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At least 19 recordsLinked to original sources
PubMed1975

Metabolic reduction of naltrexone. I. Synthesis, separation and characterization of naloxone and naltrexone reduction products and qualitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or beta-naltrexol.

Reduction of naltrexone and naloxone with sodium borohydride gave a mixture (85:15) of the 6alpha- and 6beta-hydroxy epimers, alpha- and beta-naltrexol and alpha- and beta-naloxol, respectively. Each pair of epimers was separated by preparative thin-layer chromatography and the physical and spectral properties of each compound were determined. Previous assignments for the configuration of the epimers were verified. A semi-quantitative electron capture gas-liquid chromatographic method was devised for distinguishing either alpha- or beta-naltrexol in the presence of the other and in the presence of large amounts (at least 10-fold greater) of naltrexone. The method was used to determine the approximate weight ratio of beta-naltrexol to naltrexone present in enzymatically hydrolyzed urine samples. It was found that substantially greater quantities of beta-naltrexol and/or its conjugates were excreted in the urine of man, monkey, guinea pig and rabbit after administration of naltrexone, whereas very small quantities were excreted by the mouse, rat and dog. In contrast, just trace amounts of the 6alpha-hydroxy epimer, alpha-naltrexol, were detected in the urine of only 2 of the 7 species that had received naltrexone, i.e., monkey and guinea pig. After administration of 3H-15,16-naltrexone, 1 mg/kg, i.v. to the guinea pig, 25% of the radioactivity found following thin-layer chromatography of the extract of acid-hydrolyzed urine corresponded to beta-naltrexol. In gall bladder bile from the guinea pig, only conjugates of naltrexone and beta-naltrexol were found 2 hours after administration of naltrexone. Following administration of beta-naltrexol, 1 mg/kg, i.v. to guinea pigs only beta-naltrexol and/or its conjugates were detected in urine or bile. However, urine collected after administration of alpha-naltrexol, 1 mg/kg, i.v. to guinea pigs contained alpha-naltrexol and its conjugates, as well as a yet unidentified metabolite.

Animals↗
PubMed1976

Comparison of two naltrexone treatment programs: naltrexone alone versus naltrexone plus behavior therapy.

During a period of one year naltrexone was given to twenty-nine subjects. Fifteen of these subjects concurrently participated in a comprehensive behavior therapy program. The subjects in this naltrexone/behavior therapy group were maintanine on naltrexone for nearly twice as long as naltrexone group clients who received no therapy. If the chances for readdiction are reduced by increased time on naltrexone, then the data states the naltrexone should be dispensed as part of a broader therapeutic strategy. Follow-up data, which will be collected during the next year will test the validity of this hypothesis.

Adult↗
PubMed1977

Quantitative determination of naltrexone and naltrexone prodrugs by electron-capture gas-liquid chromatography.

An electron-capture gas chromatographic method has been applied to the determination of eleven ester and ether derivatives of naltrexone believed to act as prodrugs. Standard analytical curves are presented for all prodrugs and quantitation is shown to be possible from 10 ng to 1.5 microgram of each compound. Ester derivatives of naltrexone are hydrolyzed to naltrexone prior to analysis as the perfluoroalkyl esters. Analysis of synthetic mixtures of these with naltrexone demonstrated that quantitation by difference measurements is possible with naltrexone-derivative ratios from 4:1 to 1:10. Ether derivatives are analyzed without hydrolysis. This method is applicable to biological fluids as well as aqueous solutions.

Chromatography, Gas↗
PubMed1976

Naltrexone: disposition, metabolism, and effects after acute and chronic dosing.

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.

Adult↗
PubMed1979

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.

