Showing papers in "NIDA research monograph in 1981"

Biodegradable drug delivery systems based on aliphatic polyesters: application to contraceptives and narcotic antagonists.

Abstract: The classes of polymer which form the basis of different types of drug delivery systems are discussed, and the relationships between the chemical structure of the polymer and its permeability, morphology, biodegradability, and mechanical properties are considered, using polyesters as specific examples. Studies of the permeability and biodegradability of poly epsilon-caprolactone), poly(DL-lactic acid), and various copolymers are described and used to illustrate how these properties may be varied by the choice of polymer structure. An induction period prior to bioerosion of these polymers, coupled with high permeability, permits their use as reservoir devices (capsules) which exhibit constant, diffusion-controlled drug release rates and which erode after the drug is exhausted. The applications of this approach to the long term delivery (1 year) of levonorgestrel, a contraceptive agent, and the short term delivery (1-2 months) of naltrexone, a narcotic antagonist, are described.

The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.

Abstract: The time-action of opiate antagonist activity of naltrexone was evaluated in detoxified ex-opiate addicts, using 25 mg intravenous heroin challenges. A 100 mg naltrexone dose provided 96% blockade at 24 hr, 86.5% blockade at 48 hr and 46.6% blockade at 72 hr. Following oral administration, naltrexone was rapidly and completely absorbed. Peak levels of naltrexone and its major metabolite 6 beta-naltrexol were reached 1 hr after the dose. The high 6 beta-naltrexol plasma concentrations only 1 hr after drug administration indicate a rapid biotransformation process, converting a large fraction of the dose to less active metabolites. Over 70% of the dose was excreted in the 24 hr urine and less than 0.5% in the feces. No change was observed in the rate of naltrexone disposition during chronic dosing vs. the acute study, indicating no metabolic induction. The rapid achievement of steady state naltrexone plasma levels eliminates the need of stepwise induction at the beginning of naltrexone treatment.

Marijuana and driving.

Abstract: Many are familiar with the phrases, "Don't drink and drive," and "Friends don't let friends drive drunk." Not as many people realize that getting behind the wheel of a car (or bus, train, scooter, bike, or plane) while high on marijuana (also known as pot, cannabis, or weed among other names) can pose potential health risks as well. Studies indicate that marijuana is the drug most often found in car crashes (including fatal ones), and in fact, it's the most commonly detected substance among drivers. However, whether marijuana is actually responsible for the crashes is less well understood. A large case-control study conducted by the National Highway Traffic Safety Administration found no significant increased crash risk attributable to marijuana after controlling for factors such as drivers’ age, gender, race, and presence of alcohol. Contrarily, a retrospective study of over 4,000 drivers found that the risk of being responsible for causing a fatal crash is more than three times higher for those under the influence of cannabis. The contradictory findings make it difficult to say conclusively whether marijuana impairs driving ability, but some of its effects make it almost impossible to deny the potential connection.

An improved long-acting delivery system for narcotic antagonists.

Abstract: The feasibility of using cholesterol-glyceryltristearate matrix for prolonged release of naltrexone was evaluated in rats. Implantable cylindrical pellets (cholesterol 105 mg, glyceryl tristearate 15 mg and naltrexone 30 mg), diameter 4.5 mm, length 9 mm, blocked the antinociceptive action (hot plate 55 degrees C) of 10 mg/kg s.c. challenge dose of morphine in rats for 3 months. The release rate of naltrexone from 10 or 50 mg pellets approximated first-order kinetics with t1/2 alpha of 20-26 days and t1/2 beta 40-60 days. The factors affecting the release of drug from the delivery system were the ratio of cholesterol to naltrexone, drug loading level and surface area to unit volume of dosage form. The minimum release rate of naltrexone to block the effect of 10 mg/kg s.c. dose of morphine in rats was about 4 to 5 microgram/kg/hr. The cumulative urinary excretion of radioactivity from 10 mg [3H] naltrexone pellets implanted s.c. in rats after 30, 60, and 90 days was 17.7, 23.7, and 25.7% of dose respectively and the percent dose released from pellets at these times was 55.8, 68.8, and 78.2 respectively. The devices possess the desirable characteristics of simplicity, nontoxicity, nonirritability, ease of sterilization with ethylene oxide, small size for easy insertion and removal, absence of encapsulation by surrounding tissue, and an extended period of drug release unaffected by body metabolism. Neither deterioration of implant nor gross anatomic or histological changes at the site of implant occurred 6 months to 1 year after implantation and aside from some enhanced sexual activity (e.g., spontaneous penile erections) no side effects were observed in rats, which fed well and gained weight during the entire treatment. The concentrations of free morphine in brains of 30 mg naltrexone pellet-implanted rats were significantly lower (24 and 15%) as compared to the placebo controls 0.5 and 1.0 hr after a 10 mg/kg s.c. dose of [6-3H] morphine. We are currently evaluating these long-acting devices for the duration of effective antagonism to morphine in rhesus monkeys.

