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M Tracy

Publications and source records attributed to M Tracy.

At least 37 records · Page 2Linked to original sources
PubMed1996

Vitamin B12 levels in human milk during the first nine months of lactation.

Vitamin B12 concentration was measured by competitive binding radioassay in 48 samples of human milk from healthy mothers eating unrestricted diets. Specimens were collected 1-35 weeks after full-term delivery and were subjected to proteolytic digestion before radioassay in order to destroy binding proteins. The distribution of the results was skewed, but the distribution of the logged values was not significantly different from normal. The geometric mean vitamin B12 level remained almost unchanged during the first 12 weeks postpartum (261-297 pmol/l) and then declined to a low of 139 pmol/l at 27-35 weeks. A significant (P = 0.033) decline in vitamin B12 concentration between 6-12 weeks and 19-25 weeks postpartum was observed.

Animals↗
PubMed1995

Development and validation of a solid-phase extraction and high-performance liquid chromatographic assay for a novel fluorinated 2-nitroimidazole hypoxia probe (SR-4554) in Balb/c mouse plasma.

N-(2-Hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide, a novel 2-nitroimidazole, is currently being developed as a non-invasive probe for tumour hypoxia. A sensitive (minimum quantifiable level = 25 ng/ml; C.V. = 6.01%) and selective assay has, therefore, been developed for the analysis of this compound in mouse plasma. The assay employed a solid-phase extraction followed by a rapid (10 min) HPLC analysis with UV-photodiode-array detection. No drug-related metabolites were observed in plasma when mice were treated with 180 mg/kg of the drug. The assay has proved to be suitable for studying the plasma pharmacokinetics of this fluorinated 2-nitroimidazole in mice.

Animals↗
PubMed1995

The novel fluorinated 2-nitroimidazole hypoxia probe SR-4554: reductive metabolism and semiquantitative localisation in human ovarian cancer multicellular spheroids as measured by electron energy loss spectroscopic analysis.

The novel fluorinated 2-nitroimidazole SR-4554 is undergoing preclinical development as a magnetic resonance spectroscopy and imaging probe for hypoxic tumour cells. We have used electron energy loss spectroscopic analysis (EELS) to show selective reduction and differential subcellular localisation of SR-4554 in human ovarian multicellular spheroids. SR-4554 was demonstrated to be metabolised by these A2780 cells under hypoxic but not under normal aerobic cell culture conditions. The EELS technique illustrated that the relative amount of drug within the cytoplasm of cells from both the inner region (150-160 microns from edge) and outer edge of the spheroid did not differ significantly after an initial 3 h incubation with drug. In contrast, an 8-fold differential between the amount of drug retained in the cytoplasm (primarily ribosomes and endoplasmic reticulum) of cells from the inner vs outer regions of the spheroids was observed following a subsequent 2 h 'chase' culture in drug-free medium. Within cells from the hypoxic region of the spheroid, SR-4554 was mainly associated with the endoplasmic reticulum, nucleus and the cytoplasmic side of intracellular vesicles and also to a lesser extent with the nuclear periphery. Interestingly, the drug was only weakly associated with the mitochondria and plasma membrane of the cells. The characteristics of cellular and subcellular distribution of SR-4554 are consistent with the hypothesis that 2-nitroimidazole compounds undergo hypoxia-mediated enzymatic reduction to reactive species. These reactive species are selectively retained in the cells in which they are metabolised through covalent association with subcellular components. These findings provide additional support for the clinical development of the drug as a non-invasive probe for tumour hypoxia and at the same time illustrate the utility of the EELS technique for examining the heterogeneity of drug distribution both between and within cells.

Aerobiosis↗
PubMed1995

Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones: the kinetic basis for hypoxia-selective, bioreductive drugs.

Drugs based on nitroarene, aromatic N-oxide or quinone structures are frequently reduced by cellular reductases to toxic products. Reduction often involves free radicals as intermediates which react rapidly with oxygen to form superoxide radicals, inhibiting drug reduction. The elevation of cellular oxidative stress accompanying oxygen inhibition of reduction is generally less damaging than drug reduction to toxic products, so the drugs offer selective toxicity to hypoxic cells. Since such cells are resistant to radiotherapy, these bioreductive drugs offer potential in tumour therapy. The basis for the selectivity of action entails kinetic competition involving the contesting reaction pathways. The reduction potential of the drug, radical pKa and nature of radical/radical decay kinetics all influence drug activity and selectivity, including the range of oxygen tensions over which the drug offers selective toxicity. These properties may be quantified using generation of radicals by pulse radiolysis, presenting a physicochemical basis for rational drug design.

Animals↗
PubMed1994

Radiation chemistry applied to drug design.

