Climate change impacts on aflatoxin B1 in maize and aflatoxin M1 in milk: A case study of maize grown in Eastern Europe and imported to the Netherlands.

Various models and datasets related to aflatoxins in the maize and dairy production chain have been developed and used but they have not yet been linked with each other. This study aimed to investigate the impacts of climate change on aflatoxin B1 production in maize and its consequences on aflatoxin M1 contamination in dairy cow's milk, using a full chain modelling approach. To this end, available models and input data were chained together in a modelling framework. As a case study, we focused on maize grown in Eastern Europe and imported to the Netherlands to be fed-as part of dairy cows' compound feed-to dairy cows in the Netherlands. Three different climate models, one aflatoxin B1 prediction model and five different carryover models were used. For this particular case study of East European maize, most of the calculations suggest an increase (up to 50%) of maximum mean aflatoxin M1 in milk by 2030, except for one climate (DMI) model suggesting a decrease. Results from all combinations of carryover and climate models suggest a similar or slight increase (up to 0.6%) of the chance of finding aflatoxin M1 in milk above the EC limit of 0.05 µg/kg by 2030. Results varied mainly with the climate model data and carryover model considered. The model framework infrastructure is flexible so that forecasting models for other mycotoxins or other food safety hazards as well as other production chains, together with necessary input databases, can easily be included as well. This modelling framework for the first time links datasets and models related to aflatoxin B1 in maize and related aflatoxin M1 the dairy production chain to obtain a unique predictive methodology based on Monte Carlo simulation. Such an integrated approach with scenario analysis provides possibilities for policy makers and risk managers to study the effects of changes in the beginning of the chain on the end product.

Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.

Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.

BMS-201620: a selective beta 3 agonist.

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Novel cytokine release inhibitors. Part IV: analogs of podocarpic acid.

Podocarpic acid derivatives as cytokine (IL-1beta) release inhibitors are discussed.

Novel cytokine release inhibitors. Part III: Truncated analogs of tripterine.

Truncated analogs of tripterine as cytokine (IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8) release inhibitors are discussed.