The metabolism of naltrexone in man.

Abstract: The metabolism and elimination of [15,16-3H2] naltrexone hydrochloride was studied in man following oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely in minor quantities. Naltrexone was almost completely absorbed following in the urine and only 5% in the feces. A similar urinary excretion pattern was observed after intravenous administration of naltrexone. In early time periods after oral administration there was a rapid increase in free naltrexone plasma levels up to 1 hr and then gradually declined. A similar pattern was observed for conjugated naltrexone and nonconjugated and conjugated 6 beta-naltrexol. These metabolites were found at levels 4-6 times higher than the parent compound at all times sampled. After intravenous administration, nonconjugated naltrexone plasma levels dropped sharply and continuously. The major metabolites exhibited a pattern closely resembling that found for oral administration. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine. The structure of the latter was rigorously proven by 13C-NMR. No evidence for the presence of noroxymorphone or 3-O-methyl-6 beta-naltrexol could be obtained by gas chromatography-mass spectrometry. The metabolism of naltrexone administered subcutaneously was also determined in two subjects. Larger amounts of 2-hydroxy-3-O-methyl-6 beta-naltrexol were found in plasma than had been present after oral or intravenous administration.

Development of drug delivery systems for use in treatment of narcotic addiction.

Abstract: The long term goal of the NIDA narcotic antagonist program of developing an implantable, biodegradable, naltrexone/PLGA matrix system which will sustain the delivery of naltrexone to biological systems for one month has been achieved. The dosage forms which provide the desired delivery characteristics are 1.5 mm diameter beads composed of 70% by weight naltrexone base in 40,000 molecular weight, 90L/10G poly (L(+)-lactic-co-glycolic acid). Other dosage forms, including 1.5 mm diameter rods which provide 6 months' naltrexone release, finely divided injectable powders which provide up to 30 days' naltrexone release, and 1.5 mm diameter rods which provide 2 weeks' sustained delivery of morphine, have also been investigated. In vitro and in vivo release rates have been determined by measuring chemical concentrations in pH 7 buffer solution and urine, respectively. In vivo efficacy of naltrexone sustained delivery devices has been measured by direct challenge with morphine (Dewey-Harris mouse tail-flick test) and inhibition of morphine self-administration in monkeys. Good Manufacturing Practices documentation has been developed and used to produce a large batch of the 1.5 mm diameter naltrexone bead dosage forms at an FDA-registered pharmaceutical manufacturer. These beads, produced at the University of North Carolina School of Pharmacy, are awaiting use in human clinical trials.

Adolescent marijuana abusers and their families.

