Biomedical subjects
D E Carter
Publications and source records attributed to D E Carter.
Focal-point dependency in inversion perception among Negro, urban Caucasian and rural Caucasian children.
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Pharmacokinetics of 14C-etretinate in healthy volunteers and two patients with biliary T-tube drainage.
The pharmacokinetic profile of 14C-etretinate, a retinoid that is effective in the treatment of psoriasis, was studied in six healthy male volunteers and two biliary T-tube patients. Following a 100 mg oral dose of 14C-etretinate (20 microcurie), etretinate and its major blood metabolites (etretin, isoetretin) were measured by HPLC and total carbon-14 was measured in blood, bile, urine, and feces by liquid scintillation counting. Etretinate was extensively metabolized in healthy volunteers and in T-tube patients. During the absorption phase, 75 per cent of the total radioactivity in the blood could be accounted for as etretinate, etretin, and isoetretin whereas these compounds accounted for only approximately 12 per cent of the blood radioactivity in T-tube patients over the same time period. The blood concentrations of etretinate, etretin, and isoetretin appeared to be substantially reduced in T-tube patients compared to those in healthy volunteers. A higher proportion of the total drug was excreted in the feces and bile of the T-tube patients (84 per cent) than in the feces of healthy volunteers (62 per cent). The major factor responsible for the observed decrease in etretinate blood concentrations following biliary cannulation appears to be the reduced absorption of etretinate due to the elimination of solubilizing bile salts in the duodenum. Carbon-14 related material was detected in urine and feces for as long as 3 weeks in healthy subjects supporting the previous observation that a long terminal elimination half-life exists for etretinate, even following a single dose of the compound.
Reactions of arsenic(III) and arsenic(V) species with glutathione.
Arsenic is metabolized by living systems using oxidation-reduction and methylation reactions, and reduced glutathione (GSH) has been shown to be important in that metabolism. In this study, the solution reactions between GSH and arsenate, arsenite, and their methylated metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were characterized using 1H and 13C NMR under a nitrogen atmosphere. Binding to GSH through the thiol group was primarily followed by shifts in the carbon atom bonded to the sulfhydryl group of the cysteinyl residue, i.e., the CH2 carbon atom and the protons bonded to it. The methylated metabolites also showed shifts in the methyl groups attached to the arsenic atom after reaction with GSH. Sodium arsenite, As(III), bound to GSH to form an As(SG)3 complex in solution as indicated by NMR spectra. The identity of the complex was confirmed by FAB-MS after isolation of the compound. Mixtures of sodium arsenate, As(V), and GSH showed that arsenate oxidized GSH in D2O solutions at pH 7 to form oxidized glutathione (GSSG). When the molar ratio of As:GSH exceeded 1:2, evidence for the formation of As(SG)3 was observed. MMA and DMA are both As(V) species, and mixtures with GSH showed oxidation to GSSG initially followed by formation of CH3.As(SG)2 and (CH3)2.As.SG, respectively. The effects of GSH on arsenic metabolism may result from direct reactions between the two compounds.
Early indices of methyl mercury toxicity and their use in treatment evaluation.
Mercury distribution, food consumption, body weight, and in vivo protein synthesis were compared as criteria for evaluating the efficacy of D-penicillamine (DPA) in treating experimental methyl mercury (MM) intoxication. Female rats were orally administered MM hydroxide at 40 mg/kg and, after a 7- to 8-d latency period, displayed characteristic neurological signs of MM intoxication. Within 24 h of MM exposure food consumption decreased 75% causing a 12-g drop in body weight, and synthesis of whole blood and kidney protein increased. Protein synthesis in liver was increased 39% by MM after 3 d, and that in cerebellum was decreased 15% after 7 d. Treatment with DPA (1.2 g/kg.d sc on d 2, 3, and 4) prevented the appearance of neurological signs. DPA lowered the Hg content of all tissues; restored food consumption of control levels; increased the onset and amount of body weight gain; returned synthesis of blood, liver, and kidney proteins to control levels; and prevented the decrease in protein synthesis in cerebellum. By itself, DPA produced a transitory decrease in both food consumption and body weight, which could be prevented with vitamin B6. Vitamin B6 antagonized DPA's reversal of MM's action on protein synthesis. Furthermore, DPA and/or vitamin B6 had a variety of effects on protein synthesis in control rats. Thus it was not possible to use protein synthesis to predict the efficacy of the combination of DPA and vitamin B6 as found for the parameters of food consumption, body weight, and Hg distribution. Since changes in body weight and food consumption were the earliest and most pronounced and consistent responses to MM and effective DPA treatment, they were considered the best criteria for evaluating treatment efficacy in experimental MM poisoning in rats.