Animals↗
PubMed2026

Naltrexone Is Superior to Placebo for Abstinence and Craving Reduction in Alcohol-Associated Cirrhosis: NAL-CI Trial.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) coexisting with cirrhosis carries high morbidity and mortality, with no approved pharmacotherapy for AUD. We evaluated the safety and efficacy of naltrexone, an opioid receptor antagonist, in patients with compensated alcohol-associated cirrhosis (AaC) and AUD. METHODS: One hundred patients with compensated AaC and DSM-5 AUD were randomised 1:1 to naltrexone (50&#x2009;mg/day) or placebo for 12&#x2009;weeks. The primary endpoint was point-prevalence abstinence at 12&#x2009;weeks, defined as no alcohol use in the four preceding weeks. Secondary endpoints included craving (Obsessive Compulsive Drinking Scale [OCDS]-Obsessive and Compulsive subscales), lapses, relapses, and hepatic safety. Standardised psychosocial support was provided to both arms. RESULTS: Baseline characteristics were well matched between groups (mean MELD 12.6 vs. 12.7; CTP score 5.9 vs. 6.2; age 42.9 vs. 44.3&#x2009;years). AUDIT and OCDS scores were comparable between groups. Abstinence at 12&#x2009;weeks was significantly higher with naltrexone: 64% (32/50) versus 22% (11/50), p&#x2009;<&#x2009;0.001; OR 10.86 (95% CI: 1.89-62.2). Naltrexone significantly reduced lapses at 3&#x2009;months (28% vs. 54%, p&#x2009;=&#x2009;0.008) and showed a trend toward fewer heavy-drinking relapses (12% vs. 28%, p&#x2009;=&#x2009;0.07). Maintenance of abstinence at 6&#x2009;months favoured naltrexone (22% vs. 8%, p&#x2009;=&#x2009;0.09). No patient developed hepatic decompensation attributable to study medication, and no AST/ALT elevation exceeding 5&#xd7; ULN was observed in either group. Mean craving scores were lower with naltrexone by week 12 than with placebo: OCDS-O score (6.63&#x2009;&#xb1;&#x2009;1.16 vs. 9.29&#x2009;&#xb1;&#x2009;1.78, p&#x2009;<&#x2009;0.01) and OCDS-C score (6.35&#x2009;&#xb1;&#x2009;1.23 vs. 9.02&#x2009;&#xb1;&#x2009;1.86, p&#x2009;<&#x2009;0.01). Adverse events were comparable between the groups. CONCLUSION: Naltrexone is safe and effective in patients with compensated alcohol-associated cirrhosis, achieving a threefold higher abstinence rate and significantly reducing craving compared with placebo. These findings support the use of naltrexone as a pharmacological option in patients with compensated AaC and AUD. TRIAL REGISTRATION: NCT04391764.

Humans↗
PubMedDate not supplied

The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat.

A gas-chromatographic method has been developed for the simultaneous determination of naltrexone, alpha-naltrexol, and beta-naltrexol as trimethylsiyl derivatives. Analysis of urine from rabbit, monkey, and rat demonstrated that, like man, these species reduce naltrexone primarily to beta-naltrexol. In naltrexone maintenance patients receiving 125 mg po three times per week, an average of 37% of the dose was recovered in 48-hr urine as free naltrexone (0.8%), conjugated naltrexone (7.6%), free beta-naltrexol (16.8%), and conjugated beta-naltrexol (11.8%). Thirty-four percent of the dose appeared in 0-24 hr and 3% during 24-48 hr. The ratio of beta-naltrexol to naltrexone rose from 2 at 0-4 hr to 34-48 hr. Monkeys receiving a daily dose of 12 mg/kg po, chronically, excreted very little free beta-naltrexol and exhibited an apparent sex-related difference in excretion patterns, with females excreting more than twice as much total base as males. Rabbits given a dose of 30 mg/kg ip for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 hr. In rats receiving 100 mg/kg po, less than 1% of the administered dose could be accounted for in the 24-hr urine, indicating that although the beta-naltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. Thus, in man and the monkey, beta-naltrexol is the predominant and persistent urinary metabolite. Urinary excretion profiles of naltrexone differ greatly between species commonly examined for chronic toxicity studies.

Administration, Oral↗
PubMed1979

Discriminative stimulus effects of naltrexone in the morphine-dependent rat.

Rats maintained physically dependent upon morphine by scheduled access to drinking water containing morphine were trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone in a discrete trial avoidance procedure in which a response on one of two choice levers would prevent or terminate the delivery of mild electric shocks to the floor of the test chember. Stimulus control of behavior by naltrexone in the morphine-dependent rat (defined as the reliable completion of at least 18 trials of a 20-trial session on the appropriate choice lever) had many of the features previously described for the stimulus control of behavior by morphine in the nondependent rat: long-term stability and reproducibility, orderly dose- and time-effect relationships and pharmacologic specificity. Stimulus control by naltrexone was blocked in a dose-related manner by morphine, an effect completely surmounted by a 10-fold increase in the dose of naltrexone suggesting a competitive antagonism. The naltrexone-induced discriminative stimuli appeared to be related to precipitated morphine withdrawal phenomena: following the abrupt withdrawal of morphine the amount and time course of naltrexone-appropriate responding were directly related to the degree of physical dependence; loss of body weight, a reliable index of morphine withdrawal in the rat, paralleled changes in naltrexone-appropriate responding; the maximum level of naltrexone-appropriate responding produced by a total of eight narcotic antagonists with agonist activity of differing prominence was a function of the extent of separation of the agonist and antagonist components of action of the drugs. Control of behavior by stimuli associated with morphine withdrawal may afford a specific animal model for studying factors relevant to the perpetuation of chronic drug use by human addicts.

