Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. Objective: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. Methods: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed. Received: 22 January 1999 / Final version: 16 April 1999     

Continuous infusion of rocuronium in a paediatric intensive care unit

Purpose  

To evaluate prospectively the efficacy and dose requirements of rocuronium administered by continuous infusion for neuromuscular blockade in a paediatric ICU population.     

Postoperative Intensive Care Treatment after Esophageal Resection

The aim of this article is to give a short review of problems associated with the intensive caretreatment of patients after esophageal resection.Pulmonary dysfunction,supraventricular tachyarrhyth-mia,anastomotie leakage and mental disorders are the topics covered.Systemic inflammatory reaction andsepsis is the linking topic between these specific complications.Pulmonary dysfunction having an incidenceof up to 40% is the most important complication.Low tidal volume ventilation,pain management includingepidural analgesia and early tracheostomy are the mainstay of therapy.Supraventricular tachyarrhythmiais an early indicator of emerging complications.Its symptomatic treatment is standardized using electriccardioversion,beta-blockers and amiodarone.Anastomotic leakage must be suspect in any septic episode.Endoscopy and contrast studies allow for precise diagnosis.Interventional endoscopy is increasingly suc-cessful in the therapy of these leakages.Microbiological surveillance and specific antibiotic therapy ensurethat a complication does not cause a septic cascade leading to multiorgan failure.The workload on ICUcaused by a patient after esophageal resection still exceeds that of most other patients with gastrointestinalsurgery.     

Rapacuronium administration to two children with Duchenne's muscular dystrophy

Children with Duchenne's muscular dystrophy should not be exposed to succinylcholine because of the risk of hyperkalemic cardiac arrest and rhabdomyolysis. This report describes the response to rapacuronium bromide in two patients with Duchenne's muscular dystrophy. Both patients had a recovery index 2 times longer than that reported in children with normal neuromuscular function.