Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol

delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.     

Facilitating internalization: the self-determination theory perspective

Self-determination theory (Deci & Ryan, 1985) posits that (a) people are inherently motivated to internalize the regulation of uninteresting though important activities; (b) there are two different processes through which such internalization can occur, resulting in qualitatively different styles of self-regulation; and (c) the social context influences which internalization process and regulatory style occur. The two types of internalization are introjection, which entails taking in a value or regulatory process but not accepting it as one's own, and integration, through which the regulation is assimilated with one's core sense of self. Introjection results in internally controlling regulation, whereas integration results in self-determination. An experiment supported our hypothesis that three facilitating contextual factors--namely, providing a meaningful rationale, acknowledging the behaver's feelings, and conveying choice--promote internalization, as evidenced by the subsequent self-regulation of behavior. This experiment also supported our expectation that when the social context supports self-determination, integration tends to occur, whereas when the context does not support self-determination, introjection tends to occur.     

Structure-activity relationships of a series of 1-substituted-4-methylbenzimidazole neuropeptide Y-1 receptor antagonists

A 50-year-old male is described who presented with Fournier's gangrene as what is probably the first manifestation of a newly diagnosed acute myelogenous leukemia (AML), promyelocytic type or variant type M3 according to the FAB classification. Despite aggressive fluid resuscitation, tuned infusion of vasoactive drugs, appropriate antibiotics and extensive surgical debridement, the patient died within 24 h as a result of irreversible septic shock.     

Aminohydroxybutane bisphosphonate and clenbuterol prevent bone changes and retard muscle atrophy respectively in tail-suspended rats

Hind-limb unloading by tail suspension of rats, an established model of simulated microgravity, was used to examine the efficacy of aminohydroxybutane bisphosphonate (AHBuBP) and clenbuterol in preventing bone loss and muscle atrophy, respectively. Male Sprague-Dawley rats (299-372 g) were randomized into six groups of six: 1) unsuspended, saline, 2) unsuspended, saline, pair fed with group 3, 3) suspended, saline, 4) suspended, 0.03 mg/kg/day x 2 of AHBuBP, 5) suspended, 0.3 mg/kg/day x 2 of AHBuBP and 6) suspended, 0.3 mg/kg/day x 2 of AHBuBP + clenbuterol (0.5 mg/kg/day i.p. x 6, then 1 mg/kg/day i.p. x 6). Animals in groups 3 to 6 were tail suspended for 14 days from a system of double pulleys and allowed free mobility with their hind limbs unloaded. On days -2 and -1, before suspension on day 0, all rats received a single s.c. injection of either 2 ml/kg of normal saline (vehicle) or AHBuBP. All rats were tested for exercise tolerance before day -2 and on day 10, and grip strength before day -2 and on day 13. On day 14, the rats were euthanized and their humeri, tibias and femurs analyzed in vitro for bone density (by single-photon absorptiometry), strength and stiffness (by 3-point bending). Muscles were analyzed for weight, protein concentration and enzyme activity. Pair feeding had no effect other than on food consumption and body weight. AHBuBP caused a dose-dependent increase in bone density in humeri, tibias and femurs, even in tail-suspended rats, relative to control unsuspended animals, with no significant difference in bone strength or stiffness between AHBuBP groups and unsuspended animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carcinogens in food: priorities for regulatory action

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the population. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such compounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.