DEVELOPMENT OF A METHOD FOR PRODUCING (-)-17-ALLYL-4,5Ά-EPOXY-3,14-DIHYDROXYMORPHINAN-6-ONE

Naloxone ((-)-17-allyl-4,5ά-epoxy-3,14-dihydroxymorphinan-6-one) is a pure opiate antagonist of a competitive type devoid of morphine-like activity and is widely used in clinical practice. The main raw material for the production of naloxone is thebaine, which is extracted from plant materials. This study presents a seven-step process for preparing naloxone with a yield of 35% (based on thebaine). Previously known methods of obtaining are characterized by the yield of the target product in terms of thebaine not higher than 20%. The greatest losses are recorded at the stage of obtaining oxycodone from thebaine and at the stage of O-demethylation of codeine. The use of formic acid in the hydrogenation process provides a more complete conversion of the intermediate product, and the use of boron tribromide in the environment of chloroalkanes at the stage of O-demethylation leads to the production of naloxone with a yield of more than 70%. A detailed study of the stages of obtaining oxycodone and noroxycodone allows to reduce the consumption of reagents and the time spent in the reactor, which is essential for reducing the cost of the final product. The proposed method is superior to those known in terms of productivity and economic efficiency and can be used for the development of industrial technology for the production of naloxone and its derivatives.

Naloxone Ameliorates Spatial Memory Deficits and Hyperthermia Induced by a Neurotoxic Methamphetamine Regimen in Male Rats

Background: Methamphetamine (METH) as a synthetic psychostimulant is being increasingly recognized as a worldwide problem, which may induce memory impairment. On the other hand, it is well established that naloxone, an opiate antagonist, has some beneficial effects on learning and memory. The present research aimed at evaluating naloxone effects on spatial learning and memory impairment triggered by a neurotoxic regimen of METH in male rats. Materials and Methods: The animals received the subcutaneous (sc) regimen of METH (4×6 mg/kg at 2-h intervals), intraperitoneal (ip) naloxone (4×1 mg/kg at 2-h intervals), or normal saline at four events. The Nal-METH group of rats received four naloxone injections (1 mg/kg, ip) 30 min before each METH injection (6 mg/kg, sc) at 2-h intervals. Seven days later, they were evaluated for spatial learning and memory in the Morris Water Maze (MWM) task. Result: METH regimen induced hyperthermia, as well as a poor performance, in the acquisition and retention phases of the task, indicating spatial learning and memory impairment compared to the controls. Naloxone administration (1 mg/kg, ip) before each METH injection led to significant attenuations of both hyperthermia and METH adverse effects on the rat performance in the MWM task. Conclusion: The results revealed that pretreatment with the opiate antagonist naloxone could prevent METH adverse effects on body temperature and memory performance. It seems that the opioidergic system and hyperthermia may, at least partially, be involved in METH effects on spatial memory. [GMJ. 2019;8:e1182]

Ultrarapid Opiate Detoxification

Extended opioid use results in physical dependence and neural adaptation. Opioid dependence treatment can be carried out with opioid receptor agonists, partial agonists, and antagonists. Conventional treatments have low success rates. Methadone and buprenorphine treatments involve substituting long-duration agonists for the opiate of abuse, essentially substituting one opiate for another. Rapid opiate detoxification is a 3-day process involving large amounts of an opiate antagonist. Both treatments have associated problems. Ultrarapid opiate detoxification (UROD) anesthetizes a patient and precipitates withdrawal while unconscious. It shortens withdrawal, avoiding much of the subjective withdrawal discomfort. Clonidine is critical to reduce catecholamine levels and mitigate central nervous system hyperarousal in acute withdrawal. A UROD advantage is that the withdrawal period is markedly shortened to 8 hours or less versus up to several months for conventional treatments. The patient is anesthetized during the acute withdrawal period and does not experience the unpleasant consequences of acute detoxification.

From Bench to Bedside and Back Again

Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. Anesthesiology 1988; 125:590–4. Abstract reprinted with permission. The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.