Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.
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PMID:Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats. 1293 Nov 40

Oral naltrexone, a nonselective opioid antagonist, is approved for the treatment of alcohol and opioid dependence. However, the efficacy of oral naltrexone is limited by poor patient compliance. To overcome this limitation, attempts have been made to develop an injectable extended-release formulation of naltrexone, including encapsulation into biodegradable polymer microspheres (e.g. Medisorb Naltrexone, Vivitrex (naltrexone long acting injection)). In 1980, NIDA established development goals that they considered optimal for an extended-release formulation. At Alkermes, different formulations were tested with in vitro assays and in vivo models to select a lead formulation. Pharmacokinetic studies in rats confirmed that the principle formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately one month following a single injection. The pharmacodynamic effects (antagonism of morphine analgesia) of extended-release naltrexone corresponded well with the pharmacokinetic profile from the same animals. While brain mu-opioid receptor density was found to increase over time in these rats, it did not appear to affect the ability of naltrexone to suppress morphine analgesia. Finally the pharmacokinetic profile of extended-release naltrexone in monkeys confirmed long duration of elevated plasma concentrations of naltrexone. Both naltrexone and the PLG polymer matrix in which it is encapsulated are well tolerated. Clinical trials of Vivitrex are currently ongoing in alcohol dependent patients.
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PMID:The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence. 1556 5