The role of food consumption and amino acid uptake in the action of methylmercury on protein synthesis.
The effect of methylmercury (MM) on protein synthesis was examined with respect to nutritional deficiency due to decreased food intake, method of amino acid administration, and amino acid uptake. Female rats were administered orally 40 mg MM hydroxide/kg and were compared with both ad libitum and pair-fed control groups. Synthesis of blood, liver, kidney, and cerebellar proteins of pair-fed controls was significantly lower than for ad libitum-fed controls. Relative to ad libitum-fed controls, MM transiently increased synthesis of blood proteins and then decreased it for blood and liver proteins. In contrast, using pair-fed controls, MM increased synthesis of blood and liver proteins. Comparison with either control showed MM to increase protein synthesis in the kidney and decrease it in the cerebellum. Intraperitoneal and intravenous administration of the [14C]amino acids showed similar results. The action of MM on protein synthesis seemed independent of its action on amino acid uptake, since MM did not affect aminoisobutyric acid uptake in the liver and cerebellum and decreased it in the kidney. In summary, we found that the effect of MM on food intake plays a significant role in the action of MM on protein synthesis and must be accounted for with pair-fed controls.
An improved wet digestion procedure for the analysis of total arsenic in biological samples by direct hydride atomic absorption spectrophotometry.
The presence of dimethylarsinic acid (DMAA) in biological samples can cause an underestimation of total arsenic content when analyzed relative to an inorganic arsenic standard by direct hydride flame atomic absorption spectrophotometry. An acid digestion procedure is described that quantitatively recovers DMAA as well as monomethylarsonic acid, inorganic arsenic(III), and arsenic(V) from aqueous and biological samples. Methylated arsenicals are converted to inorganic arsenic by wet digestion with HNO3, H2SO4, and K2Cr2O7 and subsequently reduced to arsenic(III) with Nal. Arsine is generated with NaBH4 and converted to atomic arsenic following immediate introduction into a nitrogen-entrained air-hydrogen flame. This method produces a linear relationship to absorbance within a mass range of 50 to 300 ng arsenic/arsine reaction. A sensitivity of 2 ng arsenic and a detection limit of 7 ng arsenic/arsine reaction were also obtained. Recovery of DMAA from water, urine, feces, or whole blood ranged from 92 to 105% with a coefficient of variation of 5 to 10%.
Effects of acute and subchronic exposure of topically applied fullerene extracts on the mouse skin.
The recent discovery that fullerenes (C60) can be produced in macroscopic quantities has sparked much interest in the chemistry of this unusual molecule. Concerns have also arisen about the potential carcinogenic effects of this molecule. We have addressed the potential acute and subchronic toxic effects of fullerenes applied in benzene on the mouse skin. The acute toxic effects measured in this study included epidermal DNA synthesis and the induction of ornithine decarboxylase activity in the epidermis. At the topical dose of fullerenes used in these studies (i.e., 200 micrograms), we found no effect on either DNA synthesis or ornithine decarboxylase activity over a 72 hour time course after treatment. The subchronic effects of the fullerenes as a mouse skin tumor promoter was assessed by repeatedly applying the chemical to the skin after initiation with the polycyclic aromatic hydrocarbon, 7,12-dimethylbenzanthracene (DMBA). Repeated administration of the fullerenes for up to 24 weeks post-initiation did not result in either benign or malignant skin tumor formation, whereas promotion with the phorbol ester, 12-O-tetradecanoyl-phorbol- 13-acetate (TPA) resulted in the formation of benign skin tumors. Our data indicate that fullerenes applied in benzene at a likely industrial exposure level do not cause acute toxic effects on the mouse skin epidermis.
The implications of head injury for family relationships.
Many of those sustaining head injury recover to the point that they no longer require hospital care. However, the family frequently has to cope with an individual with varying degrees of disability involving physical, psychological, cognitive and social dysfunctioning. This review of the literature briefly considers the possible effects that head injury may have for the injured person before going on to discuss the consequences that such an injury may have for the family of that individual. The family's need for information and education is highlighted and it is suggested that the nurse has an important role to play in this context.
Identification of the metabolites of trichlorocarbanilide in the rat.
