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Biomedical subjects

R H Adamson

Publications and source records attributed to R H Adamson.

At least 91 records · Page 5Linked to original sources
PubMed1979

Development and experimental evaluation of a contrast medium for computed tomographic examination of the liver and spleen.

A lipoid based contrast material containing 53% of ethiodized oil in emulsion form was developed for computed tomography (CT) of the liver and spleen and tested in rabbits and monkeys. An intravenous dose of 0.2 ml/kg selectively opacified the liver and spleen, resulting in an average increase of 23 EMI units (500 scales) in the attenuation of the liver and a higher increase in the attenuation of the spleen. When injected into rhesus monkeys with carcinogen induced hepatomas there was a significant improvement in the visualization of the tumor, and small lesions, undetectable on the preliminary CT scan, became visible. Toxicity studies are in progress.

Animals↗
PubMed1979

The disposition of spirohydantoin mustard (NSC 172112) in rats and dogs.

1. The disposition of spirohydantoin mustard (SHM) has been examined in rats and dogs after i.v. administration of (hydantoin-4-14C]SHM and [2-chloroethyl-U-14C]SHM. 2. Four hours after dosing to rats and dogs, renal clearance of the ethyl-14C moiety (14--21%) is lower than that of the hydantoin-14C moiety (29--68%). In contrast, biliary excretion of the ethyl-14C in rats is greater, and there appears to be enterohepatic circulation of the ethyl-14C. 3. Less than 1% of the radioactivity appearing in rat bile is unchanged SHM. Two major metabolites containing the ethyl-14C moiety are conjugates of glutathione or cysteine. 4. Levels of 14C in plasma decline in a biphasic manner. No difference in the initial plasma disappearance of the two labelled moieties is observed, but disappearance of the ethyl-14C During the second phase is slower. 5. Concentrations of ethyl14C and hydantoin-14C in the brains of rats and dogs, 4 h after i.v. administration, are equivalent to those in plasma. 6. Radioactivity is also distributed to the brain of rats after oral administration of [2-chloroethyl-J-14C]SHM, but at a concn. less than half that of plasma.

Animals↗
PubMed1979

Induction of osteogenic sarcomas and tumors of the hepatobiliary system in nonhuman primates with aflatoxin B1.

The carcinogenicity of aflatoxin B1 (AFB1) has been under evaluation in nonhuman primates for the past 13 years. A total of 47 Old World monkeys, chiefly rhesus and cynomolgus, have received AFB1 i.p. (0.125 to 0.25 mg/kg) and/or p.o. (0.1 to 0.8 mg/kg) for 2 months or longer, and 12 are currently alive and without evidence of tumor. Thirteen of the 35 monkeys necropsied to date (37%) developed one or more malignant neoplasms, yielding an overall tumor incidence of 28%. Five of the neoplasms were primary liver tumors (2 hepatocellular carcinomas and 3 hemangioendothelial sarcomas), and 2 cases of osteogenic sarcoma were found. Other tumors diagnosed were 6 carcinomas of the gall bladder or bile duct, 3 tumors of the pancreas or its ducts, and one papillary Grade I carcinoma of the urinary bladder. The tumors developed in animals receiving an average total AFB1 dose of 709 mg (range, 99 to 1354 mg) for an average of 114 months (range, 47 to 147 months). Fifteen of the 22 necropsied monkeys (68%) without tumor showed histological evidence of liver damage, including toxic hepatitis, cirrhosis, and hyperplastic liver nodules. These animals had received an average total AFB1 dose of 363 mg (range, 0.35 to 1368 mg) for an average of 55 months (range, 2 to 141 months). Our results indicate that AFB1 is a potent hepatotoxin and carcinogen in nonhuman primates and further support the hypothesis that humans exposed to this substance may be at risk of developing cancer.

Aflatoxins↗
PubMed1978

Induction of monooxygenases in rhesus monkeys by 3-methylcholanthrene: metabolism and mutagenic activation of N-2-acetylaminofluorene and benzo(a)pyrene.

Induction of content and activity of hepatic and lung cytochrome P450-dependent monooxygenases by 3-methylcholanthrene (MCA) was studied in male rhesus monkeys. Hepatic microsomes were concomitantly studied for mutagenic activation of N-2-acetylaminofluorene (AAF) as well as with the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Hepatic N-hydroxylation of AAF was increased sixfold to sevenfold after MCA treatment; aryl hydrocarbon hydroxylase was similarly increased in both liver and lung. The hepatic cytochrome P450 content was increased by 50%, and the Soret maximum in the CO-hemoprotein complex was shifted to the blue by 2 nm after MCA induction. Electrophoresis of hepatic microsomes from MCA-treated monkeys showed an increase in a polypeptide band of 54,000 molecular weight. Mutagenic activation of AAF by liver microsomes from untreated rhesus monkeys was low but was increased 40-fold after MCA treatment. No effect was observed on the mutagenic activation of N-hydroxy-2-acetylaminofluorene by liver microsomes after MCA treatment. Rhesus monkeys may provide a model for evaluation of the role of polycyclic hydrocarbon induction in chemically caused cancer and toxicity in primates.

