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Biomedical subjects

R H Adamson

Publications and source records attributed to R H Adamson.

At least 73 records · Page 4Linked to original sources
PubMed1987

Synthesis, purification and mutagenicity of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline.

Synthesis of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a reactive metabolite of 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ), was achieved by a modification of an earlier method. N-Hydroxy-IQ was purified by a two-step procedure involving C18 Sep-Pack and semi-preparative h.p.l.c. Additional h.p.l.c. methods were developed to monitor the synthesis of N-hydroxy-IQ, and to measure IQ and other IQ derivatives on the same h.p.l.c. profile. The structure of N-hydroxy-IQ was confirmed by mass spectral analysis following derivatization to azoxy-IQ, phenyl-azoxy-IQ and acetoxy-acetamido-IQ, and by chemical reactivity studies. Mutagenicity studies with the nitro-reductase-deficient strain of Salmonella TA98 showed that N-hydroxy-IQ is directly mutagenic, having a specific activity of 2 X 10(4) revertants/nmol. The data confirm that N-hydroxy-IQ is a mutagenic metabolite of IQ and further implicate the hydroxylamine in the carcinogenicity of IQ.

Imidazoles↗
PubMed1987

Quantitative fluorescence microscopy on single capillaries: alpha-lactalbumin transport.

We have extended the use of a microscope densitometric technique [Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H495-H505, 1983] to measure the solute permeability coefficients (Pa) of fluorescently labeled solutes in single perfused capillaries of frog mesentery. The method enables the transcapillary flux of solutes larger than 10,000 mol wt to be measured under conditions where the forces that determine both solute and water flows across the capillary wall are known. The Pa for alpha-lactalbumin (mol wt 14,176, Stokes radius 2.02 nm) increased from a mean value of 2.1 X 10(-6) cm/s when capillary pressure was 3.0 cmH2O (no net filtration) to greater than 4.0 X 10(-6) cm/s when capillary pressure was 15 cmH2O. Taking a value of 0.35 for the solvent drag reflection coefficient for alpha-lactalbumin, we conclude that the increased solute flux represents solvent drag through a water pathway with a hydraulic conductivity of 3.6 X 10(-7) cm X s-1 X cmH2O-1. Our data conforms to the hypothesis that alpha-lactalbumin is transported across the capillary wall by restricted diffusion and solvent drag in a pathway that carries 90% of the transcapillary water flow (the principle water pathway). In vitro and in vivo calibration experiments have been carried out to test the assumption that the measured fluorescent light intensity is proportional to the number of fluorescent molecules in the measuring window of the photometer.

Animals↗
PubMed1983

Permeability of single capillaries to intermediate-sized colored solutes.

The fiber matrix theory of capillary permeability was evaluated by measuring permeability coefficients to colored solutes with Stokes radii between 0.5 and 1.76 nm. In vivo calibration of a microscope photometer established the range of linearity for optical density measurements from a rectangular window that included the test capillary and surrounding tissue. In individually perfused capillaries of frog mesentery the following permeability coefficients, expressed as mean +/- SE X 10(5) cm/s were obtained: azure C (mol wt 277), 11.0 +/- 0.2; patent blue violet (566), 3.95 +/- 0.67; Evans blue (960), 1.15 +/- 0.23; microperoxidase (1,900), 1.13 +/- 0.31; and FITC-dextran 3 (3,400), 0.48 +/- 0.18. There is significant restriction to diffusion of all solutes larger than azure C. Fibers 0.5 nm in radius occupying 8.5% of the volume of intercellular junctions (area 2.2 X 10(-3) cm2/cm2, depth 0.6 X 10(-4) cm) account for the 22-fold range of measured permeabilities. The fiber density estimated is larger than that required to describe water flow through the junction. Negative charges on solutes larger than 0.5 nm radius may contribute to exclusion and restriction to diffusion in intercellular junctions.

Animals↗
PubMed1982

Computed tomography of the liver and spleen with intravenous lipoid contrast material: review of 60 examinations.

In 60 computed tomographic examinations of the liver and spleen in 55 patients, a new intravenous lipoid contrast material, Ethiodized Oil Emulsion 13, was used. This organ-specific contrast material, retained by the reticuloendothelial cells of the liver and spleen, caused marked increase in the attenuation of the liver and spleen, but did not appreciably change the attenuation of the tumor involving these organs, thereby significantly increasing the density differential between normal and abnormal tissue. Toxicity was considered to be well within tolerable limits with the most frequently noted untoward side effects of chills, fever, headaches, and foul metallic taste. Ethiodized Oil Emulsion 13 holds the promise to become a valuable clinical tool by which hepatic and splenic imaging may be significantly improved and lesions less than 1 cm in diameter demonstrated in the liver and spleen.

Adult↗
PubMed1981

Identification of conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide.

Conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide were identified primarily by high-pressure liquid chromatography in combination with field desorption mass spectrometry. The spontaneous metabolic pathway of the drug, as related to its susceptibility to nucleophilic attack by endogenous thiols at the 9-carbon atom of the acridine moiety, has been studied. Among the metabolite fraction of 4'-(9-acridinylamino)methanesulfon-m-anisidide excreted in rat bile after administration of a therapeutic dose, a conjugate was identified as the 9-acridinyl thioether of glutathione. This conjugation product and the corresponding 9-acridinyl conjugates were formed spontaneously after incubation of 4'-(9-acridinylamino)methanesulfon-m-anisidide with glutathione, cysteine and N-acetylcysteine in sodium phosphate buffer and other aqueous media, as established by high-pressure liquid chromatography and field desorption mass spectra. The thiolytic pathway results in the release 4-amino-3-methoxymethanesulfonanilide which was identified in all in vitro experiments and in rat serum after intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide. 9(10H)-Acridone, 9-aminoacridine and other acridine derivatives which occur as minor products during the thiolytic cleavage in vitro were identified by field desorption and partially by high resolution electron impact mass spectrometry.

