Reducing effect of a combination of Phaseolus vulgaris and Cynara scolymus extracts on food intake and glycemia in rats.

Extracts from Phaseolus vulgaris and Cynara scolymus may reduce food intake and/or postprandial glycemia. This study investigated the effect of standardized extracts of P. vulgaris and C. scolymus and their combination on food intake and glycemia in rats. P. vulgaris and C. scolymus extracts, and their 1:2 combination, were administered acutely to rats (a) given access to regular food and water, (b) given access to regular food, water, and a chocolate-flavored beverage, or (c) infused with a starch bolus. P. vulgaris extract and the combination produced comparable reductions in intake of regular food and chocolate-flavored beverage; conversely, C. scolymus extract was ineffective on both parameters. P. vulgaris and C. scolymus extracts additively contributed to the reducing effect of the combination on glycemic rise. These results suggest that a mixture of P. vulgaris and C. scolymus extracts is preferable over each single extract, as it combines the anorectic effect of the P. vulgaris extract with the hypoglycemic effect of both extracts. These data support the recent clinical use of the combination of P. vulgaris and C. scolymus extracts in the control of appetite, food intake, and postprandial glycemia and represent a successful example of translational research in the nutraceutical field.

Multiple cycles of repeated treatments with a Phaseolus vulgaris dry extract reduce food intake and body weight in obese rats.

Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris.

Evidence of glycemia-lowering effect by a Cynara scolymus L. extract in normal and obese rats.

Several recent preliminary clinical studies have suggested that artichoke (Cynara scolymus L., Asteraceae family) preparations may be capable of lowering post-prandial glycemia. The present study was designed to test this hypothesis in laboratory rats. To this aim, non-selected Wistar and genetically obese Zucker rats were treated acutely with a purified extract of Cynara scolymus flowering heads (500-1500 mg/kg by gavage) immediately prior to 1 h access to a fixed amount of food. Glycemia was recorded 60, 120 and 360 min after food presentation. Treatment with Cynara scolymus flowering head extract resulted in a significant decrease of post-prandial glycemia in both rat strains. The lack of any fiber content in this Cynara scolymus flowering head extract excludes the involvement of dietary fibers in glycemia reduction. The results obtained constitute the first evidence of a hypoglycemic effect of an artichoke preparation in laboratory rodents and confirm previous observations made in humans.

Increase in alcohol intake, reduced flexibility of alcohol drinking, and evidence of signs of alcohol intoxication in Sardinian alcohol-preferring rats exposed to intermittent access to 20% alcohol.

BACKGROUND: This study assessed in Sardinian alcohol-preferring (sP) rats a procedure known to promote alcohol drinking and based on the intermittent (once every other day) access to 2 bottles containing alcohol (20%, v/v) and water, respectively (Wise, 1973). METHODS: To this end, sP rats were exposed - under the 2-bottle choice regimen - to: (i) 10% (v/v) alcohol with continuous access (CA10%; i.e., the procedure under which sP rats had been selectively bred); (ii) 10% (v/v) alcohol with intermittent access (IA10%); (iii) 20% (v/v) alcohol with continuous access (CA20%); (iv) 20% (v/v) alcohol with intermittent access (IA20%; the "Wise" condition) (Experiment 1). Additional experiments assessed the influence of (i) adulteration with quinine of the alcohol solution (Experiment 2) and (ii) concurrent presentation of a saccharin solution (Experiment 3) on alcohol drinking under the CA10% and IA20% conditions. Finally, it was assessed whether alcohol drinking under the CA10% and IA20% conditions resulted in motor incoordination at the Rota-Rod task, as a possible sign of alcohol intoxication (Experiment 4). RESULTS: Daily alcohol intake markedly escalated in rats exposed to the IA20% condition, averaging 9.0 g/kg (in comparison with the average intake of 6.5 g/kg in the CA10% rat group). CA20% and IA10% rats displayed intermediate values of daily alcohol intake between those of CA10% and IA20% rats. Alcohol intake was virtually abolished by addition of quinine or by concurrent presentation of the saccharin solution in CA10% rats; conversely, alcohol intake in IA20% rats was only partially affected by gustatory aversion or concurrent presentation of an alternative reinforcer. Finally, alcohol intake in IA20%, but not in CA10%, rats resulted in clear motor-incoordinating effects. CONCLUSIONS: These data suggest that the "Wise" procedure is effective in inducing marked increases in alcohol intake in sP rats. These increases are associated with a reduced flexibility of alcohol drinking (suggesting the development of "behavioral" dependence) and produce signs of alcohol intoxication that are not detected when sP rats are exposed to the more conventional CA10% condition.

Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile.

New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB(1) receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB(1) receptor, with K(i) concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB(1) selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB(1) binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB(1) selective compounds 4 and 52 act as antagonists/inverse agonists.

Specific reduction of alcohol's motivational properties by the positive allosteric modulator of the GABAB receptor, GS39783--comparison with the effect of the GABAB receptor direct agonist, baclofen.

BACKGROUND: Activation of the GABA(B) receptor--either by means of direct agonists (like baclofen) or positive allosteric modulators (like GS39783)--has been observed to suppress alcohol drinking and reinforcement in rats and mice. The present study was conducted to assess and compare the effect of baclofen and GS39783 on the motivational properties of alcohol. METHODS: Selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever (on an fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) or sucrose (3%, w/v) in daily 30-minute sessions. Once lever-responding reached stable levels, rats were exposed to sessions with a progressive ratio schedule of reinforcement. The effect of nonsedative doses of baclofen (0, 1, and 3 mg/kg, i.p.) and GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on breakpoint for alcohol and sucrose (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol and sucrose) was determined. RESULTS: Baclofen administration resulted in a dose-dependent decrease in breakpoint for alcohol; this effect was not specific, as baclofen also reduced--to a comparable extent--breakpoint for sucrose. Conversely, GS39783 administration resulted in a dose-dependent and completely specific reduction in breakpoint for alcohol. CONCLUSIONS: The present results (i) confirm previous data on baclofen's capacity to suppress, although nonspecifically, alcohol's motivational properties, and (ii) extend to alcohol's motivational properties the capacity of GS39783 to inhibit alcohol drinking and reinforcement in rats.

gamma-Hydroxybutyric acid (GHB) suppresses alcohol's motivational properties in alcohol-preferring rats.

gamma-Hydroxybutyric acid (GHB) reduces alcohol drinking, promotes abstinence from alcohol, suppresses craving for alcohol, and ameliorates alcohol withdrawal syndrome in alcoholics. At preclinical level, GHB suppresses alcohol withdrawal signs and alcohol intake in rats. The present study was designed to investigate whether GHB administration was capable of affecting alcohol's motivational properties (the possible animal correlate of human craving for alcohol) in selectively bred Sardinian alcohol-preferring rats. To this aim, rats were initially trained to lever press for alcohol (15%, vol/vol) under a procedure of operant, oral alcohol self-administration (fixed ratio 4 in 30-min daily sessions). Once responding for alcohol had stabilized, rats were divided into two groups and allocated to two independent experiments. Experiment 1 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on breakpoint for alcohol, defined as the lowest response requirement not achieved by each rat when exposed to a single-session progressive ratio schedule of reinforcement. Experiment 2 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on single-session extinction responding for alcohol (alcohol was absent and unreinforced responding was recorded). Breakpoint and extinction responding for alcohol are reliable indexes of alcohol's motivational strength. In Experiment 1, all doses of GHB reduced--by approximately 20% in comparison to saline-treated rats--breakpoint for alcohol. In Experiment 2, administration of 25, 50, and 100mg/kg GHB reduced--by approximately 25%, 40%, and 50%, respectively, in comparison to saline-treated rats--extinction responding for alcohol. Conversely, no dose of GHB altered breakpoint and extinction responding for sucrose (3%, wt/vol) in two independent subsets of Sardinian alcohol-preferring rats. Together, these data suggest that GHB administration specifically suppressed alcohol's motivational properties in Sardinian alcohol-preferring rats. These results are consistent with the anticraving properties of GHB observed in clinical studies.

