| 1. |
- Krebs, Alice, et al.
(författare)
-
The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods
- 2020
-
Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 94:7, s. 2435-2461
-
Tidskriftsartikel (refereegranskat)abstract
- Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.
|
|
| 2. |
- Monticelli, Serena, et al.
(författare)
-
Sustainable Asymmetric Organolithium Chemistry : Enantio- and Chemoselective Acylations through Recycling of Solvent, Sparteine, and Weinreb "Amine"
- 2019
-
Ingår i: ChemSusChem. - : Wiley. - 1864-5631 .- 1864-564X. ; 12:6, s. 1147-1154
-
Tidskriftsartikel (refereegranskat)abstract
- The well-established Hoppe-Beak chemistry, which involves enantioselective generation of organolithium compounds in the presence of (-)-sparteine, was revisited and applied to unprecedented acylations with Weinreb amides to access highly enantioenriched alpha-oxyketones and cyclic alpha-aminoketones. Recycling of the sustainable solvent cyclopentyl methyl ether, sparteine, and the released Weinreb amine [HNMe(OMe)] was possible through a simple work-up procedure that enabled full recovery of these precious materials. The methodology features a robust scope and flexibility, thus allowing the enantioselective preparation of scaffolds amenable of further derivatization.
|
|
| 3. |
- Pace, Vittorio, et al.
(författare)
-
Increasing the Reactivity of Amides towards Organometallic Reagents : An Overview
- 2014
-
Ingår i: Advanced Synthesis and Catalysis. - : Wiley. - 1615-4150 .- 1615-4169. ; 356:18, s. 3697-3736
-
Forskningsöversikt (refereegranskat)abstract
- The nucleophilic addition of carbon nucleophiles to amides has traditionally been a difficult task, both due to reactivity and selectivity problems. When successful, these processes would represent straightforward routes towards carbonyl-type or amine compounds, depending on the fate of the generated tetrahedral intermediate. The direct addition of nucleophiles to amides for the preparation of ketones has been studied and applied to the syntheses of several natural products. On the other hand, the addition of nucleophiles to amides to obtain substituted amines represented a major challenge, and only scattered applications on particular substrates have appeared. Initial improvements were based on the activation of amides by introduction of particular substituents, such as in N-methoxy amides (Weinreb amides) or electron-withdrawing groups able to increase the carbon nucleophilicity. Although these strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (i.e., carbonyls) are present, thus decreasing the versatility of the methods. In recent years, important advancements towards fully chemoselective methods have been realized. The capture of tetrahedral intermediates with acids generates highly electrophilic iminium species able to undergo chemoselective additions of various nucleophiles, thus accessing substituted amines. Alternatively, the in situ generation of an iminium triflate ion allows highly chemoselective additions of nucleophiles, yielding amines, ketones or ketimines. Also thioamides can be used as precursors of ketones or alpha-substituted amines. The success of the above methodologies is further showcased by the application in various syntheses of natural products or biologically active molecules.
|
|
| 4. |
- van Gelder, Teun, et al.
(författare)
-
Renal Transplant Patients at High Risk of Acute Rejection Benefit From Adequate Exposure to Mycophenolic Acid.
- 2010
-
Ingår i: Transplantation. - 1534-6080. ; 89, s. 595-599
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND.: To better define subpopulations in which achieving adequate mycophenolic acid (MPA) concentrations quickly would be important, a post hoc exploratory analysis on the fixed-dose concentration-controlled database was performed, comparing high- versus low-risk renal transplant patients. METHODS.: Renal transplant patients were treated with mycophenolate mofetil, corticosteroids, and cyclosporine A or tacrolimus. Patients were defined as "high risk" if they had one or more of the following characteristics: delayed graft function, second or third transplantation, panel reactive antibodies >15%, four or more human leukocyte antigen mismatches, or were of black race. RESULTS.: A total of 549 patients (61%) were classified as high risk, of whom 284 were on cyclosporine A treatment and 265 on tacrolimus. In high-risk patients, the difference in rejection incidence was 14.3% in the MPA-area under the concentration (AUC) less than 30 mg hr/L vs. 7.8% in the MPA-AUC more than or equal to 30 mg hr/L groups (P=0.025) during the first month after transplantation; whereas, in low-risk patients, there were similar rejection rates (5.7% vs. 4.5%). In the subgroup of high-risk tacrolimus-treated patients, the difference in acute rejection incidence in the first month between patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was most pronounced: 16 of 67 patients (23.9%) vs. 18 of 173 patients (10.4%); P=0.012. CONCLUSIONS.: The incidence of acute rejection is higher in high-risk patients if MPA-AUC0-12 is below 30 mg hr/L. In contrast, a difference in acute rejection incidence in low-risk patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was not observed. This supports the use of a higher mycophenolate mofetil starting dose in selected patient populations early after transplantation.
|
|