The metabolism and excretion of 14C-labeled 3,4,4'-trichlorodiphenylurea has been studied in the rat after oral and iv administration. More than 80% of the administered radioactivity was excreted in the feces and urine over 5 days. Five isolated metabolites were characterized by mass spectrometry and by comparative thin-layer chromatography with synthesized compounds. Metabolites found include 2'-hydroxy-, 3'-hydroxy-, 6-hydroxy-, 2',6-dihydroxy- and 3',6-dihydroxy-3,4,4'-trichlorodiphenylurea.
A relationship between the metabolism of bumetanide and its diuretic activity in the rat.
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Pharmacokinetics of 14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage.
The pharmacokinetics of isotretinoin and 4-oxoisotretinoin in blood, as well as the blood concentrations and urinary, biliary, and fecal excretion of carbon-14 were studied using liquid scintillation counting techniques and reverse phase HPLC methods following a single 80-mg oral suspension dose of 14C-isotretinoin to four healthy male subjects and two patients with biliary T-tube drainage. Approximately 80% of the dose was recovered as 14C in excreta during the course of the study of which about equal fractions were in the urine and feces. Secondary peaks in blood concentrations of 14C were observed in the healthy subjects whereas they were not seen in the patients with T-tubes. The harmonic mean apparent half-life for isotretinoin in the blood of the healthy subjects was 13.6 hr, whereas the corresponding value for the 14C was 90 hr. Although a rigorous comparison of pharmacokinetic parameters between healthy subjects and T-tube patients was not feasible due to the limited number of subjects studied, comparisons of certain trends in the pharmacokinetic profiles gave some possible insights into the role of biliary excretion and enterohepatic cycling on the disposition of isotretinoin. The data for isotretinoin and 4-oxoisotretinoin coupled with the total carbon-14 data suggest that the oral dose of 14C-isotretinoin is absorbed to a similar extent by the healthy subjects and T-tube patients, whereas T-tube patients clear the drug more rapidly. The biliary excretion and possible enterohepatic circulation of isotretinoin and its metabolites may have significant impact on the pharmacokinetic profile of isotretinoin in man.
Pharmacokinetics of o-nitroanisole in Fischer 344 rats.
The pharmacokinetics and metabolism of o-nitroanisole (ONA) were studied in male Fischer 344 rats. Three dose levels of [14C]ONA (5.0, 50, or 500 mg/kg) were administered orally to rats and daily excreta were analyzed for 14C. Since the highest dose altered the urinary excretion rate of ONA, a dose of 25 mg/kg was used for subsequent pharmacokinetic studies. Following a single 25 mg/kg iv dose of [14C]ONA, blood, tissues, and excreta were collected at times ranging from 15 min to 7 days. Urinary excretion accounted for 82% of the dose by 24 hr and 86% by 7 days. Fecal excretion was 7.5% in 24 hr and 9.0% by 7 days. Fifteen min after ONA administration, most of the 14C content was found in muscle (20%), skin (10%), adipose tissue (6.8%), and blood (6.5%). All other tissues contained less than 5% of the dose. Within 8 hr, less than 1% of the dose was present in any tissue. The initial elimination t1/2 for 14C in all tissues was 1-2 hr and the terminal t1/2 was approximately 4 days. The elimination of parent ONA from blood followed first order biphasic elimination kinetics (initial t1/2 = 30 min; terminal t1/2 = 2.2 hr). Parent ONA was rapidly eliminated from all other tissues in a monophasic manner (t1/2 = 15 min to 2 hr). Skin and fat demonstrated an uptake phase prior to the elimination of parent. Only 0.5% of the dose was excreted as ONA in the urine. Urinary metabolites of ONA were predominantly conjugated compounds (63% as sulfates; 11% as glucuronides).
Isolation and identification of the polar metabolites of chlorpheniramine in the dog.
The metabolites of chlorpheniramine were isolated from dog urine. After daily repeated dosing with chlorpheniramine, [methylene-14C]chlorpheniramine maleate was given as a tracer and urine was collected until less than 1% of the labeled dose was excreted daily. An average of 54% of the oral radioactive dose was recovered in the urine. In addition to the N-demethylated metabolites, one very polar metabolite accounting for about 18% and two less polar metabolites accounting for a total of about 30% of the total urine radioactivity were isolated. Hydrolysis studies of the most polar metabolite indicated that it was a conjugate, though not a glucuronide or sulfate. The metabolite identified after hydrolysis was 3-(p-chlorobenzyl)-3-(2-pyridyl)propionic acid. One of the two less polar metabolites was identified as the corresponding alcohol. The least abundant metabolite could not be identified.