The cannabinoid CB1 receptor system is involved in feeding behaviors and the CB1 receptor antagonist SR141716A is an effective antiobesity drug. However, SR141716A also has serious side effects, which prompted the exploration of alternative strategies to modulate this important drug target. Recently a CB1 receptor allosteric modulating site has been discovered and the allosteric modulating activity of several modulators including ORG27569 has been characterized in vitro. Yet, little is known of the in vivo pharmacological effects of ORG27569. This study examined the behavioral pharmacology of ORG27569 in rats. ORG27569 (3.2–10 mg/kg, i.p.) selectively attenuated the hypothermic effects of CB1 receptor agonists CP55940 (0.1–1 mg/kg) and anandamide (3.2–32 mg/kg). In contrast, SR141716A only attenuated the hypothermic effects of CP55940 but not anandamide. SR141716A but not ORG27569 blocked CP55940-induced catalepsy and antinociception. In addition, ORG27569 did not modify SR141716A-elicited grooming and scratching behaviors. In feeding studies, ORG27569 decreased palatable and plain food intake which was partially blocked by CP55940. The hypophagic effect of ORG27569 developed tolerance after 4 days of daily 5.6 mg/kg treatment; however, the effect on body weight gain outlasted the drug treatment for 10 days. These data suggest that ORG27569 may not function as a CB1 receptor allosteric modulator in vivo, although its hypophagic activity still has potential therapeutic utility.
A dosimetry model of refractory ceramic fibers in the hamster lung has been developed based upon the data from recent exposure and recovery experiments conducted by the Research and Consulting Company in Geneva, Switzerland. The modeling results of hamsters showed significant differences from those of an earlier study in rats regarding deposition and clearance of these fibers in the lung. Despite smaller airway size of hamsters, alveolar deposition per breathing cycle in the hamster was found to be higher than that in the rat due to the higher upper airway deposition in rats. The calculated mean deposited fiber size was found to be larger in the hamster, and there were more thin and long fibers deposited in the hamster lung. It was also found that alveolar clearance of refractory ceramic fibers was faster in the hamster. The clearance rate in the hamster did not appear to be fiber size dependent but it varied with lung burden. The higher clearance rate in the hamster resulted in a lower fiber accumulation per unit weight of lung after a long period of exposure. The results of the dosimetry model presented here may contribute to an explanation of different tumorigenic responses observed in the hamster and rat.Recent exposure experiments have shown that hamsters and rats have different tumorigenic responses to kaolin refractory ceramic fibers (RCF) of the same concentration Mast et al., 1994). W h e n these animals inhaled at an exposure concentration of 30 mg/m3, the maximum tolerated dose, 42% of the exposed hamsters developed mesothe-
Orthosteric cannabinoid CB1 receptor antagonists are effective for treating obesity but also have serious side effects (e.g., depression) which limit their clinical utility. Negative allosteric modulators might possess different therapeutic and side effect profiles. This study examined the behavioral effects of a CB1 receptor negative allosteric modulator ORG27569 in rats. CB1 receptor agonists CP55940 (0.1‐1 mg/kg) and anandamide (3.2‐32 mg/kg) dose‐dependently decreased the body temperature in rats. ORG27569 alone had no effect on the body temperature but markedly antagonized CP55940‐ and anandamide‐induced hypothermic effects. CP55940 (0.032‐1 mg/kg) produced marked cataleptic effect. Although the CB1 receptor orthosteric antagonist rimonabant markedly antagonized the cataleptic effect of CP55940, ORG27569 did not alter such an effect. Rimonabant dose‐dependently increased the frequency of grooming and scratching behaviors in rats. ORG27569 alone did not increase the frequency of these observational behaviors and did not alter the potency of rimonabant in this assay. These data suggest that ORG27569 has a different antagonism profile from the orthosteric CB1 receptor antagonist rimonabant in vivo. A better understanding of the antagonism profile of ORG27569 is warranted which may eventually lead to useful therapeutic actions via biased CB1 receptor blockade.(DA034806 and DA033426)
A general model has been developed to describe the deposition and clearance processes of man-made vitreous fibers (MMVFs) in the rat lung at chronic exposure. Fiber removal from the lung by macrophage-mediated mechanical clearance, fiber dissolution, and breakage were considered in the model, and the rates for these mechanisms were determined from the experimental data. It was found that the breakage of long fibers (lf > 20 ym) into short segments and subsequent removal of short segments by macrophages is principally responsible for the fast clearance of long fibers as observed in the experiment. The breakage rate was found to increase with the fiber solubility and decrease with lung burden. An expression for the breakage rate as a function of the fiber in-vitro dissolution rate and lung burden is proposed. AEROSOL SCIENCE AND TECHNOLOGY 29:152-162 (1998) 1998 American Association for Aerosol Research
KINETIC EQUATIONThere are three possible mechanisms for fiber clearance from the lung: (1) macrophage-mediated process, (2) dissolution in the extracellar fluid, and (3) disintegration of fibers and subsequently removal by macro
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