Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity

In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.     

Iron status and risk of cancers in the SU.VI.MAX cohort

The aim of the present study was to evaluate the relation between iron status and cancer in a population of middle-aged adults living in France where iron supplementation and iron-fortified foods are rarely used. The SU.VI.MAX study is a randomized, double-blind, placebo-controlled primary prevention trial evaluating the effect of antioxidant supplementation on chronic diseases in women aged 35-60 and men aged 45-60 y. At baseline, concentrations of hemoglobin, serum transferrin and serum ferritin were measured in 10,197 subjects. Data on dietary intake were estimated from six 24-h dietary records completed during the first 2 study years and available for 5287 subjects. All cancer cases that occurred during the 7.5-y follow-up were validated. In men, baseline serum transferrin and serum ferritin concentrations did not differ between subjects with cancers (n = 467) and those without. In women, serum ferritin was higher (P < 0.0001) and serum transferrin tended to be lower (P < 0.08) in cancer cases. Iron status was not related to cancer risk in men, but women with serum ferritin concentrations > 160 microg/L had an increased risk of cancer (odds ratio = 1.88, 95% CI: 1.05,3.35). No relation was found between dietary iron intake and risk of all cancer sites combined for either men or women. Our results suggest that iron status is not a predictor of cancer risk in men, whereas a serum ferritin concentration > 160 microg/L may be associated with an increase in cancer risk in women.     

Dietary purified cis-9,trans-11 conjugated linoleic acid isomer has anticarcinogenic properties in chemically induced mammary tumors in rats

To determine whether the purified 9c,11t conjugated linoleic acid (CLA) isomer, the main dietary isomer, is biologically active on mammary tumor growth, we carried out a dietary intervention study designed to compare its effects with those of a mixture of CLA isomers on the incidence and growth of autochthonous mammary tumors induced by methylnitrosourea in rats. After the initiation step, rats were fed a sunflower oil-based diet (5%) and separated into three experimental groups supplemented with either a 1% homemade synthesized 9c,11t isomer, a 1% CLA isomer mixture, or free fatty acids prepared from sunflower oil for the control group. We found that, in the two CLA groups compared with the control group, CLA levels were about 30 times higher in mammary fat pads and about 10 times higher in tumor tissues. Compared with the control group, there was a 44% and 45% decrease in tumor mass per rat in the CLA mixture and the 9c,11t groups, respectively, at 20 wk of diet (P < 0.05). There was a nonsignificant trend for a decrease multiplicity in CLA groups compared with the control group, with a 30% and 35% decrease in the CLA mixture and the 9c,11t groups, respectively. Incidence and latency were not significantly different between the dietary groups. Although the effect was specifically restricted in reduction in tumor mass, we concluded that the main CLA isomer found in human diet has anticarcinogenic properties in experimental mammary carcinogenesis.     

Calcium,magnesium, sodium and potassium levels in foodstuffs from the second French Total Diet Study

Calcium (Ca), magnesium (Mg), sodium (Na) and potassium (K) contents in 1319 foodstuffs habitually consumed by the French population were determined for the second French Total Diet Study (TDS), using micro-sampling flame atomic absorption spectrometry after microwave-assisted digestion. Concentration and distribution of these minerals in food samples were reported and compared with results from the previous French TDS. For Ca, the results indicate that the food presenting the highest levels are dairy products (1597 mg kg^?1), tofu (802 mg kg^?1) and some fish and cereal products; for Mg, tofu (1340 mg kg^?1), “Sweeteners, honey and confectionery” (672 mg kg^?1) especially dark chocolate (2225 mg kg^?1) and certain grains such as nuts and oilseeds (1069 mg kg^?1) and some cereal products; for Na, processed meats such as delicatessen (12,422 mg kg^?1), “Salts, spices, soup and sauces” (21,028 mg kg^?1), some cheeses and cereal products; and for K, “Cereal and cereal products” (4378 mg kg^?1), “Meats and offal” (3993 mg kg^?1), “Nuts and oilseeds” (7355 mg kg^?1) and “Sweeteners, honey and confectionery” (3445 mg kg^?1) (especially chocolate).     

Food and nutrient intakes of French frequent seafood consumers with regard to fish consumption recommendations: results from the CALIPSO study

Besides providing n-3 fatty acids with nutritional and health benefits, seafood consumption may contribute to the reduction of nutrient prevalences of inadequacy. To evaluate the contributions of seafood and other food groups to nutrient intakes of frequent seafood consumers, food consumption was evaluated through an FFQ on 991 French men and women (18-81 years) consuming seafood at least twice a week. Intakes, prevalence of inadequacies, risks of upper limit excess and food contributions to intakes were assessed for thirty-three nutrients. Mean fat contributions to total energy intakes (38·3 and 39·0?% for men and women, respectively) met French recommendations, but mean carbohydrate intakes (40·9 and 39·7?%, respectively) were insufficient. Micronutrient inadequacies were lower than in the French general population, the highest being for vitamin C (41·3 and 40·1?% for men and women, respectively), vitamin E (35·0 and 35·3?% for men and women, respectively) and Mg (37·5 and 25·5?% for men and women, respectively). Upper safety limits (USL) were exceeded mostly for Zn (6·2?%), Ca (3·7?%), retinol (2·0?%) and Cu (0·9?%). Mean contributions of seafood to vitamin D, B12, I and Se intakes ranged 40-65?%. Molluscs and crustaceans significantly contributed to vitamin B12 (13·7?%), Cu (11·4?%), Fe (11·5?%), Zn (8·4?%) and I (6·1?%) intakes, and canned fish contributed to vitamin D intake (13·4?%). Besides fish, contributions of mollusc and crustacean consumption to nutrient intakes should be considered from a public health viewpoint. Consuming seafood at least twice a week induces moderate inadequacies and risks of exceeding USL for some micronutrients, whereas macronutrient intakes remained imbalanced.     

Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore

Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for individual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.     

Ages at Initiation of Cigarette Smoking and Quit Attempts Among Women: A Generation Effect

OBJECTIVES: This study sought to determine whether the age at initiation of regular cigarette smoking and the likelihood of quitting smoking through age 35 differ among women from younger versus older generations. METHODS: Annual population-based, random surveys (total of 3676 female residents of Geneva, Switzerland, aged 35-74 years) were conducted from 1992 to 1998. RESULTS: Women younger than 55 years were more likely to be past or current smokers, began smoking earlier (median age < 20 years), and smoked more cigarettes per day than older women, yet attempted to quit smoking more often before age 35 (log-rank P <.001). CONCLUSIONS: Young female smokers have a higher propensity to quit smoking compared with older women. Encouraging young smokers to quit-in addition to preventing nonsmokers from starting-may be an important facet of reducing cigarette smoking prevalence among adolescents.     

Application of genomics to drug design: the example of the histamine H3 receptor

The histamine H₃ receptor was characterized in the 1980s as an autoreceptor regulating histamine release in brain. Since then, selective drugs have been designed, many of them displaying a high potency in vivo, and used in many studies to delineate the implications of cerebral histaminergic systems in physiological functions such as arousal or cognitive functions. The recent cloning of the H₃ receptor, more than 15 years later, has allowed to start molecular studies that led to important findings for optimization of drug design. In agreement some ligands display distinct affinities for the recombinant rat and human H₃ receptors, a difference that we assign to two amino acids in the third transmembrane domain. In addition, H₃ autoreceptors present in the brain display high constitutive activity including in vivo. As a consequence, inverse agonists enhance histamine neuron activity and constitute a novel potential therapeutic approach to schizophrenia and Alzheimer’s disease.