Animals↗
PubMed1976

Tritiated naltrexone binding in plasma from several species and tissue distribution in mice.

The binding of 15,16,-3H-naltrexone in human, monkey, dog, guinea pig, rat, and mouse plasma was investigated over a range of concentrations, including predicted therapeutic levels. Studies using equilibrium dialysis at 37 degrees indicate that the extent of binding is independent of naltrexone concentration over the concentration range of 1-500 ng/ml for dog plasma and of 0.1-500 ng/ml for human, monkey, guinea pig, rat, and mouse plasma. The extent of naltrexone binding in plasma is similar in the six species studied, the range being from 20% bound in rat plasma to 26% in plasma from beagle and mongrel dogs. This relatively low extent of naltrexone binding in plasma is consistent with previous findings of a large apparent volume of distribution of this drug in the dog. To investigate further the distribution of tritiated naltrexone, the tissue levels of radioactivity in mice at 1, 5, and 15 min after intravenous administration of 8-3H-naltrexone were determined. Naltrexone was rapidly distributed from plasma to tissues, with less than 4% of the dose being present in plasma at 1 min after injection.

Animals↗
PubMed1978

Narcotic antagonist treatment: clinical experience with naltrexone.

Narcotic antagonist (naltrexone) treatment experience with 22 opioid addicts over a 29-month period shows that the mean duration of receipt of naltrexone was 6.2 weeks, and 12 subjects (55%) continued in treatment after cessation of naltrexone for an average of 5.6 weeks. Analysis of physical and behavioral measured revealed no toxicity, indicating that naltrexone appears to be a safe drug. Clinical evaluation of the patients receiving naltrexone suggests that ingestion of naltrexone provides a degree of external control, reducing the preoccupation with heroin and releasing energy for the pursuit of other goals. Subject follow-up at an average of 45.3 weeks after cessation of naltrexone indicated that 11 (58%) were known to be abstinent, and 9 (47%) subjects were employed compared with 3 (16%) employed at the onset of treatment.

Adolescent↗
PubMedDate not supplied

Disposition of (15,16-3H)naltrexone in the central nervous system of the rat.

After injection of (15,16-3H)naltrexone (10 mg/kg s.c.) in male Wistar rats, peak concentrations of drug occurred in brain and plasma within 0.5 hr. Levels of naltrexone were sustained in brain between 2 and 24 hr and were barely detectable at 48 hr. Significant amounts of metabolities were present in brain and plasma at longer time periods. The t1/2 of naltrexone in brain and plasma were approximately 8.0 and 11.4 hr. respectively. The brain/plasma ratios of naltrexone at earlier times (0.5-1 hr) were higher than those at later times. The binding of naltrexone in vitro with rat plasma proteins in concentrations of 1-10 mug/ml ranged between 41 and 59% 6beta-Naltrexol was present in very small amounts in brain but not in plasma. In addition to 7,8-dihydro-14-hydroxynormophinone and 7,8-dihydro-14-hydroxynormophine, tentative evidence was obtained for three other metabolites of naltrexone in brain. These metabolites were also present in plasma in addition to free and conjugated naltrexone and its N-dealkylated metabolites.

Animals↗
PubMed1979

Evidence supporting lack of discriminative stimulus properties of a combination of naltrexone and morphine.

The aim of the present experiment was to study the potentially discriminable effects of combinations of morphine and naltrexone during long-term treatment. Three groups of gerbils had to discriminate the effects of morphine (12 mg/kg) and those of either saline (4 ml/kg), naltrexone (2 mg/kg), or a combination of this dose of morphine plus naltrexone injected IP 60 min prior to the start of the discriminative training in a T-shaped maze. Rapid development of drug discriminative control of choice behavior (left or right turn in the maze) was evident in these 3 groups which is in marked contrast to the performance of gerbils trained with morphine-naltrexone combination vs. saline or gerbils trained with naltrexone only vs. saline. Neither of these latter groups reached the criterion of performing 8 correct first-trial choices in 10 consecutive training sessions during the 60 training sessions allowed, while the 3 other groups began their criterion performance after only 7--8 training sessions. Thus the discriminative properties of certain combinations of morphine and naltrexone are weak and therfore are not easily discriminable from the effects induced by saline.

Animals↗
PubMed1978

Continuous intravenous naltrexone effects on morphine self-administration in rhesus monkeys.

