Thornton Sargent

Leukocytes of Humans Exposed to Lysergic Acid Diethylamide: Lack of Chromosomal Damage

Leukocyte cultures from eight human subjects who had had recent exposure to large doses of lysergic acid diethylamide were examined for chromosome abnormalities. The number of abnormalities was not significantly greater than that in control cultures.

Reduced chromium retention in patients with hemochromatosis, a possible basis of hemochromatotic diabetes

Chromium (III) has recently been shown to be an essential trace mineral in rats, being required for normal function of insulin in controlling glucose metabolism. Chromium is transported in the body bound to transferrin, where it binds competitively with iron. Hemochromatosis is an iron storage disease in humans characterized by highly saturated transferrin levels and sometimes by diabetes. We postulated that the diabetes may be due to exclusion of chromium by iron at metabolic binding sites. 51Cr(III) was administered i.v. to 5 normal males, 6 patients with hemochromatosis prior to therapeutic removal of iron, and 5 patients with varying levels of iron loading. The retention of 51Cr was measured with a whole-body counter for 8 mo and blood levels were measured for 40--80 days. Analysis of the whole-body retention curves revealed 3 exponential components with T1/2s of .56 days, 12.7 days, and 192 days; the blood curves had 4 components with T1/2s of 13 min; 6.3 hr, 1.9 days, and 8.3 days. The T1/2s were not significantly different between the normals and patients. The coefficients of these components however, were significantly lower for the long T1/2 components in the iron-loaded patients, demonstrating reduced retention of 51Cr as postulated. Whether this reduced retention of chromium is causally related to diabetes in hemochromatosis and whether abnormal chromium metabolism is involved in endogenous diabetes, thus, becomes an important question for future study.

In vivo human pharmacodynamics of the psychodysleptic 4-Br-2,5-dimethoxyphenylisopropylamine labelled with 82Br or 77Br

Abstract The psychodysleptic compound 4-Br-2,5-dimethoxyphenylisopropylamine (4-Br-DPIA) was synthesized with 82Br or 77Br and administered to five human subjects in three oral and three intravenous experiments. In vivo organ concentrations were measured by gamma ray scintigraphy with computerized area integration, and by whole-body counting. Urine was analyzed by solvent separation, and thin layer chromatography of dansylated metabolites. The urine contained less than 5% radiobromine precipitable by acidic AgNO3, demonstrating that the Br label remained organically bound. Upon intravenous administration, radioactivity appeared immediately in the lungs by first-pass extraction, was rapidly released and reached maximum concentrations in the liver at 0.5–1.5 hr, plasma at 2–3 hr and brain at 3–6 hr. Orally the pattern was the same except that the initial lung concentration did not occur. This sequence of maximum organ concentrations suggests that a metabolite of 4-Br-DPIA is the centrally active compound which concentrates in the brain. Solvent separation of urine showed 81.8% of metabolites to be aqueous soluble and 12.5% free base; slower whole-body excretion correlated with higher levels of free base in the urine. The methods used demonstrate a new approach to the study of in vivo distribution and kinetics of drugs which can be labelled with gamma-emitting radioisotopes.

Abnormal methionine metabolism in schizophrenic and depressive states: A preliminary report

IT HAS been proposed that schizophrenia is a consequence of metabolic abnormalities associated with endogenous production of psychotogenic compounds. The original hypothesisi noted the chemical similarity between adrenaline and mescaline, and postulated an abnormal methylation of adrenaline as the source of the psychotoxin. Since then, methylation processes have been implicated by a number of studies: the controversial finding of dimethoxyphenethylamine (DMPEA) in the urine of schizophrenics;2 the similarity of many psychotomimetic compounds to known methylated metabolites of norepinephrine;s the differential metabolism of the methoxyl groups of DMPEA;4 the claimed improvement of schizophrenics after administration of the methyl acceptor nicotinamide;s and exacerbation of the disease by administration of the methyl donor methionine.617 The involvement of aromatic amines in affective disorders has recently been reviewed,8 although methylation reactions have not been strongly implicated. Since the major methyl donor for methylation processes within the body is methionine, we decided to study an aspect of the metabolism of the S-methyl moiety of this compound in patients with schizophrenic and affective disorders.