Abstract: The NIDA Research Monograph series is prepared by the Division of Research of the National lnstitute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques. the content of state-of-the-art conferences, integrative research reviews and significant original research its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. The contents of this monograph are in the public domain and may be used and reprinted without special permission. Citation as to source is appreciated. ACKNOWLEDGMENTS This study of the lives of adolescent marijuana abusers and their families was supported by Grant No. DA-01489 from the National Institute on Drug Abuse. We wish to acknowledge, but cannot individually list, the many physicians, social workers, family court judges, probation officers, and guidance counsellors in New York City and suburban counties who referred cases to us. We also owe a great debt of gratitude to all the youngsters and their families for their willingness to share their lives with us. Foreword Substantial evidence is accumulating which emphasizes the significant role the family plays in the initiation, maintenance, cessation , and prevention of drug abuse by its members. This monograph depicts and investigates that role by studying the families of a small number of adolescents involved in heavy marijuana use. The study provides a robust \" real life \" description of the interplay between family dynamics and heavy adolescent marijuana use. As the authors state, their specific aims are, \" first, to explore through psychodynamic techniques what in the adolescent's adaptation and interaction with his or her family contributed to the marijuana abuse; and second, to identify the functions which marijuana plays in the adolescent's overall psychosocial adaptation. \" Dr. Hendin and his colleagues offer a number of insightful perspectives and approaches to their subject. First, they utilize the psychodynamic approach, both in the design of the study and interpretation of its results, that has not often been taken in the drug field. Second, they present extensive information about nondrug-abusing siblings of the target adolescents, comprising an informal control or comparison group about whom little has been known. Third, they delineate the adolescent's family interactions and relationships in terms of such themes as self-destructiveness, anger, and grandiosity, an approach superbly utilized in such family studies as Jules Henry's Pathways to Madness, but seldom seen in the drug abuse literature. Fourth, few previous studies …

History of drug exposure as a determinant of drug self-administration.

Abstract: Drug self-administration is controlled, in part, by the subject's history of drug exposure. Although a history of drug administration is not necessary for many drugs to function as reinforcers, prior exposure can increase the likelihood that certain drugs, such as ethanol, will maintain behavior. While it has been demonstrated that physiological dependence is not necessary for a drug to function as a reinforcer, the conditions under which such dependence is maintained can control the later self-administration of the drug. Once drug-maintained behaviors are established, the particular drug that maintains behavior can influence the initial pattern of intake of a new drug and thus the dose of that drug that will maintain behavior. Additionally, under certain conditions, similarity between the discriminative stimulus effects of the drug that previously maintained behavior and those of a new drug can increase the likelihood that the new drug will function as a reinforcer. Finally, stimuli that have been paired with drug administration can powerfully control later drug-maintained behavior, the direction of such control being determined by the conditions under which such pairing occurred. In summary, both the type of drug with which a subject has experience as well as the contingencies governing that experience contribute to subsequent drug self-administration.

Pharmacological evaluation of narcotic antagonist delivery systems in rhesus monkeys.

Abstract: Rhesus monkeys were chronically restrained, intravenously catheterized, and allowed to self-administer morphine, methamphetamine, and saline. Various sustained-release systems containing naltrexone were then implanted in the animals and examined for selective morphine blockade. Similarly, continuous intravenous infusions of naltrexone, buprenorphine, and methadone were tested against morphine or heroin self-administration.

Historical perspective on the chemistry and development of naltrexone.

Abstract: The first clinically useful narcotic antagonist was nalorphine. This compound was relatively weak, short-acting, and produced a number of side effects, the most prominent of which were psychotomimetic in nature. For these reasons nalorphine did not qualify as a possible modality for the treatment of heroin addiction. Cyclazocine is a totally synthetic narcotic antagonist which is much more potent and longer acting than nalorphine. It was the first compound used by Martin in clinical trials in postaddicts. However, its dysphoric effects necessitated long induction periods and these CNS effects precluded its use in long-acting delivery systems. Naloxone was a "pure" antagonist which did not produce the psychotomimetic effects of either nalorphine or cyclazocine. Although it is a potent antagonist when given parenterally, it is shorter acting than cyclazocine. Replacement of the N-allyl substituent of naloxone with the cyclopropylmethyl radical of cyclazocine led to naltrexone, which is even more potent than either naloxone or cyclazocine and has a longer duration than naloxone. Because of this favorable combination of properties naltrexone proved to be the drug of choice for inclusion in long-acting delivery systems.

Treatment of heroin-dependent persons with antagonists: current status.

