DSM (Austria)

In 2005, the American Chemical Society (ACS) Green Chemistry Institute (GCI) and global pharmaceutical companies established the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and engineering into the pharmaceutical industry. The Roundtable developed a list of key research areas in green chemistry in 2007, which has served as a guide for focusing green chemistry research. Following that publication, the Roundtable companies have identified a list of the key green engineering research areas that is intended to be the required companion of the first list. This publication summarizes the process used to identify and agree on the top key green engineering research areas and describes these areas, highlighting their research challenges and opportunities for improvements from the perspective of the pharmaceutical industry.

1. Preamble; 2. Introduction; 3. Estimation of total cardiovascular risk and implications for dyslipidaemia management; 4. New low-density lipoprotein cholesterol-lowering therapies; 5. Combination of lipid-lowering therapies during index hospitalization for acute coronary syndromes; 6. Lipoprotein(a); 7. Hypertriglyceridaemia; 8. Primary prevention in people with human immunodeficiency virus infection; 9. Patients with cancer at high or very high chemotherapy-related cardiovascular toxicity risk; 10. Dietary supplements; 11. Evidence tables; 12. Data availability statement; 13. Author information; 14. Appendix; 15. References

Novel enzyme activity: Biocatalytic Henry reactions with nitromethane and nitroethane yielded the corresponding nitroalcohols with good enantio- and diastereocontrol in the presence of the hydroxynitrile lyase from the tropical rubber tree Hevea brasiliensis. Molecular modeling and deuterated starting materials were used in mechanistic investigations.

Comparative screening of gene expression libraries employing the potent industrial host Pichia pastoris for improving recombinant eukaryotic enzymes by protein engineering was an unsolved task. We simplified the protocol for protein expression by P. pastoris and scaled it down to 0.5-ml cultures. Optimising standard growth conditions and procedures, programmed cell death and necrosis of P. pastoris in microscale cultures were diminished. Uniform cell growth in 96-deep-well plates now allows for high-throughput protein expression and screening for improved enzyme variants. Furthermore, the change from one host for protein engineering to another host for enzyme production becomes dispensable, and this accelerates the protein breeding cycles and makes predictions for large-scale production more accurate.

A review of recent developments in the applications and actions of intumescent fire-retardance is given. An attempt has been made to classify the main systems of importance such as melamine, ammonium polyphosphate, melamine phosphate, pentaerythritol phosphate, sodium silicate, vermiculite, expandable graphite and microbeads. They are defined in terms of the Berthelot number which is the product of heat of vaporization or decomposition and volume of gases evolved. In principle, only two kinds of gases are produced from this group, namely water vapour and ammonia (from melamine). The heats of decomposition are readily calculated from heats of formation. An important aspect which is not included in the Berthelot number is the ignition residue in the shape of glassy foam or a cellular enamel. © 2000 Society of Chemical Industry

Abstract The hydroxynitrile lyase from Hevea brasiliensis not only catalyzes – according to the natural activity of this enzyme – the formation and cleavage of cyanohydrins but also the reaction of nitroalkanes with aldehydes (Henry reaction). This is the first example of an enzymatic nitroaldol reaction. With nitromethane and nitroethane a broad range of aldehydes can be transformed into the corresponding nitro alcohols in yields up to 77 % and enantiomeric excess ( ee ) up to 99 %.

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

A custom-made enzyme: The gene and protein sequence of a new (R)-hydroxynitrile lyase from Prunus amygdalus was cloned and engineered for recombinant production on a large scale. The enzyme is stable and active at low pH values. A rationally designed active-site mutant now permits the rapid and stereoselective synthesis of sterically hindered cyanohydrins such as ortho-chloromandelonitrile (see picture). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z52141_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Neuartige Enzymaktivität: Henry-Reaktionen mit Nitromethan und Nitroethan, katalysiert durch das Enzym Hydroxynitrillyase aus dem Kautschukbaum Hevea brasiliensis, führten mit guter Enantio- und Diastereokontrolle zu den Nitroalkoholen (siehe Schema). In ersten mechanistischen Untersuchungen wurden deuterierte Nitroalkane und Molecular Modeling eingesetzt. Hintergrundinformationen zu diesem Beitrag sind im WWW unter http://www.wiley-vch.de/contents/jc_2001/2006/z504230_s.pdf zu finden oder können beim Autor angefordert werden. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Random mutagenesis and recombination of PaHNL5 was carried out in Pichia pastoris by employment of an overlap extension PCR-based strategy. New fast and stereoselective enzyme variants were obtained, and these led to improved turnover rates with the nonnatural substrate 2-chlorobenzaldehyde. A new catalyst combining all favorable mutations was generated, and even very small amounts of this variant enabled complete conversion of 2-chlorobenzaldehyde into the (R)-hydroxynitrile with >99 % ee in only 4 h. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2268/2008/z700514_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND: Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. OBJECTIVES: The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. METHODS: In this hospital-based randomized controlled trial, 226 children (6-59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. RESULTS: No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. CONCLUSION: MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.

