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Biomedical subjects

P Webb

Publications and source records attributed to P Webb.

At least 19 recordsLinked to original sources
PubMed1992

2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.

A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.

Antibiotics, Antineoplastic↗
PubMed1992

Inhomogeneity correction for in vivo spectroscopy by high-resolution water referencing.

One of the most common sources of distortion in in vivo spectroscopy is the inhomogeneity of the main magnetic field. This effect is particularly problematic when performing spectroscopic imaging, as the shim cannot be simultaneously optimized for all voxels. In this paper we present a technique to measure inhomogeneity rapidly, then show how to use the measurement to improve the analysis of the spectrum. This technique can be applied in conjunction with any spectroscopic localization method and any spectral quantitation algorithm. We present results from spectroscopic imaging of phantoms, then show application to a single-voxel water-suppressed proton brain study. We find that the quantitation of the in vivo spectrum is made immune to inhomogeneous line broadening.

Brain↗
PubMed1992

Temperatures of skin, subcutaneous tissue, muscle and core in resting men in cold, comfortable and hot conditions.

To examine the core-shell model of temperature distribution and the possible role of subcutaneous temperature in heat regulation, comprehensive temperature measurements were made on six nude resting men exposed for 2-3 h to comfort (27 degrees C), cold (15 degrees C) and heat (45 degrees C). Cold produced strong shivering and heat caused heavy sweating. Temperatures were recorded every 10 min from: esophagus, rectum and auditory canal; back muscle and thigh muscle at 20 mm and 40 mm depths; 6 subcutaneous sites; and 16 skin sites. Average temperatures at these 29 sites were tabulated at the ends of comfort, hot and cold and the onsets of sweating and shivering. Body temperature changes were slow to develop, the skin temperatures being fastest, and successively deeper tissues progressively slower. There was occasional after-drop and after-rise. The data were consistent with the core-shell concept. The temperature gradient from subcutaneous tissue to skin, which differed substantially with comfort, the onset of shivering and the onset of sweating, could serve as a regulatory signal. The data are now in computer format and may be of interest to biothermal modelers.

Adult↗
PubMed1992

The limits of the cellular capacity to mediate an estrogen response.

While steroid response is generally restricted by the availability of steroid receptors, the theoretical limits of the response are not known. We have constructed a series of cell lines that stably express the estrogen receptor (ER) at levels up to 5,000,000 ERs per cell and employed these cells to explore the limits of the estrogen response. Several reporter genes with estrogen response elements upstream of the herpes thymidine kinase promoter showed hyperbolic saturation kinetics with increasing ER. Maximum response was 10 times that seen in cell lines with receptor titers comparable to physiological levels. Half-maximal responses required 500,000 receptors per cell, and cells with 5,000,000 ERs showed greater than 90% maximum induction. Estradiol dose-response studies indicated that the receptors are limiting below 500,000 ERs per cell, but at higher ER titers there are spare receptors. In contrast to most reporters, the widely used reporter pA2-CAT, which has 200 base pairs of Xenopus vitellogenin DNA between the response element and the promoter, showed squelching at ER levels beyond 500,000 per cell. Cell lines that expressed ER above this level activated pA2-CAT with a distorted hormone dependence, where saturating ligand concentrations were inhibitory. All reporters displayed squelching when the ER was provided by transient transfection at a level that we judge is 20,000,000 per cell by extrapolation from the behavior of stable cell lines. These findings suggest that saturation of the cellular capacity to mediate an estrogen response and ER-dependent squelching occur at receptor titers well above those encountered in nature. If current models of steroid hormone action are correct, the findings also imply that estrogen response elements are occupied to very small extents under normal conditions.

Animals↗
PubMed1991

Rapid, fully automatic, arbitrary-volume in vivo shimming.

MR spectroscopy and many MR imaging methods benefit from a well-shimmed magnet. We have developed a pulse sequence which enables fast and accurate measurement of three-dimensional field maps in vivo, and a data analysis package that allows calculation of shim currents to optimally shim arbitrary selected volumes. A data link to the shim power supply allows automatic update of currents. No intervention by the operator is required. Typical in vivo shimming time is less than 5 min. Performance analysis, phantom, and in vivo results are presented.