Rhesus monkeys, surgically prepared with intravenous catheters, were given opportunities to self-administer morphine for 3 days, methamphetamine for 2 days and saline for 2 days in a constantly repeating cycle. Access to drugs was limited to a 15-minute period every 4 hours. After stable base-line self-administration rates, saline or various concentrations of naltrexone were infused continuously through the catheter. In the first phase of the study each concentration of naltrexone was infused for 4 weeks (separated by 3 weeks of saline) while the dose of morphine available for self-administration was held constant at 8 microgram/kg/injection. Stable naltrexone dose-related suppression of morphine self-administration occurred throughout each 4-week infusion. In the second phase of the study, various doses of morphine were made available for self-administration during 6- to 8-week continuous infusions of saline or various concentrations of naltrexone. The dose-effect curve relating self-administration rate to morphine dose per injection shifted to the right and decreased in maximum as the rate of infusion of naltrexone increased. Methamphetamine and saline self-administration rates were unaffected by naltrexone.

Animals↗
PubMed1976

Short-term effects of naltrexone in 155 heroin ex-addicts.

The narcotic antagonist naltrexone was administered for periods of up to 8 months to a total of 155 patients at a dose of 40-200 mg per day. The antagonistic effect of naltrexone was tested by injections of heroin. Eighty milligrams of natrexone was effective for 48hr. The antagonistic effect decreased at 72 hr after the administration of 120-200 mg of naltrexone. Laboratory tests indicated no signs of toxicity. Naltrexone may elicit an increase in blood pressure and opigastric pain. Neither of these side effects appear clinically important. No signs of dependence on naltrexone were detected. These results suggest that naltrexone may be useful for clinical treatment of opiate dependence.

Abdomen↗
PubMed1975

Narcotic antagonist activity of several metabolites of naloxone and naltrexone tested in morphine dependent mice (38558).

A rabbit liver enzyme system was used to produce the 6beta-OH reduced metabolites of naloxone and naltrexone. GC analysis indicated the presence of some 6alpha-OH metabolite in these samples. The narcotic antagonist activity of these 6beta-OH metabolite samples were compared to naloxone, naltrexone and standard 6alpha-OH naltrexone (EN-2260A) using the jumping response of morphine pellet implanted mice. For the naloxone series, the potencies were: Naloxone greater than EN 2265A greater than 6 beta-OH maloxone. For the naltrexone series: Naltrexone greater than EN 2260A greater than beta-OH naltrexone. The low potency of the reduced metabolites the rapid onset of action of the parent compounds militate against the formation of these metabolites contributing substantially to the overall narcotic antagonist action of the parent compounds.

Animals↗
PubMed1977

Naltrexone and cyclazocine. A controlled treatment study.

The induction side effects of cyclazocine and naltrexone were compared in double-blind placebo-controlled studies involving 40 patients (20 for each drug). These studies were carried out with a twice-a-day dosage regimen. Naltrexone produced fewer side effects than cyclazocine. Naltrexone side effects fell to levels indistinguishable from those of placebo in the "induction after placebo" phase. In contrast, cyclazocine "induction after placebo" produced an even higher level of side effects than found in its induction. In no case was naltrexone discontinued because of side effects. On the other hand, three of 20 cyclazocine-treated patients discontinued the drug because of distressing side effects. No toxicity was noted with either agent. The controlled data reported supports the clinical impression that naltrexone produces fewer induction side effects than cyclazocine.

Administration, Oral↗
PubMed1976

Naltrexone-induced hypothermia in the rat.

Naltrexone, in relatively high doses, has been reported to cause a fall in body temperature in human ex-heroin addicts who had been abstinent for at least 6 weeks. The underlying mechanism of this hypothermic effect has been investigated in rats. The first consideration was that the temperature change was a reflection of delayed withdrawal but rats implanted with a morphine pellet 45 days earlier showed no significant change in temperature after a dose of naltrexone that caused marked withdrawal hypothermia in dependent rats implanted 3 days previously. A fall in core temperature was only induced in rats after doses of 80 and 160 mg/kg i.p. of naltrexone. Behavioral thermoregulatory studies revealed that the animals correct the falling body temperature by increased exposure to a radiant heat source indicating that the central thermostats had not been significantly affected by the drug. These data suggest that the major component in the hypothermic effect of naltrexone is activation of efferent heat loss pathways or peripheral heat loss mechanisms. Due to current suggestions that opiate receptors might represent the receptors for an endogenous transmitter the results are discussed in relation to this consideration. When compared to the sites and mechanism of action of opiates on thermoregulation the results with naltrexone lend little support to the hypothesis that the fall in temperature is due to displacement of an endogenous substance from central opiate receptors.

Animals↗