Nathan B. Eddy

Addiction liability and narcotics control.

A MONG the most effective measures for the prevention of drug addiction are the Federal laws and international treaties controlling the production and distribution of the drugs of addiction and the source materials from which these drugs are derived. The application and administration of these laws have steadily become more complex. A large number of synthetic drugs with pharmacological effects and addiction liability similar to that of morphine have been discovered and have created some difficult problems of classification and control. It is now also known that substances, such as the barbiturates and the amphetamines, covered by the food and drug but not by the narcotic laws, are susceptible to abuse and may produce a different addiction from that caused by the opiates. It is the purpose of this paper to review the historical origin of the present narcotic laws and to discuss changes in them which seem desirable in the light of recent knowledge.

Pharmacology of Morphinans

This chapter presents the pharmacology of morphinans. Morphine is always taken as the standard preparation in investigations of new analgesics. Its outstanding action on the central nervous system is that of raising the pain threshold. This action of therapeutic doses in man is accompanied by a sedative and euphoric action. With increasing dosage, a state of somnolence approaching narcosis is reached, which, with a further increase in the dose, can develop into deep coma. A further effect of morphine is the depression of the respiratory center, which can appear even with therapeutic doses. Breathing is then slowed down and deepened, finally with reduction of the minute volume. A depression of the cough reflex parallels the analgesic action and respiratory paralysis. With continued use of morphine, the sensitivity of the organism to this substance diminishes. Habituation is developed, which necessitates a continual increase of the dosage to maintain the full analgesic effect. This tolerance can lead to the most dreaded side effect of morphine, namely, addiction. The withdrawal of morphine from addicts leads to abstinence phenomena, which are manifested in both physical and mental changes. The resulting symptoms can only be relieved by giving morphine or morphine-like analgesics.

Chemistry of Morphinans

This chapter describes morphinans as members of a class of compounds possessing the main structural skeleton of morphine. The chemistry of the morphinan is very closely connected with that of morphine, and it starts from the elucidation of the structure of morphine. The chapter discusses the synthesis of analgesics with morphine-like activity, synthesis of N-methyl-morphinan, and synthesis of N-methyl-morphinan. By subjecting natural products to reactions that were either already well known or recently developed, many investigations were undertaken to confirm the morphine structure and to find compounds of greater pharmacological value. The desirable effect of morphine on pain that sets in rapidly even when the drug is administered in small doses is accompanied by a number of clinically undesirable side effects. These side effects—such as respiratory depression and development of tolerance that soon leads to addiction—limit its application. The primary aim of the chemists in modifying the morphine molecule was to obtain analgesics without side effects, especially without addictive properties. Although this has not yet been fully achieved, partial successes have been obtained.

SECRETIN: III. Its Mode of Action in Producing an Increase in the Number of Corpuscles in the Circulating Blood

It is well known that each phase of digestion is influenced by that which precedes it; the mastication of food and the secretion of saliva in some way ?cause ail increased secretion of gastric juice; the ?discharge of chyle through the pylorus causes an increased secretion of pancreatic juice; and so forth. The mechanism by which the secretion of pancreatic juice is thus influenced has been the subject of much

Commissioning and Operation of FAST Electron Linac at Fermilab

We report results of the beam commissioning and first operation of the 1.3 GHz superconducting RF electron linear accelerator at Fermilab Accelerator Science and Technology (FAST) facility. Construction of the linac was completed and the machine was commissioned with beam in 2017. The maximum total beam energy of about 300 MeV was achieved with the record energy gain of 250 MeV in the ILC-type SRF cryomodule. The photoinjector was tuned to produce trains of 200 pC bunches with a frequency of 3 MHz at a repetition rate of 1 Hz. This report describes the aspects of machine commissioning such as tuning of the SRF cryomodule and beam optics optimization. We also present highlights of an experimental program carried out parasitically during the two-month run, including studies of wake-fields, and advanced beam phase space manipulation.

Opiate Antagonists in the Benzomorphan Series

This chapter presents various studies on opiate antagonists in the benzomorphan series. It was earlier shown that nalorphine, in spite of its specific opiate antagonistic action, could affect relief of postoperative pain and morphine on an mg for mg basis. Unfortunately, the relief was accompanied by bizarre subjective reactions, which were very disturbing to the patient. However, the wide range of antagonistic potency suggested that among the antagonists, there might have been an effective analgesic that produced little or none of the disturbing nalorphine-like side effects. To this end, a number of the benzomorphans with specific antagonistic properties are under clinical investigation: SKF 10,047; Win 19,362; Win 20,228; Win 20,264; and Win 20,740. SKF 10,047 could be used clinically as an opiate antagonist, having potency equal to or greater than that of nalorphine. Win 20,740 is a most interesting compound. It was the most potent antagonist tried in the benzomorphan series that showed some analgesic effects in animals. It was a very potent analgesic in man at doses that produced no nalorphine-like subjective effects. The latter have occurred occasionally when the dose is increased severalfold.

Pharmacology of the 6,7-Benzomorphans

This chapter presents a study of compounds for analgesia and toxicity. In an experiment described in the chapter, all compounds were tested by subcutaneous administration in mice and most of the more active ones by oral administration. In many instances, a substance was dissolved in a small amount of propylene glycol with subsequent dilution to make the propylene glycol concentration not more than 25 percent. If the material was supplied as a base, the solution was effected by the addition of the approximately calculated amount of N HCL. The final concentration of the active ingredient was always such that the dose administered was 0.01 mg/g mouse weight.

Chemistry of 6,7-Benzomorphans

This chapter discusses the chemistry of 6,7-benzomorphans—such as 5-alkyl-2(N)-methyl-6,7-benzomorphans; α- and β-5,9-dlalkyl-2(N)-methyl-6,7-benzomorphans; α- and β-9-hydroxy-2(N)-methyl-6,7-benzomorphans; N-substituted -6,7-benzomorphans; and optically active 5,9-dialkyl-6,7-benzomorphans. In a study described in the chapter, the simplest compound of the benzomorphan series—2,5-dimethyl-6,7-benzomorphan—was synthesized in three different ways. In the first and longest method, hydratroponitrile was the starting substance from which both the hydroaromatic and heterocyclic rings of 2,5-dimethyl-6,7-benzomorphan was constructed. The second route, with a starting compound 3,4-dihydro-l-methyl-2(1H) naphthalenone already containing the tetrahydronaphthalene skeleton of 2,5-dimethyl-6,7-benzomorphan, initially gave lower yields than the longer method. However, significant improvement of the shorter sequence was subsequently achieved. It was earlier believed that the substitution of any group for the N-methyl of morphine and similar entities would have a detrimental effect on analgesic activity. However, it was reported in 1956 that the replacement of methyl by phenethyl in the morphine molecule resulted in an eightfold increase in potency. This and similar modifications were reported for the morphinans and 4-phenylpiperidines. In many instances, the increase in potency was dramatic.

CHAPTER VI – Summary

Publisher Summary The chapter describes the results of certain experiments conducted on morphine, morphinan and benzomorphan compounds. The structure–activity relationships for changes at 2’ or 2 for the most part run parallel in the morphine, morphinan, and benzomorphan series. In an experiment discussed in the chapter, the introduction of hydroxyl at a certain position decreased analgesic action, whereas similar substitution in morphine or morphinan increased it notably. In all the three series, analgesic properties were exhibited predominantly by the laevo isomer. From these experiments, it was concluded that the physical dependence capacity of benzomorphans in the monkey is generally low, especially relative to analgesic potency. However, this characteristic has not carried over well to man. Suitable substitution on nitrogen of benzomorphan, as in the morphine or morphinan series, can enhance analgesic effectiveness or result in the appearance of antagonistic properties. The benzomorphans as a class are morphine-like, but there are quantitative differences that suggest that some dissociation between useful and undesirable properties is being attained.

Influence of Tyramine on the Number of Red Corpuscles in the Circulating Blood

Rabbits were given tyramine subcutaneously in single doses of various sizes, in hourly doses and in daily doses. With but few exceptions the effect was to increase the number of red corpuscles per cubic millimeter in the circulating blood. The hydrochloride was used. This was dissolved in 0.9% sodium chloride solution in such proportion that 1 cc. contained the dose per kilo of body weight, and the solution warmed to body temperature before injection. Single doses of from 0.1 mgm. to 20.0 mgm. per kilo of body weight were used. The average results of these are given in Table 1. A dose of 0.5 mgm. per kilo caused an increase in the red blood corpuscle count of 18.46% and was selected as an average effective dose. Each of 4 rabbits was given 0.5 mgm. per kilo of body weight and the dose repeated at intervals of one hour until 4 doses had been given. The results are summarized in Table II. Twelve rabbits, 15 weeks old, were divided into 3 groups of 4 each. Two groups received tyramine and the third served as a control. The tyramine was given daily for 2 weeks, then 3 times a week for 2 weeks, then daily for 2 weeks, and finally 3 times a week for 2 weeks. The dose for one group was 0.5 mgm. of the hydrochloride per kilo of body weight and for the other 5.0 mgm. per kilo. At the same time the control rabbits were given a subcutaneous injection of an equal quantity of 0.9% sodium chloride solution. Living conditions were the same for all. The red corpuscles were counted twice each week and the body weight was noted once a week.