Aminoacridines↗
PubMed1981

Chemically induced leukemia in humans.

The human population may be exposed to potentially leukemogenic agents, either in the form of drugs and food additives or as environmental contaminants and pollutants. However, in spite of the large number and diversity of these chemicals, only a few have been implicated as human leukemogens. One such agent is benzene, a known bone marrow depressant. A number of case reports have associated chronic exposure to this agent with the development of acute leukemia, as have several epidemiologic surveys. Treatment with various antitumor agents, including procarbazine, melphalan, thio-TEPA, chlorambucil, and cyclophosphamide, has also been associated with the development of acute leukemia. In addition, chloramphenicol and phenylbutazone have been implicated as human leukemogens, but the association between exposure to these two agents and acute leukemia appears at present to be weaker than it is for benzene and antitumor agent exposure. Despite such associations between exposure to chemicals and acute leukemia, several important problems exist with regard to implicating specific agents in the development of this neoplasm in man, including the paucity of animal models for chemically induced leukemia, and the frequent necessity to rely on single case reports or clusters of cases in which chemical exposures are associated with acute leukemia. Future efforts should be directed at performing properly designed and well executed epidemiologic studies, and at developing new in vitro and in vivo models for the study of this neoplasm.

Benzene↗
PubMed1980

The clinical pharmacology of the adenosine deaminase inhibitor 2'-deoxycoformycin.

2'-deoxycoformycin (2'-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2'-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kg X 1 to 0.25 mg/kg/day X 5; ado deaminase and 2'-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential (alpha and beta t 1/2 values about 1 and 10 h respectively). Recovery of unchanged 2'-dCF from urine (48 h) was 32%--48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2'-dCF/kg/day X 5.

Adenosine Deaminase Inhibitors↗
PubMed1980

Clinical trials with a new intravenous liposoluble contrast material for computed tomography of the liver and spleen.

Ten patients with disseminated cancer were given intravenous injections of 0.2 ml/kg (40 mg l/kg) of the experimental contrast material EOE 13. Ct scans of the liver and spleen were taken prior to and 30 minutes after contrast infusion. Visualization of the liver was significantly improved in 5, moderately improved in 3, and not appreciably improved in 2. The spleen showed an obvious increase in density in all cases. No significant toxicity was encountered: untoward side effects consisted of fever, headaches, foul metallic taste, and weakness for a short period. Four patients had no side effects, and 2 experienced only abnormal taste sensation. Further experimental and clinical work is needed before the advantages and safety of this contrast material can be documented.

Autopsy↗
PubMed1980

Cardiotoxic and possible leukemogenic effects of adriamycin in nonhuman primates.

10 monkeys (macaques) received adriamycin by monthly intravenous injections at 12 mg/m2 (1 mg/kg). 8 of the 10 monkeys developed congestive heart failure at an average cumulative adriamycin dose (310 mg/m2) well below that considered the safe upper limit (550 mg/m2) in man. Histologically, the myocardial lesions resembled those found in human anthracycline-induced cardiomyopathy. 1 of the 10 monkeys developed acute myeloblastic leukemia after receiving 324 mg/m2 of adriamycin; the 10th monkey is alive and well 26 months after the last dose of drug. Our results suggest that adriamycin is a more potent cardiotoxin in monkeys than in man, and that leukemia may be a consequence of prolonged treatment with this drug.

Animals↗
PubMed1980

Lactose malabsorption in two sibling rhesus monkeys (Macaca mulatta).

Observation of two sibling rhesus monkeys, Macaca mulatta, indicated that they were intolerant to lactose. While on a lactose formula the monkeys had severe diarrhea and weight loss but were otherwise healthy. When a lactose-free formula was instituted, the diarrhea abated and there was a steady weight gain.

Animals↗
PubMed1980

Carcinogenicity and hepatotoxicity of cycasin and its aglycone methylazoxymethanol acetate in nonhuman primates.

The carcinogenic potential of cycasin and methylazoxymethanol (MAM) acetate was investigated in nonhuman primates. Old-world monkeys (rhesus, cynomolgus, and African green monkeys) received cycasin and/or MAM acetate by oral or ip routes up to 11 years. Eighteen monkeys survived longer than 2 months after initiation of treatment with cycasin (50-75 mg/kg) or MAM acetate (1.5-3.0 mg/kg) given orally 5 days/week; 9 of the animals were necropsied. Histopathologic examination of a liver tumor from 1 of these monkeys revealed well-differentiated hepatocellular carcinoma. A second monkey had multiple tumors, including hepatocellular carcinoma, intrahepatic bile duct adenocarcinoma, renal carcinoma and adenomas, and adenomatous polyps of the colon. Although liver tumors were not observed in the other monkeys, all but 1 monkey had hepatic lesions such as toxic hepatitis and cirrhosis. These monkeys had received cycasin and/or MAM acetate for an average of 57 months (range, 2-133 mo). A group of 10 monkeys received MAM acetate by weekly ip injections (3-10 mg/kg). Six of these animals developed tumors after receiving an average of 6.14 g (range, 3.58-9.66 g) of MAM acetate for an average of 75 months (range, 50-89 mo). Four of the monkeys developed hepatocellular carcinomas, and 2 had multiple primary tumors including hepatocellular carcinomas, renal carcinomas, squamous cell carcinomas of the esophagus, and adenocarcinomas of the small intestine. Our results showed that long-term administration of cycasin and/or MAM acetate by oral and ip routes was hepatotoxic and carcinogenic in old-world monkeys.

Animals↗