Radiation chemistry can contribute to drug design by quantifying redox properties of drugs (useful parameters in quantitative structure-activity relationships), and where free radicals are suspected intermediates in drug action, radiation can be used to generate these putative species and help characterize relevant reactions. Steady radiolysis produces radicals at a readily-varied but quantified rate; pulse radiolysis with fast spectrophotometric and/or conductimetric detection enables the kinetic properties of radicals to be monitored directly. Using these methods, radical intermediates from drugs with specific cytotoxicity towards hypoxic cells have been shown to react rapidly with oxygen, a reaction probably responsible for the therapeutic differential. Radical oxidants from activated neutrophils include superoxide and hydroxyl radicals, and radiation-chemical methods have an important role to play in rational drug design to exploit such oxidative chemistry. Antioxidants can also be evaluated quantitatively by radiolysis methods; the conjugation reactions of thiyl radicals with thiolate and oxygen are now recognised to be major contributions of pulse radiolysis to thiol biochemistry.

Drug Design↗
PubMed1993

Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998.

Positive inotropic agents that increase the sensitivity of myofilaments to calcium have recently been described (Kitada et al., 1987; Cottney et al., 1990; Ferroni et al., 1991; Lee and Allen, 1991; Beier et al., 1992). These drugs appear to augment contractility independently of cAMP or calcium, and thus may have fewer of the adverse side effects seen with other currently available agents (Katz, 1986; Packer 1989). The clinical utility of "calcium-sensitizers" has been questioned on the theoretical grounds that such agents may interfere with relaxation and impair diastolic function (Hajjar and Gwathmey, 1991). Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility. Modelling studies have suggested that the impairment of relaxation by calcium-sensitizers may be even more severe when myocardial calcium is abnormally elevated, such as in hypoxia (Allen and Orchard, 1987; Lodge and Gelband, 1988) and end-stage heart failure (Hajjar and Gwathmey, 1991). We have examined the effects of EMD 53998 and milrinone on contractility and calcium flux in a cell culture model of myocardial hypoxia. The results indicate that increased calcium sensitivity results in marked impairment of relaxation under hypoxic conditions, possibly due to the impaired calcium sequestration and increased calcium availability exhibited by hypoxic myocytes. These studies show that the effects of calcium sensitizers can be strongly influenced by the prevailing status of intracellular calcium handling, and may be deleterious in the diseased or ischemic myocardium.

Animals↗
PubMed1992

Second-generation 1,2,4-benzotriazine 1,4-di-N-oxide bioreductive anti-tumor agents: pharmacology and activity in vitro and in vivo.

SR 4233 (1,2,4-benzotriazine-3-amine 1,4-dioxide) will soon be entering Phase I clinical trials as a new bioreductive cytotoxic agent for the treatment of solid tumors in combination with fractionated radiotherapy. We have selected 3 from over 50 analogues of SR 4233 which showed particular promise as second generation bioreductive antitumor agents. These compounds, when compared to SR 4233, have higher hypoxic toxicity and comparable or higher oxic to hypoxic cytotoxicity ratios in vitro and similar animal toxicity. We have compared the effectiveness of these three compounds with SR 4233 in two tumor systems and have examined some pharmacokinetic properties. The results show that replacement of the amino group at the 3-position of SR 4233 with either a hydrogen or an N,N-dialkylaminoalkylamino group shortens the half-life of these compounds in the blood because of the combined effects of partition coefficients, basicity, and higher reactivity. SR 4754 and SR 4755, the N,N-dialkylaminoalkylamino derivatives, exhibited shorter plasma half-lives than SR 4233 but exhibited lower anti-tumor activity than SR 4233 based on equal mouse toxicity in a fractionated regimen. SR 4482, with the hydrogen substitution and very high electron affinity, possessed a very short blood half life yet retained similar anti-tumor activity as SR 4233.

Animals↗
PubMed1992

Cardiac tamponade from a fine silastic central venous catheter in a premature infant.

A 790 g infant developed cardiac tamponade 17 h after starting parenteral nutrition through a fine silastic catheter, the tip of which was accidentally positioned against the wall of the right atrium. Cold light examination suggested the diagnosis and pericardial aspiration of clear fluid with a high glucose content restored the circulation.

Cardiac Tamponade↗
PubMed1990

An investigation of bulk tank milk selenium levels in the San Joaquin Valley of California.

We evaluated selenium determination of bulk milk tank samples as an alternative to testing blood selenium for evaluating herd selenium status in DHIA dairy herds in the San Joaquin Valley of California. A method of determining milk selenium levels using inductively coupled plasma spectrometry is described. Mean bulk tank milk selenium levels were 0.0224 mg/L (Range 0.0126-0.0418 mg/L). No statistically significant relationships were found between bulk tank milk selenium levels of a herd and calving interval, days open or log somatic cell counts. Mean herd blood and milk levels were directly proportional to bulk tank milk selenium levels. Within a herd milk selenium levels of a cow were directly proportional to the cow's blood selenium level. Herd selenium levels were not significantly related to soil selenium levels. Determination of bulk tank milk selenium levels has the potential to be a low cost, non-invasive means of evaluating herd selenium levels in order to determine selenium deficiency. Further studies with this technique in areas which are deficient in selenium may provide estimates of the sensitivity, specificity and predictive value of bulk milk tank selenium for determining selenium deficiency in dairy herds.

Analysis of Variance↗
PubMed1989

Early-life undernutrition impairs the development of the learning and short-term memory processes mediating performance in a conditional-spatial discrimination task.

Previously undernourished and well-nourished control rats 23, 30, 40, and 90 days old were compared in a win-shift version of a conditional-spatial discrimination task. Control animals at each age were able to reach criterion on this problem. In contrast, the underfed rats were unable to solve this problem until they were at least 40 days old. The short-term memory of the 40- and 90-day-olds was further evaluated by increasing the interval between the forced run and choice run to 30, 60, and 180 s. Control animals could bridge all intervals; however, the undernourished animals' performance fell to chance when the interval was only 60 s. Thus, early-life undernutrition severely impaired the development of the ability of animals to solve spatial-conditional discrimination tasks and permanently impaired their short-term memory capacity. A simple threshold model relating undernutrition, brain development, and behavior is proposed to account for these data.

Animals↗
PubMed1989

Structure-activity relationships for benzotriazine di-N-oxides.

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent that selectively kills and radiosensitizes hypoxic mammalian cells in vitro and murine tumors in vivo. In an attempt to better understand the mechanism of action of the drug, and to determine whether a superior analog may exist, 15 benzotriazine-di-N-oxide analogs of SR 4233 have been evaluated to date for the following properties: hypoxic and aerobic toxicity toward CHO cells in vitro, drug-induced stimulation of oxygen consumption by incubation with respiration-inhibited cells, and acute LD50 evaluated in BALB/c mice. We noted several correlations between these biological properties of the drugs and some of their physicochemical characteristics. Both the hypoxic cytotoxicity and stimulation of oxygen consumption by respiration-inhibited cells were positively correlated with E1/2, the polarographic half-wave reduction potential, and a measure of electron affinity. The air-to-nitrogen differential cytotoxicity reached a maximum (corresponding to SR 4233) and then declined with increasing E1/2. The acute LD50 of each analog in mice decreased with increasing E1/2. One new compound, SR 4482, was found to be more toxic to hypoxic cells in vitro, but less toxic to mice, than SR 4233. It is similar in structure to SR 4233, but lacks any substituent in the 3-position of the triazine ring. This promising drug may represent a member of a new subseries of 1,2,4-benzotriazines with different structure-activity relationships.

Animals↗
PubMed1987

[Use of flour of pejibaye fruit (Bactris gasipaes H.B.K.) in bread making].

Trial were conducted in Costa Rica in 1984 and 1985, to determine the possibility of substituting pejibaye (Bactris gasipaes H.B.K.) meal for wheat flour in bread. Utilization in three distinct mixtures was examined: 90:10, 85:15 and 80:20 percentage of wheat flour to percentage of pejibaye meal, respectively. The breads were made, and dough analyses were conducted at "Molinos de Costa Rica, S.A.", the country's principal flour mill. Chemical analyses were carried out at the University of Costa Rica. Results indicate a marked inverse relationship between both initial dough development time and dough strength maintenance, and the content of pejibaye meal present in the flour mixture. Consequent problems with sufficient dough expansion preclude utilization of this fruit meal for bread-making in proportions significantly greater than 10% of the total composite flour. The above-mentioned findings reflect the high nutritional value of the pejibaye fruit. Although the protein content is inversely correlated with the amount of pejibaye meal in the mixture, vitamin A and fat contents are positively correlated. This fact demonstrates that the utilization of pejibaye meal in bread-making may well be in some ways considered as a form of nutritional enrichment. As a final conclusion drawn from the results of analyses of the trials and sensory observations, the 90% wheat flour with 10% pejibaye meal mixture apparently was the optimum substitution level of the breads examined. The potential macroeconomic ramifications on the Costa Rican economy of producing and utilizing pejibaye meal in bread-making, are highly favorable.

Bread↗
PubMed1985

Preparedness to accept psychiatric referral.

A survey of 312 patients attending 13 Sydney general practices suggested that preparedness to accept psychiatric referral by a general practitioner related most clearly to preparedness to consult the general practitioner in the first instance and the perceived likelihood of the general practitioner suggesting a psychological problem, while the sociodemographic characteristics of the patient did not appear of relevance. Data on actual psychiatric referrals by the contributing general practitioners suggested a higher psychiatric referral by practices in lower social class regions of Sydney and a differential referral pattern, with referral to a community psychiatric facility being rare in other than low social class general practices.

Adult↗