2-Acetylaminofluorene↗
PubMed1978

In vitro alpha-fetoprotein synthesis by monkey hepatocellular carcinoma.

Five monkeys were treated ip with N-nitrosodiethylamine (DENA), and one was treated with 1-nitrosopiperidine (PIP), starting within 2 months of birth, until hepatocellular carcinoma (HCC) developed. All animals except the PIP-treated monkey had much elevated serum alpha-fetoprotein (AFP) values. Fresh, minced, biopsy-derived tumor was cultured with L-[14C]leucine and L-[14C]lysine. Synthesis of AFP was determined by radioimmunoassay and by specifically precipitable [14C]AFP. Good agreement between these two parameters was obtained for the 4 DENA-induced tumors synthesizing AFP in culture. Tumor from 1 DENA-treated monkey did not synthesize AFP. In addition, neither normal liver nor tumor from the PIP-treated monkey showed AFP synthesis. Rates of synthesis were 0.37-5.50 ng AFP/mg tumor/day, or 0.0012-0.0183 pg AFP/cell/day (if one assumes 3.0 X 10(5) cells/mg tissue) over 48 or 72 hours. Different nodules from the same animal had similar rates of synthesis. For tumors that synthesized AFP in culture, a positive correlation was generally found between rate of synthesis and serum AFP level. The rate of in vitro AFP synthesis observed was lower than that of immunoglobulin synthesis in human myeloma or of AFP synthesis in a rat HCC, but it was close to the estimated rate of AFP synthesis in a monkey HCC line in long-term culture.

Animals↗
PubMed1978

Oral absorption and selective tissue localization of 4'-(9-acridinylamino)-methanesulfon-m-anisidide.

The disposition of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (AMSA), a new antitumor agent presently undergoing clinical evaluation, was studied in mice and rats following oral administration and compared to that observed following intravenous administration. The metabolic fate of AMSA was the same with either intravenous or oral administration; however, the tissue distribution of AMSA differed significantly between the two routes of administration. Following absorption from the GI tract, AMSA was rapidly cleared from plasma by the liver and excreted in the bile as metabolites. Concentrations of AMSA in the liver were relatively high after oral administration and were sufficient to exert a cytotoxic effect on L1210 cells implanted at the site. The results indicate the use of AMSA orally to attain selective localization in the liver with decreased systemic exposure, which may prove useful against tumor metastases to the liver or primary hepatocellular carcinoma.

Absorption↗
PubMed1978

Initial studies on the disposition of quinolinium dibromide (NSC-176319) in mice and rats.

The disposition of quinolinium dibromide (QdB), a highly active agent against murine L1210 leukemia was studied using 14C-labeled drug. Excretion of radioactivity was slow, with only 10 and 16% of the dose eliminated in the urine and 19 and 24% in the feces, 96h after intraperitoneal administration of QdB to mice and rats, respectively. Plasma levels of 14C were low and decreased with time, whereas tissue concentrations were high and remained elevated. Differences in tissue concentrations observed in the rat 96 h following intravenous and intraperitoneal dosing could be explained by QdB binding. A strong association between QdB and DNA was indicated by the effect of DNA on the absorption spectrum and Sephadex G-200 elution profile of QdB.

Animals↗
PubMed1978

Carcinogenic and other adverse effects of procarbazine in nonhuman primates.

The carcinogenic potential of procarbazine is under investigation in three species (Macaca mulatta, Macaca fascicularis, and Cercopithecus aethiops) of nonhuman primates. A total of 55 monkeys have received procarbazine s.c., p.o., or i.p. for periods of up to 12 years. Eleven of the 42 monkeys (26%) necropsied thus far have had malignant neoplasms, 6 of which were acute leukemia. Two monkeys developed osteogenic sarcomas, two monkeys developed hemangiosarcomas, and a single case of lymphocytic lymphoma was found. The average total dose of procarbazine received by the monkeys developing cancers was 36.0 g; the average duration of procarbazine treatment was 75 months. A number of the toxic effects of procarbazine seen in humans were also noted in this series of monkeys, including vomiting and myelosuppression. Another striking toxic effect was on the reproductive system of the males. The majority of the adult males necropsied to date have had testicular atrophy with complete aplasia of the germinal epithelium.

Animals↗
PubMed1977

Computed tomographic demonstration of hepatic tumor with the aid of intravenous iodinated fat emulsion. An experimental study.