Role of 3,4-Dimethoxyphenethylamine in Schizophrenia

IN 1962, Friedhoff and Van Winkle reported the detection of 3,4-dimethoxyphenethylamine (DMPEA) in the urine of schizophrenic patients but not in that of normal individuals1. Attempts to confirm these findings have led to conflicting results. Two independent groups have verified that DMPEA is indeed produced by a high percentage of mental patients2,3, but another has also found it in the urine of control subjects as well4; yet others have been unable to detect it in either5,6. A recent report7 has presented a convincing correlation between the appearance of the “pink spot” equated with urinary DMPEA. and the diagnosis of schizophrenia. The interest in this specific base stems both from its close structural kinship to mescaline, a well established psychotogen, and from its implication in the metabolic chemistry of the endogenous catecholamines. 3,4 -Dihydroxyphenethylamine (dopamine) serves, in normal metabolism, as the precursor of noradrenaline and epinephrine, but it has been argued that an abnormal methylation might occur preferentially in psychotics. This specific conversion, yielding DMPEA, has been shown in vivo2,8. Alteration of dopamine metabolism has been observed in schizophrenic patients9 and this has been associated with abnormal transmethylation10. An important question has not been answered; is DMPEA a psychotomimetic agent in normal human subjects?

A 122Xe122I generator for remote radio-iodinations

A 122Xe-122I generator system is described that produces 122I extraction efficiencies of approximately 60%. Radiocontaminants were less than 0.1% at the time of 122I removal following a 10 min ingrowth period. The chemical form of 122I was identified as [122I]iodide, and the [122I]iodide was remotely incorporated into radiopharmaceuticals for PET studies with an overall efficiency of as much as 40%.

Rapid brain scanning radiopharmaceutical

A method for detecting the blood flow in animals, particularly in the brain, is provided wherein a detectable amount of a novel radioactive compound of the formula I is administered to one animal: ##STR1## wherein R1 and R2 are independently alkyl of 1 to 6 carbon atoms or benzyl; R3 is alkyl of 1 to 6 carbon atoms, benzyl, cyclopropylalkyl of 4 to 6 carbon atoms, or cyanoalkyl of 2 to 6 carbon atoms; R4 is hydrogen, benzyl or alkyl of 1 to 6 carbon atoms; with the provisos that R4 is not isopropyl and when R4 is methyl, R3 is not benzyl; and X is a radioactive halogen.

Whole-body counting of retention of 67CU, 32P and 15Cr in man

Abstract Whole-body counting is capable of providing information about retention of trace elements in the body not available by other means; this is useful in studying diseases including disorders of the metabolism involving the element, in cases of acute or chronic toxicity, or in case of increased environmental levels. Whole-body retention in humans is reported using 67 Cu. 32 P and 51 Cr. Copper retention is reported for 1 normal subject and two patients with hemochromatosis whose iron stores had been reduced to normal levels; the retention in all three subjects was a single exponential, T 1 2 = 25 d . In a patient who was a presumptive heterozygote for Wilsons disease, a T 1 2 = 54 d was found. 32 P turnover was studied by measuring the bremsstrahlung from 5 patients given the isotope therapeutically; the curves consisted of two exponentials with mean T 1 2 = 3.6 d and 63 d . Chromium has been found to be an essential trace element, required for control of glucose metabolism. In 5 normal subjects, 51 Cr was found to have a three-component retention curve, with mean T = 0.56 d, 13.2 d and 195 d. The relationship of these measurements to physiological processes and disease states is discussed.

MEASUREMENT OF IN VIVO DECARBOXYLATION OF DOPA AND TYROSINE

ABSTRACT A method is presented by which the rates of decarboxylation of l-14C-L-tyrosine and l-14C-L-dopa are measured after injection into the ventricles of rats by continuous measurement of expired 14CO2 with automatic digitized output and computer analysis of the respiration pattern.

18F-labelled N,N-dimethylamphetamine analogues for brain imaging studies

The radiochemical yields of nine N,N-dimethyl-2-(substituted phenyl)-isopropylamines (amphetamine analogues) were determined following reaction with [18F]acetyl hypofluorite in a 0.1 M HCl solution at room temperature. The meta-dimethoxy substituted amphetamines gave the highest radiofluorination yields (24-32% at EOB). Purification of the 18F-labelled amphetamines was achieved in 10-20 min. 5-18F-2,4-Dimethoxy-N,N-dimethylamphetamine (5-18F-2,4-DNNA) was utilized to determine brain and lung uptake in rates. Positron emission tomography studies were conducted in a dog to determine the dynamic brain uptake and retention of this agent. The 5-18F-2,4-DNNA exhibited decreased initial uptake and more rapid loss of radioactivity in cerebral tissue compared to the iodinated homologue.