Abstract: Naltrexone is an important new pharmacologic adjunct to the treatment of heroin dependence. The development of naltrexone has been nurtured in the mature recognition that simple detoxification or simple opiate replacement therapy is not appropriate for every heroin addict. Our current data indicate that naltrexone is safe and effective. Its use may be limited to a minority of addicts, those who are highly motivated and opiate free, because patient compliance has been a major problem with which clinicians using naltrexone have had to contend. Patient compliance is a problem, because there are no immediate consequences to the patient for stopping his naltrexone regimen. Side effects from naltrexone have been minimal and have occurred in a minority of patients. They consist primarily of gastrointestinal symptoms, including nausea and occasionally abdominal pain.

A review of parenteral sustained-release naltrexone systems.

Abstract: The ideal naltrexone sustained-release delivery system should be easy to inject or implant, not cause adverse tissue reaction, release the drug at a relatively constant rate for at least 30 days, and biodegrade within a short time afterwards. Mechanisms which can be used for sustaining drug release include reducing solubility and surface area, coating, encapsulation and microencapsulation, complexation, binding and hydrophilic gelation. Drug release from such systems is controlled by diffusion through a barrier/film, diffusion from a monolithic device, erosion of the surface, hydrolysis, ion exchange, biodegradation, or a combination of these. Injectable systems would seem to be ultimately preferred because of the ease of administration and handling, while the implantable devices may find first use in man since they are easily removable, should that be necessary. Maintaining particulate-free products and sterilization methods are two problems with all parenteral dosage forms. Production must be particularly well controlled and validated.

A comparative study of the oral, intravenous, and subcutaneous administration of 3H-naltrexone to normal male volunteers.

Abstract: 3H-naltrexone was administered orally, intravenously, and subcutaneously to groups of normal, male, paid volunteers. The doses given were: 50 mg orally (specific activity 4 microCi/mg), 1 mg intravenously (specific activity 200 microCi/mg), and 5 mg subcutaneously (specific activity 30 microCi/mg). At these doses, the subjects did not experience any noticeable effects. Following intravenous injection, plasma levels of radioactivity were immediately high and declined rapidly during the first 30 minutes and declined gradually thereafter. Following oral or subcutaneous administration, maximal plasma levels were observed to occur one hour after dosing, and reached similar levels to those obtained when the drug was intravenously injected. This finding indicates the excellent bioavailability of naltrexone following oral or subcutaneous administration 3H-naltrexone and/or its metabolites were predominately excreted in the urine, and the renal excretion was similar for all three routes of administration. Fecal excretion is a minor pathway of elimination. The urinary and fecal excretion of 3H-naltrexone was studied in one subject for 133 hours after drug ingestion, and it was found that essentially all of the dose administered was excreted in this period.

Comparative studies of the pharmacological effects of the d- and l-isomers of codeine.

Abstract: Opiates are known for their stereospecificity. The following studies show that l-codeine was active in the mouse tail-flick test as well as in the hot plate test whether given p.o. or s.c. The ED50 in the first test was 4.09 mg/kg s.c. (2.01-8.34 mg/ kg) and 13.41 mg/kg p.o. (6.91-26.0 mg/kg). In the second antinociceptive test, the ED50 was 20.66 mg/kg s.c. (11.52-37.08 mg/kg) and 20.47 mg/kg p.o. (14.63-28.57 mg/kg). The d-isomer of codeine was inactive ina both tests up to 100 mg/kg but caused hyperexcitability, convulsions and ultimately death. Although l-codeine was more potent than d-codeine inhibiting the cough reflex in the anesthetized cat, the d-compound did have good activity. The ED50 of the l-isomer was 0.27 mg/kgi.v. (0.14-0.47 mg/kg) and that of the d-isomer was 1.61 mg/kg i.v. (0.98-2.65 mg/kg). In these animals, l-codeine did not significantly affect the cardiovascular parameters at the doses tested, whereas d-codeine caused a significant but transient decrease in the blood pressure and heart rate. The specific and nonspecific properties of d- and l-codeine were further delineated in the opiate receptor binding assay. l-Codeine inhibited the stereospecific binding of 2.2 x 10(-9) M [3H]dihydromorphine in mouse brain homogenate with the IC50 being 1.6 x 10(-5) M (1.2 x 10(-5)--2.0 x 10(-5) M). d-Codeine had no effect up to 10(-4) M.