Reducing effect of an extract of Phaseolus vulgaris on food intake in mice--focus on highly palatable foods.

Different lines of experimental evidence indicate that treatment with extracts from and derivatives of Phaseolus vulgaris reduces intake of food, including highly palatable foods and beverages, in rats. The present study was designed to extend to mice these lines of evidence. To this end, CD1 mice were treated acutely with a standardized extract of P. vulgaris and then exposed to unlimited access to regular food pellets (Experiment 1) or 1-hour limited access to three different palatable foods/beverages, such as butter cookies (Experiment 2), a condensed-milk beverage (Experiment 3), and a chocolate-flavored beverage (Experiment 4). Treatment with P. vulgaris extract resulted in a significant reduction in the intake of regular food pellets, that was still evident 24h later, as well as of the three palatable nourishments. Together, these results (a) extend to mice several previous findings on the capacity of P. vulgaris extracts to suppress food intake in rats, (b) suggest that P. vulgaris extracts may interfere with the central mechanisms regulating appetite, food intake, palatability, and/or the rewarding and hedonic properties of food, and (c) P. vulgaris extracts may represent a potentially effective therapy for overeating, obesity, and food craving.

Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands.

A series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB1. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB1 receptor affinity (compound 24: Ki=45.6 nM; 29: Ki=37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands.

Potential efficacy of preparations derived from Phaseolus vulgaris in the control of appetite, energy intake, and carbohydrate metabolism.

Preclinical data on extracts of and preparations derived from beans of Phaseolus vulgaris are reviewed as potential remedies for use in controlling food consumption, body weight, lipid accumulation, and glycemia. A growing body of evidence suggests that acute and chronic administration of P. vulgaris derivatives reduces food intake (including highly palatable foods), body weight, lipid deposit, and glycemia in rats exposed to multiple experimental procedures. Two possible lectin-mediated mechanisms of action have been proposed: (a) inhibition of α-amylase, resulting in a reduced carbohydrate metabolism and absorption; (b) phytohemoagglutinin-induced modulation of the activity of cholecystokinin and glucagon-like peptides, resulting in a reduced appetite. Preliminary clinical data, as well as reports focusing on the use of several traditional medicines, apparently extend these findings to humans. Should these initial clinical data be confirmed by future surveys, P. vulgaris derivatives might constitute novel remedies for the treatment of obesity and metabolic syndrome. Future studies are also expected to identify active structures leading to the development of new pharmaceutical agents.

Reducing effect of a Phaseolus vulgaris dry extract on food intake, body weight, and glycemia in rats.

Extracts of kidney beans ( Phaseolus vulgaris ) are known to reduce food intake and glycemia in rodents and humans. This study evaluated the effect of a novel extract of P. vulgaris on food (regular food pellets, starch-enriched diet, and chocolate-flavored beverage) intake, body weight, and glycemia in rats. The effect of the combination of the colecistokinin (CCK) receptor antagonist, lorglumide, and P. vulgaris dry extract on food intake was also investigated. Administration of doses of P. vulgaris dry extract devoid of any behavioral toxicity dose-dependently decreased food intake (irrespective of the diet), body weight gain, and glycemia. Pretreatment with lorglumide blocked the reducing effect of P. vulgaris dry extract on food intake. The capacity of this P. vulgaris dry extract to reduce food intake, body weight, and glycemia in rats may be due to (a) inhibition of alpha-amylase, (b) stimulation of CCK release from the intestinal brush border cells, and/or (c) interference with the central mechanism(s) regulating appetite, food intake, and food palatability.