Computed tomography showed improved visualization of carcinogen-induced hepatoma in monkeys following intravenous injection of an experimental contrast material AG 60-99; selective opacification of the liver and spleen was accomplished with a dose of greater than or equal to 0.1 ml/kg, a fraction of the dose used in conventional x-ray tomography. This marked reduction was made possible by the improved density resolution of the CT scanner. This may be the first organ-specific contrast material intended primarily for use with CT scanners.

Animals↗
PubMed1977

Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2'-deoxycoformycin.

The potent adenosine deaminase inhibitor 2'-deoxycoformycin ((R)-3-(2-deoxy-beta-D-erythropentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol) inhibits the enzymic inactivation and potentiates the cytotoxic activity of a variety of adenosine analogs in the P388 murine leukemia cell culture system. The activity of all seven adenosine analogs examined was enhanced by 2'-deoxycoformycin with the exception of tubercidin (7-deaza-adenosine) which is not a substrate for the deaminase. In vivo, 2'-deoxy-coformycin potentiated the antineoplastic activity of 9-beta-D-xylofuranosyladenine in mice with P388 murine leukemia.

Adenosine↗
PubMed1977

Initial studies on the penetration of spirohydantoin mustard into the cerebrospinal fluid of dogs.

A gas-chromatographic-mass-spectrometric method using selected ion monitoring has been developed to detect and quantitate levels of spirohydantoin mustard (SHM) as low as 1 ng per injected sample. The ions chosen for analysis of the drug were at m/e 154, 156, and 299. Using this procedure, the distribution of SHM in the blood and cerebrospinal fluid (CSF) of dogs following intravenous administration has been studied. The initial blood decay of SHM is rapid with a half-life of 1.78 and 1.85 min for 2 different dogs. SHM enters the CSF and, after reaching a peak value at approximately 10 min, exhibits a decay curve similar to that found in blood.

Animals↗
PubMed1977

Composition, associated tissue methyltransferase activity, and catabolic end products of transfer RNA from carcinogen-induced hepatoma and normal monkey livers.

This investigation was designed to explore transfer RNA (TRNA) methyltransferase activity, urinary excretion levels of tRNA degradation products, and tRNA base composition in normal monkeys and in those with hepatocellular carcinomas induced by N-nitrosodiethylamine. After the development of the tumor, 24-hr urine specimens were collected, the monkeys were sacrificed, and the livers were removed for tRNA isolation and methyltransferase activity studies. The tRNA methyltransferase activity and capacity and the urinary excretion levels for selected tRNA degradation products (pseudouridine, N2,N2-dimethylguanosine, 1-methylinosine, 7-methylguanine, and beta-aminoisobutyric acid) were elevated for the hepatoma-bearing monkeys when compared to those with normal liver. The isolated tRNA pools were analyzed by high-resolution liquid chromatography, and similar base compositions were found for the hepatoma-bearing and normal monkeys. With the use of methyl-deficient Escherichia coli tRNA as the methyl receptor and the analytical procedure for tRNA anlysis, the methylating ability of the tRNA methyltransferases in hepatoma and normal liver extracts was determined. The hepatoma methyltransferase homogenates were found to produce increased levels of 7-methylguanine, N2,N2-dimethylguanine, and thymine, while the normal liver extracts gave higher levels of N2-methylguanine. These differences were not apparent in the base composition of the tRNA pools. The increased urinary excretion and higher methyltransferase activity of the hepatoma-bearing monkeys without an apparent increase in the methylated base content of their tRNA suggest increased tRNA tf individual isoaccepting tRNA's would be missed by analyzing the tRNA pools. The variations in the individual tRNA methyltransferase activities of the hepatoma and normal liver homogenates indicate a difference in the methlation of their tRNA's.

Animals↗
PubMed1977

Pharmacologic disposition of DL-alanosine in mice, rats, dogs, and monkeys.

The pharmacologic disposition of DL-alanosine was studied in mice, rats, dogs, and monkeys. The major portion of the parenterally administered drug was excreted in the urine by all of the species studied; however, in rodents an important fraction of the dose was expired as CO2. Organs in which DL-alanosine accumulates include the kidneys, lungs, liver, and small intestine. Considerable drug-derived radioactivity persists for periods up to 14 days in the hepatic and renal parenchyma. Studies on the clearance of DL-alanosine in mice using a specific enzymatic assay procedure indicated that the plasma half-life of the parent drug was shorter than the half-life of total radioactivity. In both cases, however, the kinetics were complex and not readily resolvable into discrete phases. In murine lymphoblasts (L5178Y/AR) the transport of DL-alanosine was found to be a sodium-stimulated, saturable, and thermosensitive process which was inhibited by L-threonine, L-asparagine, L-glutamine, L-serine, L-leucine, L-isoleucine, L-valine, L-cysteine, and L-homoserine. Kinetic studies on the influence of L-asparagine and L-glutamine on this transport revealed that the inhibition was competitive in nature.

Alanine↗