<div class="htmlview paragraph">In 3D simulation of vehicle accidents the vehicles are typically treated as one rigid body. This simplification can be used for vehicle to vehicle collisions as well as in impacts with solid objects. To get a realistic movement of the pedestrian in the impact simulation, the pedestrian has to be modeled as a system of rigid bodies interconnected by joints.</div> <div class="htmlview paragraph">This paper describes in detail the extension of the discrete kinetic time forward simulation program PC-Crash to deal with multi-body-systems.</div> <div class="htmlview paragraph">As one application of this model pedestrians have been modeled. During the generation of this pedestrian model special interest has been focused on a realistic movement of the pedestrian and a short calculation time.</div> <div class="htmlview paragraph">The pedestrian model shows to be a good tool to analyze the movement of the pedestrian regarding its post impact kinematics and contact locations on the vehicles and the ground. In addition specific contact locations on the vehicle can be correlated with the movement of the pedestrian and damage locations on the vehicle.</div> <div class="htmlview paragraph">For the validation of this model several crash tests have been performed and will be done. The second part of this paper describes the results of some crash tests and a comparison of the simulation results. A good agreement between crash-tests and simulation results could be found. For these crash-tests different typical shapes of the front hood of modern cars have been used to study the influence on the movement of the pedestrian during and after the impact.</div> <div class="htmlview paragraph">The model also involves the capability to deal with different kinds of pedestrians (size and mass) under various initial conditions (standing, walking, running).</div>

New drug combinations against falciparum malaria which are both effective and affordable for Sub-Saharan African populations are urgently needed. The combination of the well-known drugs chloroquine (CQ) and methylene blue (MB) is such a promising new regimen. However, there is some concern that MB could cause development of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition which is prevalent in malaria-endemic regions. Against this background, 74 G6PD-deficient but otherwise healthy adult men were given a 3-day oral regimen of a total of 1500 mg CQ and 780 mg MB in the District Hospital of Nouna in north-western Burkina Faso. Haemolysis did not occur, haemoglobin levels remained stable or even rose in the study participants, and the drug regimen was well tolerated. Therefore, standard dosages of MB appear to be safe in G6PD-deficient African populations with predominantly class III G6PD deficiency.

Structure-guided redesign of the active site of almond (R)-PaHNL5 for increased enantioselectivity resulted in four improved muteins. In particular, mutation V360I gave enhanced conversion rates and enantioselectivities higher than 96 % ee for two structurally related substrates 1 and 2. Chiral building blocks for the synthesis of pharmaceutically active “prils” (example shown) can thus be produced on a large scale. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z500435_s.html or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Six of one: A hexanuclear iron p-nitrobenzoate compound (see structure; green Fe, red O, blue N, gray C), a novel type of iron cluster was prepared and characterized. The complex has an [Fe6(μ3-O)3(μ2-OH)]11+ core and shows a remarkable catalytic activity in the oxidation of cyclohexane.

<div class="section abstract"><div class="htmlview paragraph">The pedestrian model in PC-Crash is based on a multi-body system, where several bodies are interconnected by joints. Each of these bodies can have different properties to represent the different parts of the human body. The joint properties can be specified independently as well. The theoretical background of the pedestrian model has been introduced in SAE 1999-01-0445 and the model shows to give a good correlation of the gross movement of the pedestrian compared to crash test data.</div><div class="htmlview paragraph">As there are many parameters, which can and have to be specified for the pedestrian model as input parameters, an in depth validation of the different parameters has to be done to validate this model.</div><div class="htmlview paragraph">This paper describes in detail the validation process for the pedestrian model. A significant number of crash tests (approx. 30) was used as a basis to compare the results of the simulations and the real movement of the test subjects. Different test configurations were selected to provide a set of crash tests, which represents real cases as close as possible. For this reason crash tests with different vehicle types and vehicle shapes were investigated and crash tests with different driving conditions (braking, sliding) were used as well. To show the difference between dummy movement and the movement of human test subjects some tests with human test subjects and some real cases, which were very well documented, have been used. Each of the different tests was reconstructed using PC-Crash and the pedestrian model and the significant difference between simulation results and crash tests are pointed out. A special interest has been focused on the pedestrian trajectories and the contact locations between the pedestrian and other objects.</div><div class="htmlview paragraph">All tests and simulations are compared in the conclusion and the usability of the pedestrian model in different accident configuration is discussed. Typical parameter ranges for the different input parameters like pedestrian geometry, weight and stiffness parameters are presented as well.</div></div>

