rate of oral corticosteroids dropped from 15.7% in 2006 to 13.6% in 2007, and again from 7.5% in 2008 to 5.9% in 2010 (P < .001). The proportion of subjects with asthma self-management education increased from 4.4% to 23.4% (P < .001). Utilization of an individual asthma action plan increased from 40.3% to 69.3% (P < .001). Hospitalization decreased from 2.8% to 0.7% (P < .001). CONCLUSIONS: In the first 4 years of DMP there was an improvement in pharmacotherapy and patient self management. The proportion of subjects requiring hospitalization decreased. Our results suggest that the German DMP for asthma has been effective in enhancing the quality of care in regard to an improved symptom frequency, adherence to guidelines, pharmacotherapy, and hospitalization.

Mechanistic insights into a supramolecular self-assembling catalyst system: evidence for hydrogen bonding during rhodium-catalyzed hydroformylation.

The structural integrity and flexibility provided by intermolecular hydrogen bonds leads to the outstanding properties of the 6-diphenylphosphinopyridin-(2H)-1-one ligand (see scheme) in the rhodium-catalyzed hydroformylation of terminal alkenes, as demonstrated by the combination of spectroscopic methods and DFT computations. Hydrogen bonds were also detected in a competent intermediate of the catalytic cycle.

Higher tobramycin concentration and vibrating mesh technology can shorten antibiotic treatment time in cystic fibrosis.

Poor adherence to recommended therapy in cystic fibrosis (CF) is often because of the time demands of therapy. Tobramycin (TOBI®, 300 mg at 60 mg/ml) inhaled from the PARI LC PLUS® nebulizer requires about 20 min. This study determined if equivalent levels of pulmonary deposition could be achieved in shorter time using 1.5 ml of 100 mg/ml tobramycin solution delivered by an investigational eFlow® nebulizer. Sixteen males with stable CF, 8 children and 8 adults, and an FEV(1) > 45% predicted inhaled both preparations on two occasions with (99m) Tc-DTPA added to the tobramycin. Blood samples were taken for quantification of tobramycin in the serum. The PARI LC PLUS® delivered 45.4 (39.3-51.6), mean and 95% CI, mg to the lungs in 17.0 ± 2.5 min (mean ± SD) with serum levels of 1,089 ± 388 µg/L. The investigational eFlow® delivered 46.3(40.3-51.7) mg in 4.0 ± 1.0 min with blood levels of 909 ± 458 µg/L. Only the time of delivery was significantly different with P < 0.0001 (paired t-test). Tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients. These results demonstrate the possibility of delivering equivalent levels of tobramycin much faster into the lungs of CF patients when using eFlow®, a very efficient electronic nebulizer.

A technical feasibility study of dornase alfa delivery with eFlow® vibrating membrane nebulizers: aerosol characteristics and physicochemical stability.

Dornase alfa (Pulmozyme®) is an inhaled mucus-active drug that decreases viscoelasticity of sputum in vitro, improves lung function and reduces respiratory exacerbations in cystic fibrosis (CF) patients of 5 years age and older. The regulatory approval of dornase alfa 15 years ago stipulated that only certain jet nebulizer-compressor combinations should be used to deliver the drug. Since that time there have been significant advances in aerosol delivery technology, including development of electronic perforated vibrating membrane devices. Three independent laboratories studied aerosol characteristics, nebulization time, dose delivery, and stability of dornase alfa after nebulization to determine the feasibility of using perforated vibrating membrane devices to deliver the drug. These studies determined that the eFlow® vibrating membrane technology delivers dornase alfa more rapidly and efficiently than jet nebulizers, and does not affect the physicochemical properties of the drug. These in vitro results demonstrate only the technical feasibility of using vibrating membrane devices to deliver dornase alfa. Clinical studies will be required before any conclusions can be made regarding clinical safety and efficacy of these drug-device combinations for cystic fibrosis.

Have inadequate delivery systems hampered the clinical success of inhaled disodium cromoglycate? Time for reconsideration.

IMPORTANCE OF THE FIELD: Disodium cromoglycate (DSCG) fits with the perception of a safe drug, but conclusions from questionable meta-analyses reduced its use. In addition, drug delivery aspects, such as hygroscopicity and the poor performance of delivery systems, were not considered to be important determinants of therapeutic failures. AREAS COVERED IN THIS REVIEW: Drug delivery aspects and parameters affecting lung deposition and distribution, important parameters for therapeutic efficacy, are addressed. In addition, the distribution and ratio of mast cell tryptase and chymase-positive phenotypes in the lungs and their role in the prostaglandin and leukotriene pathway are discussed. WHAT THE READER WILL GAIN: Information on why in vitro data are an excellent tool to understand better therapeutic failures associated with the moisture sensitivity of DSCG and the difficulty in handling and operating DSCG delivery systems in a therapeutically reliable way. TAKE HOME MESSAGE: Pharmacological efficacy of DSCG has been demonstrated in animals and humans. If the drug is delivered to the site of inflammation in an effective dose, a reliable therapeutic effect can be expected. DSCG has extra properties and potential unspecific antiviral properties and may offer new therapeutic treatment aspects for asthma and viral-induced bronchiolitis in early childhood.

Ligand self-assembling through complementary hydrogen-bonding in the coordination sphere of a transition metal center: the 6-diphenylphosphanylpyridin-2(1H)-one system.

