The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse

Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on the rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way.     

Morphine in combination with metabotropic glutamate receptor antagonists on schedule-controlled responding and thermal nociception

The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule-controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose-addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] all decreased rates of schedule-controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685 and LY341495 potentiated the antinociceptive effects of morphine, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.     

Hospitalization patterns before and after liver transplantation

BACKGROUND: Mortality among patients with chronic liver failure is significantly reduced upon liver transplantation. However, decreases in mortality may not be accompanied by decreases in morbidity metrics, such as hospitalization rates. We compared pre- and posttransplant hospitalization rates for liver transplant recipients. METHODS: Statewide hospitalization data were analyzed among 215 adult chronic liver failure patients in Pennsylvania who received a deceased donor transplant from September 2001 to December 2002. Generalized estimating equation (GEE) models were fitted to compare covariate-adjusted pre- and posttransplant hospital admission rates and mean length of stay per admission. The study minimized biases by calculating pre- and posttransplant morbidity in a cohort restricted to patients who received a transplant and were compared to themselves. RESULTS: Liver transplant recipients experienced a significant 70% reduction in hospitalization rates (P<0.0001) posttransplant versus pretransplant. The decline, which occurred for all Model for End-Stage Liver Disease (MELD) subgroups, was significant for patients transplanted at all MELD scores except 6-9. However, even patients with MELD 6-9 experienced a significant decrease in mean length of stay, post versus pretransplant. Higher MELD scores at transplant were generally associated with a greater reduction in hospitalization rates. Also, patients transplanted with lower MELD scores appeared to receive lower quality livers. CONCLUSIONS: Our results indicate that the benefit of transplantation extends beyond patient survival and that an important reduction in hospitalization rates is experienced by transplanted patients. Further study is required to determine whether these results are generalizable to the entire United States and to evaluate the donor liver quality used for recipients of different MELD scores.     

Continuous exposure to the competitive <Emphasis Type="BoldItalic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate receptor antagonist,LY235959, facilitates escalation of cocaine consumption in Sprague–Dawley rats

Rationale Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood. Objectives This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-d-aspartate (NMDA) receptors. Materials and methods Male Sprague–Dawley rats (n = 63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions. Results Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08–1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment. Conclusions These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure. Preliminary reports of these data were presented at the 2003 meeting of the Society for Neuroscience (New Orleans, LA) and the 2005 meeting of the College on Problems of Drug Dependence (Orlando, FL).     

Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells.

Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationic-substituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin. The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P. carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I- and II-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.     

Predicted Lifetimes for Adult and Pediatric Split Liver Versus Adult Whole Liver Transplant Recipients

Split liver transplantation allows 2 recipients to receive transplants from one organ. Comparisons of predicted lifetimes for two alternatives (split liver for an adult and pediatric recipient vs. whole liver for an adult recipient) can help guide the use of donor livers. We analyzed mortality risk for 48,888 waitlisted candidates, 907 split and 21,913 whole deceased donor liver transplant recipients between January 1, 1995 and February 26, 2002. Cox regression models for pediatric and adult patients assessed average relative wait list and post-transplant death risks, for split liver recipients. Life years gained compared with remaining on the waiting list over a 2-year period were calculated. Seventy-six splits (152 recipients) and 24 re-transplants resulted from every 100 livers (13.1% [adult] and 18.0% [pediatric] 2-year re-transplant rates, respectively). Whole livers used for 93 adults also utilized 100 livers (re-transplant rate 7.0%). Eleven extra life years and 59 incremental recipients accrued from each 100 livers used for split compared with whole organ transplants. Split liver transplantation could provide enough organs to satisfy the entire current demand for pediatric donor livers in the United States, provide more aggregate years of life than whole organ transplants and result in larger numbers of recipients.     

Use of phenylpropanolamine to reduce nicotine cessation induced weight gain in rats

The present study was conducted to determine if phenylpropanolamine (PPA) administered during the first week of nicotine termination could reduce or eliminate the body weight rebound which accompanies nicotine cessation. Sprague-Dawley rats were administered nicotine for 2 weeks after which they received either PPA or saline for 1 week. Control animals received saline during both drug periods. Body weight, food consumption, and water consumption were measured daily before drug, during nicotine and PPA administration, and for 14 days after PPA administration. In contrast to animals receiving saline upon termination of nicotine, animals receiving PPA did not gain weight at an accelerated rate. Termination of PPA did not result in a body weight rebound. To the extent that these results generalize to humans, they suggest that PPA could be used to reduce or eliminate postcessation weight gain in smokers who stop smoking.     

Efficacy of a simplified lower gastrointestinal flexible endoscope cleaning method

Published guidelines from the Center for Disease Control (CDC) “strongly recommended” gas sterilization or 30 minutes of high-level disinfection with either 2 percent glutaradehyde or 6 percent hydrogen peroxide following each flexible endoscope cleansing for proper care. The guidelines were proposed on the basis of previous CDC studies performed on glutaraldehyde disinfection of respiratory equipment. A prospective study was performed culturing flexible endoscopes following cannulation of the lower gastroinstestinal tract and cleansing. A uniform endoscope cleansing method without gas sterilization or high-level disinfection was used between patients. Thirty aerobic and 30 anaerobic RODAC bacterial culturings revealed no obligate anaerobic organism growth and only sparse, aerobic, environmental and cutaneous organism growth. These were no instances of documented or suspected postendoscopy infectious complications. Our results indicate that high-level disinfection and gas sterilization of flexible endoscopes are not necessary to prevent bacterial disease transmission from patient to patient. Read at the joint meeting of the American Society of Colon and Rectal Surgeons with the Section of Colo-Proctology, Royal Society of Medicine, and the Section of Colonic and Rectal Surgery, Royal Australasian College of Surgeons, New Orleans, Louisiana, May 6 to 11, 1984.     

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