Mycotoxins are ubiquitously present in feeds and raw materials and can exert toxicity on animals and humans. Therefore, mycotoxin occurrence should be monitored. We report here a multi-mycotoxin survey of feed samples in China from 2017 to 2021. Concentrations of aflatoxins, trichothecenes type B, fumonisins, and zearalenone were determined in a total of 9392 samples collected throughout China. Regional differences and year-to-year variation of mycotoxin occurrence were also assessed in new-season corn. Generally, Fusarium mycotoxins were prevalent, while mycotoxin contamination in each feed commodity showed a distinct pattern, e.g., wheat and bran were typically affected by trichothecenes type B, peanut meals were highly susceptible to aflatoxins, and finished feeds exhibited a comparatively high prevalence of all mycotoxins. In new-season corn, trichothecenes type B and fumonisins were most prevalent, with positive rates of 84.04% and 87.16%, respectively. Regions exhibited different patterns of mycotoxin occurrence. The Anhui and Jiangsu provinces of East China exhibited a high prevalence and concentrations of aflatoxins with a positive rate and a positive average of 82.61% and 103.08 μg/kg, respectively. Central China obtained high fumonisins levels of 4707.84 μg/kg. Trichothecenes type B and zearalenone occurred more frequently in temperate regions of Northeast China, and their positive rates reached 94.99% and 55.67%, respectively. In these regions, mycotoxin concentrations in new-season corn exhibited pronounced year-to-year variations and this could be due to the unusual changes of rainfall or temperature during sensitive periods of corn growing. A large fraction of new-season corn samples contained multiple mycotoxins with two to three classes (75.42%), and the most frequently observed co-contaminants were the combination of trichothecenes type B and fumonisins (73.52%). Trichothecenes type B and zearalenone concentrations were highly positively correlated with a coefficient of 0.775. In conclusion, mycotoxins contamination and co-contamination of feeds are common. Mycotoxin contamination in new-season corn exhibited regional patterns and year-to-year variations, with climate and weather conditions as determinant factors.

Modern agriculture depends highly on pesticides and pharmaceutical preparations, so controlling exposure to these substances in the feed and food chain is essential. This article presents the first study on residues of a broad spectrum of pesticides and veterinary drugs in the diets of dairy cattle. One hundred and two representative samples of the complete diets, including basal feed rations and additional fed concentrate, were collected in three Austrian provinces (Styria, Lower and Upper Austria) in 2019 and 2020. The samples were tested for >700 pesticides, veterinary drugs and related metabolites using a validated method based on liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI–MS/MS). In total, 16 residues (13 pesticides and three veterinary drug residues) were detected. > 90% of the diets contained pesticide residues and <10% veterinary drug residues, whereas banned pesticides were not found. The most frequent pesticide residues were fluopyram (62%), piperonyl butoxide (39%) and diethyltoluamide (35%). The following pesticides exceed the default EU maximum residue level (MRL) (10 μg kg−1) for products exclusively used for animal feed production: Benzovindiflupyr (proportion of samples > MRLs: 1%), bixafen (2%), fluopyram (6%), ipconazole (1%) and tebuconazole (3%). Three residues (dinitrocarbanilide, monensin and nicarbazin) of veterinary drugs were identified, all below the MRLs. Over 60% of the evaluated samples contained mixtures of two to six residues/sample. Only one pesticide (diethyltoluamide) presented a significant difference among regions, with higher concentrations in Upper Austria. Brewery's spent grains were the dietary ingredient that showed the strongest correlation to pesticide residues. These findings evidence the realistic scenario of highly occurrent low doses of pesticides cocktails in the feed/food chain, which may affect the animal, human and environmental health. Since the risk assessments are based on single pesticides, the potential synergistic effect of co-occurring chemicals (“cocktail effect”) requires further investigations.

To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer–Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.

Abstract Screening for stereoselective cyanohydrin synthesis in 96‐well plates was employed in the development of an efficient, pH‐stable hydroxynitrile lyase for the conversion of sterically hindered aliphatic aldehydes. Site‐saturation mutagenesis (SSM) resulted in a powerful catalyst for the stereoselective conversion of hydroxypivalaldehyde and pivalaldehyde to their corresponding ( R )‐cyanohydrins ( ee &gt;97%) which are used as chiral building blocks (e.g., for pantothenic acid production). Furthermore, redesigning the Pa HNL5 gene and improving its expression by Pichia pastoris with the help of a new P AOX1 promoter variant and the helper protein PDI (protein disulfide isomerase) led to elevated amounts of today’s most efficient biocatalyst for vitamin B 5 synthesis.