Motivated by previous findings which had shown that transition metal catalysts based on the 6-diphenylphosphanylpyridone ligand (6-DPPon, 2) display properties as a self-assembling bidentate ligand-metal complex, we have performed a thorough study on the bonding situation of this ligand, alone and in the coordination sphere of a late transition metal. Thus, combining a number of spectroscopic methods (UV-vis, IR, NMR, X-ray), we gained insights into the unique structural characteristics of 2. These experimental studies were corroborated by DFT calculations, which were in all cases in good agreement with the experimental results. The free ligand 2 prefers to exist as the pyridone tautomer 2A and dimerizes to the pyridone-pyridone dimer 4A in solution as well as in the crystal state. The corresponding hydroxypyridine tautomer 2B is energetically slightly disfavored (ca. 0.9 kcal/mol within the up-conformer relevant for metal coordination); hence, hydrogen bond formation within the complex may easily compensate this small energy penalty. Coordination properties of 2 were studied in the coordination sphere of a platinum(II) center. As a model complex, [Cl(2)Pt(6-DPPon)(2)] (11) was prepared and investigated. All experimental and theoretical methods used prove the existence of a hydrogen-bonding interligand network in solution as well as in the crystal state of 11 between one 6-DPPon ligand existing as the pyridone tautomer 2A and the other ligand occupying the complementary hydroxypyridine form 2B. Dynamic proton NMR allowed to determine the barrier for interligand hydrogen bond breaking and, in combination with theory, enabled us to determine the enthalpic stabilization through hydrogen-bonding to contribute 14-15 kcal/mol.

Pulsating aerosols for drug delivery to the sinuses in healthy volunteers.

OBJECTIVE: Approximately 10 to 15 percent of the European and U.S. population have chronic rhinosinusitis, but effective treatment remains a challenge. There has been limited success using topical drug delivery to the nose and the paranasal cavities/sinuses, in part because most nasally administered aerosol drug formulations are efficiently filtered at the nasal valve and fail to reach the osteomeatal area and sinuses. STUDY DESIGN: Feasibility study. SETTING: Nuclear medicine department. SUBJECTS AND METHODS: Pulsating airflows were applied to the nasal cavity and sinus ventilation was studied in five healthy human volunteers using dynamic (81m)Kr-gas gamma camera imaging. Furthermore, deposition and retention of (99m)Tc-DTPA radiolabeled aerosols delivered by nasal pump sprays or by pulsating aerosols was assessed in each volunteer over a 24-hour period. RESULTS: Only the pulsating airflow demonstrated efficient (81m)Kr-gas ventilation of the paranasal sinuses. No drug was deposited into the sinuses using nasal pump sprays, but up to 6.5 percent of the nasally administered drug was deposited into the sinuses using pulsating airflow. Clearance kinetics of the drug was reduced after pulsating aerosol delivery compared to nasal pump sprays. Residence time of the drug at the site of deposition was up to three-fold longer with pulsating aerosol delivery than with nasal pump sprays. CONCLUSION: Our data support the hypothesis that topical drug delivery in relevant quantities to the nose and osteomeatal areas, including the paranasal sinuses, is possible using pulsating airflows. Furthermore, the frequency of drug applications may be reduced due to a delayed clearance and longer residence time.

Transition-state stabilization by a secondary substrate-ligand interaction: a new design principle for highly efficient transition-metal catalysis.

A library of monodentate phosphane ligands, each bearing a guanidine receptor unit for carboxylates, was designed. Screening of the library gave some excellent catalysts for regioselective hydroformylation of beta,gamma-unsaturated carboxylic acids. A terminal alkene, but-3-enoic acid, was hydroformylated with a linear/branched (l/b) regioselectivity up to 41. An internal alkene, pent-3-enoic acid was hydroformylated with regioselectivity up to 18:1. Further substrate selectivity (e.g., acid vs. methyl ester) and reaction site selectivity (monofunctionalization of 2-vinylhept-2-enoic acid) were also achieved. Exploration of the structure-activity relationship and a practical and theoretical mechanistic study gave us an insight into the nature of the supramolecular guanidinium-carboxylate interaction within the catalytic system. This allowed us to identify a selective transition-state stabilization by a secondary substrate-ligand interaction as the basis for catalyst activity and selectivity.

German new onset diabetes in the young incident cohort study: DiMelli study design and first-year results.

BACKGROUND: Diabetes incidence in childhood and youth is increasing worldwide, including autoimmune and non-autoimmune cases. Recent findings suggest that there is a larger than expected proportion of type 2 diabetes in youth, and potential cases of intermediate diabetes phenotypes. Most pediatric diabetes registries focus on type 1 diabetes. Also, there is an absence of reliable data on type 2 diabetes incidence in youth. AIMS: The DiMelli study aims to establish a diabetes incidence cohort registry of patients in Germany, diagnosed with diabetes mellitus before age 20 years. It will be used to characterize diabetes phenotypes by immunologic, metabolic, and genetic markers. DiMelli will assess the contribution of obesity and socio-demographic factors to the development of diabetes in childhood and youth. METHODS: Recruitment of patients started in 2009, and is expected to continue at a rate of 250 patients per year. RESULTS: 84% of the 216 patients recruited within the first year were positive for multiple islet autoantibodies, 12% for one islet autoantibody, and 4% were islet autoantibody-negative. Patients with multiple islet autoantibodies were younger and had lower fasting C-peptide levels, compared to islet autoantibody-negative patients (median age 10.0 vs. 14.1 years, p < 0.01). CONCLUSIONS: Results from the first year of the study show that DiMelli will help to reveal new knowledge on the etiology of diabetes, and the contribution of genetic predisposition and environmental risk factors to the different types of diabetes.