Nalmefene - d3

In vivo characterization of the opioid antagonist nalmefene in mice.[Pubmed:20159022]

Life Sci. 2010 Apr 10;86(15-16):624-30.

AIMS: The current study assessed the in vivo antagonist properties of nalmefene using procedures previously used to characterize the opioid antagonists naloxone, naltrexone, 6beta-naltrexol and nalbuphine. MAIN METHODS: ICR mice were used to generate antagonist dose-response curves with intraperitoneal (i.p.) nalmefene against fixed A(90) doses of morphine in models of morphine-stimulated hyperlocomotion and antinociception. Additional dose-response curves for antagonist precipitated opioid withdrawal were run in mice treated acutely (100mg/kg, s.c., -4h) or chronically (75mg pellet, s.c., -72h) with morphine. Comparisons were made between antagonist potency and degree of precipitated withdrawal. KEY FINDINGS: Nalmefene produced dose- and time-related antagonism of morphine-induced increases in locomotor activity with a calculated ID(50) (and 95% confidence interval) of 0.014 (0.007-0.027)mg/kg. Nalmefene produced rapid reversal of morphine-induced locomotor activity (5.1min for 50% reduction in morphine effect). A 0.32mg/kg dose of nalmefene produced blockade of morphine-induced antinociception in the 55 degrees C tail-flick test that lasted approximately 2h. Nalmefene was able to potently precipitate withdrawal in mice treated acutely or chronically with morphine. SIGNIFICANCE: These results demonstrate that nalmefene is similar to naloxone and naltrexone with respect to its in vivo pharmacology in mice. Specifically, nalmefene produces potent antagonism of morphine agonist effects while precipitating severe withdrawal. The compound has a slower onset and longer duration of action compared to naloxone and naltrexone. The data allows for a more complete preclinical comparison of nalmefene against other opioid antagonists including the putative opioid neutral antagonist 6beta-naltrexol.

Nalmefene: a long-acting opioid antagonist. Clinical applications in emergency medicine.[Pubmed:9610980]

J Emerg Med. 1998 May-Jun;16(3):471-5.

The use of the opioid antagonist naloxone is well known to the experienced health care provider. The availability of the longer acting opioid antagonist nalmefene has several potential benefits in clinical practice. Nalmefene has a plasma half-life of almost 11 h, compared to 60-90 min for naloxone. Nalmefene has been shown to reverse opioid intoxication for as long as 8 h, reducing the need for continuous monitoring of intoxicated patients and repeated dosing of naloxone. Single dose administration has also been used effectively in the reversal of opiate-assisted conscious sedation. In addition, this agent has been used in the treatment of diseases as diverse as interstitial cystitis and chronic alcohol dependence. However, the long duration of action enables extended withdrawal reactions in the chronically opioid-dependent patient. The prolonged opioid antagonism of nalmefene has several applications in the clinical practice of emergency medicine, and is a useful addition in certain situations to the pharmacologic armamentarium of the practicing emergency physician.

Binding of a new opiate antagonist, nalmefene, to rat brain membranes.[Pubmed:2991678]

Methods Find Exp Clin Pharmacol. 1985 Apr;7(4):175-7.

Nalmefene (6-methylene-naltrexone) is a potent, orally active, opiate antagonist. IC50's were obtained for nalmefene, naloxone and naltrexone using radiolabelled prototype ligands for mu, kappa and delta receptors in homogenates of rat brain minus cerebellum. Nalmefene antagonized the bindings of [3H]-dihydromorphine, [3H]-ethylketocyclazocine and [3H]-D-ala-D-leu enkephalin with IC50's in the low nanomolar range. At the central mu receptor, nalmefene bound with an IC50 of 1.0 nM, equal to that of naltrexone and approximately four times lower than that of naloxone. At central kappa and delta sites the IC50's for nalmefene were somewhat lower than those of naltrexone and considerably lower than those of naloxone. All three antagonists had sodium indices less than 1.0. These results indicate that nalmefene is a universal opiate antagonist, has no agonist character at the central mu site and binds more effectively to central opiate receptors than either naloxone or naltrexone.