Box plots of DVWA of MDA concentrations in 23 children 3–11 years of age for 15 consecutive days in which conventional and organic diets were consumed

<p><b>Copyright information:</b></p><p>Taken from "Organic Diets Significantly Lower Children’s Dietary Exposure to Organophosphorus Pesticides"</p><p>Environmental Health Perspectives 2005;114(2):260-263.</p><p>Published online 1 Sep 2005</p><p>PMCID:PMC1367841.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p> The top row of numbers on the -axis represents numbers of children

Box plots of DVWA of TCPY concentrations in 23 children 3–11 years of age for 15 consecutive days in which conventional and organic diets were consumed

<p><b>Copyright information:</b></p><p>Taken from "Organic Diets Significantly Lower Children’s Dietary Exposure to Organophosphorus Pesticides"</p><p>Environmental Health Perspectives 2005;114(2):260-263.</p><p>Published online 1 Sep 2005</p><p>PMCID:PMC1367841.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p> The top row of numbers on the -axis represents numbers of children

Mouth Level Intake of Nicotine from Three Brands of Little Filtered Cigars with Widely Differing Product Characteristics Among Adult Consumers

Little filtered cigars are tobacco products with many cigarette-like characteristics. However, despite cigars falling under the U.S. Food and Drug Administration regulatory authority, characterizing flavors, which are still allowed in little filtered cigars, and filter design may influence how people use the products and the resulting exposure to harmful and potentially harmful constituents. We estimated nicotine mouth level intake (MLI) from analyses of little cigar filter butt solanesol levels, brand characteristics, carbon monoxide boost, and puff volume in 48 dual cigarette/cigar users during two repeat bouts of ad lib smoking of three little filtered cigar brands. Mean nicotine MLI for the three brands was significantly different with Swisher Sweets (0.1% ventilation) Cherry at 1.20 mg nicotine, Cheyenne Menthol (1.5%) at 0.63 mg, and Santa Fe unflavored (49%) at 0.94 mg. The association between nicotine MLI and puff volume was the same between Cheyenne Menthol and Santa Fe unflavored. However, these were different from Swisher Sweets Cherry. At least five main factorsflavor, ventilation, filter design, nicotine delivery related to tar, and user puff volumemay directly or indirectly impact MLI and its association with other measures. We found that users of little filtered cigars that have different filter ventilation and flavor draw dissimilar amounts of nicotine from the product, which may be accompanied by differences in exposure to other harmful smoke constituents

Novel S1P₁ Receptor Agonists - Part 2: From Bicyclo[3.1.0]hexane-Fused Thiophenes to Isobutyl Substituted Thiophenes

Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]­hexane fused thiophene derivatives that serve as potent and selective S1P₁ receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P₁ agonists (e.g., <b>87</b>), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure

Novel S1P₁ Receptor Agonists – Part 1: From Pyrazoles to Thiophenes

From a high-throughput screening campaign aiming at the identification of novel S1P₁ receptor agonists, the pyrazole derivative <b>2</b> emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]­hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P₁ efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound <b>85</b> showed EC₅₀ values of 7 and 2880 nM on S1P₁ and S1P₃, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P₁ selective compound <b>85</b> showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only

Novel S1P₁ Receptor Agonists − Part 3: From Thiophenes to Pyridines

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P₁ agonists such as the thiophene derivative <b>1</b>. As a continuation of these efforts, we replaced the thiophene in <b>1</b> by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P₁ agonists (e.g., <b>2</b>) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds’ receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P₁ agonists, compound <b>53</b> showed EC₅₀ values of 0.6 and 352 nM for the S1P₁ and S1P₃ receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound <b>53</b> maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg