Francis F. Foldes

THE DISTRIBUTION OF ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE IN THE HUMAN BRAIN

IT has been suggested that the choline acetylase-acetylcholine-cholinesterase system plays an important role in synaptic transmission in the central nervous system (LOEWI, 1945; FELDBERG, 1945; FELDBERG and VOGT, 1948; KOELLE, 1955; PATTON, 1958). In recent years, in addition to acetylcholine (ACh)

The pharmacology of neuromuscular blocking agents in man

, other cholinesters, e.g., butyrylcholine (BuCh), propionylcholine, y-aminobutyrylcholine and j3-imidazolyl-4(5) acryloylcholine have been extracted from the nervous system of various species (KURIAKI et al., 1958; HOLTZ and SCHUMANN, 1954; BANISTER et al., 1953; ERSPAMER and BENATI, 1952). Manometric methods have been used by many workers to study the distribution of specific or acetylcholinesterase (AChE) and non-specific or butyrylcholinesterase (BuChE) in different brain areas of various mammalian species (NACHMANSOHN, 1939 ; MENDEL and RUDNEY, 1943 ; NACHMANSOHN and ROTHENBERG, 1945 ; AUGUSTINSSON, 1948 ; BURGEN and CHIPMAN, 1952 ; KOELLE, 1950 ; 1954; ABRAHAMS et al., 1957; DAVISON, 1953) and in human brain areas (NACHMANSOHN, 1939; BIRKHAUSER, 1940; OKINAKA et al., 1951; ORD and THOMPSON, 1952; TOWER and ELLIOTT, 1952; POPE et al., 1952; BULBRING et al., 1953). NACHMANSOHN (1939) demonstrated that the concentration of cholinesterase (ChE), although constant in identical areas of the same species, varies considerably in different areas of the same species and in the same areas of different species. He also reported that, in comparison with the caudate and lentiform nuclei, the cortical areas of the human brain exhibited low ChE activity, and that ACh was split by brain ChE at a higher rate than were any of the other cholinesters studied (NACHMANSOHN and ROTHENBERG, 1945). BIRKHAUSER (1940) published quantitative data on the AChE activity in several areas of the human brain. Later, OKINAKA et al. (1951) and ORD and THOMPSON (1952) also investigated the ChE activity of several human brain areas. OKINAKA et al. (1951) used only ACh as substrate, and ORD and THOMPSON (1952) used ACh, BuCh, acetylj3-methylcholine (MeCh), benzoylcholine, propionylcholine and tributyrin as substrates. Both groups of workers obtained their material as soon as possible after death,

THE IN VITRO INHIBITORY EFFECT OF LSD, ITS CONGENERS AND 5-HYDROXYTRYPTAMINE ON HUMAN CHOLINESTERASES ?

Because of great species variation in the effects of neuromuscular blocking agents, the results are often not applicable to man. Although the subject has been very extensively studied in experimental animals, the necessity has been pointed out for determining the actions of these drugs in man as well. Symposia have been held and monographs written, but this is the first attempt to review the entire literature of the pharmacology of the muscle relaxants in man.

Interrelationship of Murexine, Dihydromurexine and Human Cholinesterases.

ALTHOUGH it has been known since 1943 that D-lySergiC acid diethylamide (LSD)§ is a potent psychotropic drug (STOLL and HOFMANN, 1943; STOLL, 1947), no satisfactory explanation has been offered for its mechanism of action (ROTHLIN, 1957~; ROTHLIN and CERLETTI, 1956). POLONI and MAFFEZZONI (1952) observed an increase of the acetylcholine (ACh) content in the brain of guinea pigs after the administration of LSD. Subsequently, THOMPSON, TICKNER and WEBSTER (1954) studied the effect of LSD on human cholinesterases, They reported that it reversibly inhibited human plasma cholinesterase (plasma ChE) and the pseudo cholinesterase of the human brain, but in concentrations which inhibited plasma ChE by 50 per cent, it had only slight effect on red cell ChE and the true cholinesterase of the brain. It was also reported by the same authors (THOMPSON et al., 1955) that human cholinesterases were inhibited by LSD to a greater extent than cholinesterases of the rat, guinea pig, rabbit, chicken and monkey brain. TONINI (1955) found that rat brain cholinesterase activity was potentiated by 5-hydroxytryptamine (serotonin; 5-HT), LSD, and lysergic acid monoethylamide (LAE) in low concentrations. He, as well as FRIED and ANTOPOL (1956, 1957), who also noticed potentiation of human plasma ChE by LSD attempted to relate this effect to the psychotropic action of these compounds. ZEHNDER and CERLETTI (1956) reported, however that the non-hallucinogenic 2-brom-~-lysergk acid diethylamide (BOL) (ROTHLIN and CERLETTI, 1952 ; CERLETTI and ROTHLIN, 1955) had an inhibitory effect on human plasma ChE similar to that of LSD. Although in recent years the psychotropic activity of many, newly synthetized derivatives of LSD was studied in man (SOLMS, 1953, 1956; ISBELL et al., 1959; GIBERTI and GREGORETTI, 1958; GOCERTY and DILLE, 1957; CALLIERI, 1958; MURPHREE et al., 1958; HOFMANN, 1959; SCHNECKLOTH et a/ . , 1957; ABRAMSON et al., 1958) relatively little work has been done on the anticholinesterase effect of these compounds (GOGERTY and DILLE, 1957).

THE FATE OF MUSCLE RELAXANTS IN MAN

Summary 1. Murexine (Mur) and dihydromurexine (DhMur) are both hydrolyzed by human plasma cholinesterase. The hydrolysis rate of DhMur is as fast as that of acetylcholine (ACh) and is 18 times faster than that of Mur. 2. Neither Mur nor DhMur are hydrolyzed by human red cell cholinesterase. 3. Both Mur and DhMur inhibit the hydrolysis of ACh by red cell cholinesterase. Mur also inhibits plasma cholinesterase.

Succinylmonocholine iodide: its enzymatic hydrolysis and neuromuscular activity.

Knowledge of the distribution, metabolism and excretion of neuromuscular blocking agents is a “sine qua non” for the understanding of both the therapeutic actions and the unwanted side effects of these compounds. Because of the considerable species variation in the metabolism of muscle relaxants, the ensuing discussion will be mainly concerned with the fate of these drugs in the human organism. Results of animal experiments will only be referred to when corresponding data for man are not available. Since in anesthetic practice muscle relaxants are usually administered intravenously, their fate in the body will only be followed after this route of administration. From the point of view of metabolic changes in the body, the clinically used muscle relaxants may be divided into 3 groups: members of the first group (e. g., decamethonium, gallamine) , according to presently available evidence, undergo no metabolic changes and are excreted unchanged mostly in the urine (W. W. MUSHIN et al. (1949)29, and W. D. M. PATON and E. S. ZAIMIS ( 1952)31) ; members of the second group (e.g., d-tubocurarine or dimethy1 d-tubocurarine) undergo partial, slow destruction in the body but a considerable part of the injected material is excreted unchanged mostly in the urine (D. F. MARSH (1952)27) ;members of the third group (e. g., suxamethonium and suxethonium) are broken down rapidly and almost completely primarily by plasma cholinesterase (D. GLICK (1941)20; F. BOVET-NITTI (1949)3) and only insignificant amounts are excreted unchanged in the urine (S. NORTON and E. S. DEBEER (1954)30; F. F. FOLDES and S. NORTON (1954)13).

The accelerating effect of narcotic analgesics on the hydrolysis of aromatic substrates by human plasma cholinesterase

Summary The hydrolysis of succinylmono-choline iodide in normal and heat inactivated human plasmas was compared to the hydrolysis of succinyldicholine dichloride. In normal plasma, the hydrolysis rate of succinylmonocholine iodide was found to be about 8 times slower than that of succinyldicholine dichloride. In heat inactivated plasma, the hydrolysis rate of succinylmonocholine iodide was negligible in the 2-hour observation period. Succinylmonocholine iodide in 1.0 to 2.5 mg/ kg doses inhibited neuromuscular transmission in the sciatic-gastrocnemius preparation of cats.

The in vitro inhibitory effect of psilocybin and related compounds on human cholinesterases

Abstract The activating effect of twelve narcotic analgesics on the hydrolysis of two aromatic substrates (procaine and benzoylcholine) by plasma cholinesterase was investigated. Allyl substitution decreased the accelerating effect. Oxidation of the alcoholic hydroxyl to a ketone at C 6 of the morphine molecule markedly increased the accelerating effect on the enzymic hydrolysis of procaine. This was further enhanced by the simultaneous substitution of H by OH at C 14 . Some of the possible explanations of these accelerating mechanisms are discussed.

The use of echothiophate in myasthenia gravis.

SummaryThe comparison of the anticholinesterase activity of psilocybin, bufotenin and 5-hydroxytryptamine in human plasma, red cells and gray matter homogenate indicates that like with LSD and its derivatives, there is no correlation between the in vitro anticholinesterase activity and the hallucinogenic effect of these compounds.

Recent developments in the pharmacology and clinical application of muscle relaxants

Echothiophate is a potent inhibitor of human plasma butyrylcholinesterase and red cell acetylcholinesterase. In vitro, plasma butyrylcholinesterase was maximally inhibited within two hours, whereas maximal inhibition of red cell acetylcholinesterase occurred after eight hours. In vivo, both enzymes were maximally inhibited in about tour hours. Echothiophate was used for the treatment of subjects whose myasthenia was poorly controlled on short‐acting anticholinesterases. In most, the initial results were good. However, in about one half of the patients it subsequently became necessary to discontinue echothiophate because good control could not be maintained with it. In one third of the patients, however, it was possible to maintain good contral with the drug for over six years. In same instances pyridostigmine supplementatian was necessary to relieve bulbar symptoms. Our experience indicates that echothiophate is most useful in the treatment of severe but stable myasthenia gravis, primarily involving the skeletal muscles. After discontinuation of echothiophate therapy, plasma butyrylcholinesterase and red cell acetylcholinesterase returned to control levels in about one hundred days.