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Biomedical subjects

L W Masten

Publications and source records attributed to L W Masten.

27 records · Page 2Linked to original sources
PubMed1979

Additional metabolic correlates of 1-alpha-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: the role of the hepatic microsomal electron transport system.

The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.

Animals↗
PubMed1979

Development of cellular tolerance to lethality and analgesia concurrent with physical dependence following repeated oral administration of LAAM.

Following the repeated oral administration of l-alpha-acetylmethadol (LAAM) employing a dose (28 mg/kg per day) shown to induce its own metabolism by three- to four-fold, mice exhibited a rapid development of cellular tolerance and physical dependence which correlated on a temporal basis with this self-induction of LAAM metabolism. Evidence of cellular tolerance included significant elevations in the LAAM oral LD50, LAAM ICV (intracerebroventricular) LD50, LAAM oral AD50 and the LAAM ICV AD50 following repeated administration of this narcotic. Since the ICV parameters and the morphine AD50 were elevated over water control values, cellular tolerance appeared to play an important role in explaining the elevations noted for the oral parameters because the former were not influenced by changes in the rate of LAAM metabolism. Moreover, SKF-525A, a microsomal enzyme inhibitor, had little effect on the LAAM oral LD50 and the LAAM oral AD50, further indicating a minor role for dispositional tolerance. It is concluded that the induction noted for repeated oral LAAM administration most likely is responsible for generating more potent metabolites which in turn act to produce the cellular tolerance and physical dependence in these mice through constant exposure of the CNS.

Administration, Oral↗
PubMed1978

Tolerance, dependence and lethality in morphine-dependent mice after repeated oral administration of methadone.

Mice were rendered tolerant to and dependent on morphine via a morphine pellet implantation. Three days later methadone hydrochloride was administered at a dose of 100mg/kg per os 3 hours after pellet removal and then daily for a total of 5--6 days. This dose of methadone was shown to exhibit a high efficacy for the blockade of morphine abrupt withdrawal jumping and only minimal toxicity. Under these conditions, the level of analgetic tolerance with respect to morphine and methadone and the level of dependence as measured by the naloxone ED50 were initially elevated by the morphine treatment. However, upon substitution with oral methadone these levels declined with time at a rate which did not differ from that of a group of mice receiving only water after morphine pellet removal. Despite these findings, the methadone treatment was associated with an increasing tolerance to methadone lethality during the administration of this narcotic which was nearly double that of a similarly treated water control group by the sixth day. This observation could not be explained by an elevation in the level of cellular tolerance rendered by the methadone treatment since the morphine LD50 was not elevated following identical treatment with morphine and then methadone. The significance of these results is discussed with respect to the role of methadone administration and its metabolism in the modification of tolerance and dependence.

Administration, Oral↗
PubMed1978

Microsomal enzyme induction following repeated oral administration of LAAM.

The oral administration of 1-alpha-acetylmethadol (LAAM) in the mouse was shown to cause a significant elevation in the hepatic LAAM N-demethylase activity. Compared to the self-induction phenomena found with methadone and propoxyphene, LAAM was three and two times more potent, respectively, on a molar basis than these two structurally similar narcotic analogs. Moreover, microsomal induction by LAAM resulted in significant elevations of aminopyrine N-demethylase and aniline hydroxylase activities. These effects were also correlated with a dose related decrement of pentobarbital sleeping time. Thus LAAM appears to be a relatively potent inducer of microsomal metabolism.

Aminopyrine N-Demethylase↗
PubMedDate not supplied

Isopropanol: acute vapor inhalation neurotoxicity study in rats.

Five groups of 25 Fischer 344 rats of each sex were exposed for 6 h to isopropanol vapor at 0, 500, 1500, 5000 or 10,000 ppm. Behavioral observations for 10 rats of each sex were made prior to and 1, 6, and 24 h after exposure. Motor activity was evaluated for 15 rats of each sex prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10,000 ppm and sedation at 5000 ppm. Prostration or severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10,000 ppm isopropanol vapor. Similar, but less severe, alterations were observed in animals in the 5000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor activity were observed in males and females in the 5000 and 10,000 ppm groups and slight decreases in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5 h. Based on this study, exposure of male and female rats to isopropanol vapor produces transient, concentration-related narcosis and/or sedation at concentrations of 5000 and 10,000 ppm and minor decreases in motor activity in males at a concentration of 1500 ppm. The no-observed-effect level (NOEL) for this was 500 ppm isopropanol.

1-Propanol↗