Brain↗
PubMed1991

Heat regulation during exercise with controlled cooling.

During heavy sustained exercise, when sweating is usually needed to dissipate the extra metabolic heat, controlled cooling caused heat loss to match total heat production with little sweating. The total heat produced and metabolic rate were varied independently by having subjects walk uphill and down. Heat loss was measured directly with a suit calorimeter; other measurements included metabolic energy from respiratory gas exchange and body temperatures. Thermoregulatory sweating was minimized by adjusting cooling in the calorimeter suit. Heat loss rose to match total heat, not metabolic rate, and there was a slow rise in rectal temperature. In the absence of major thermoregulatory response rectal temperature correlated most closely with total heat; it also correlated with the relative oxygen cost of exercise. Heat flow or heat content appeared to be the controlled variable and body temperature rise a secondary event resulting from thermal transport lag.

Adult↗
PubMed1991

Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.

A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethyl-amino)ethyl]-3-nitrothiophene-5- carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.

Animals↗
PubMed1991

Sedentary daily expenditure: a base for estimating individual energy requirements.

As a base for estimating individual energy requirements, we propose using the energy expenditure of a sedentary day with regular meals and sleep at night. Ninety-five 24-h measurements of sedentary daily expenditure (SDE) by direct calorimetry on 37 men and women were analyzed, showing that fat-free mass combined with body mass index correlated highly with SDE (r2 = 0.92) with an SE of 5%. Weight and fat mass were better predictors for women and excellent predictors for men. We found that weight and height accurately predicted fat mass if suitable exponents were used in the expression wt/htx. Testing predictive equations with our own and other sets of data showed good agreement between estimated and observed SDEs. As a base for estimating individual energy requirements. SDE is more precise than basal metabolic rate and it can be predicted with useful accuracy from simple measures of weight and height.

Adipose Tissue↗
PubMed1991

The measurement of energy expenditure.

This is a brief account of the development of energy expenditure measurements, from speculations by early philosophers on the nature of the "innate fire," through the beginnings of quantitative animal calorimetry and to the combined material and energy balances of Rubner and of Atwater and Benedict, which established the science of nutritional energy. The equivalence of oxidation rate and heat loss led to the simplification of indirect calorimetry, followed by the era of studies of basal metabolic rate. Current practices are reviewed for measuring energy expenditure by indirect calorimetry (respiration chambers, ventilated hoods, doubly labeled water) and direct calorimetry (rooms, suits). Because problems remain in the exact account of energy balance during weight change, growth, pregnancy and exercise, perhaps it may be time to combine once again carbon balance with energy balance, using modern methods.

Calorimetry, Indirect↗
PubMed1991

Aziridinyl nitropyrroles and nitropyrazoles as hypoxia-selective cytotoxins and radiosensitizers.

A series of 1- and 2-substituted 4- and 5-nitropyrroles and 3- and 4-nitropyrazoles has been prepared and evaluated in vitro as radiosensitizers of hypoxic cells and as bioreductively-activated cytotoxins. Both the nitropyrroles and the nitropyrazoles were considerably less effective, based upon the differential between hypoxic and aerobic toxicity, than were similar 2-nitroimidazoles bearing alkylating moieties. The trends in radiosensitizing efficiency observed for both classes of drugs corresponded with their one-electron reduction potentials (E1(7] as measured by pulse radiolysis, although they were generally more effective than predicted from previous correlations of E1(7] with sensitizing efficacy and reactivities. Furthermore, the enhancement of sensitizing efficiency by the incorporation of alkylating groups is considerably greater than has been observed for nitroimidazoles. alpha-[(1-Aziridinyl)methyl]-3-nitropyrazole- 1-ethanol (10, E1(7) = -456 mV) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25, E1(7) = -326 mV) were the most effective radiosensitizers in vitro. Only 3-[cis-2,3-dimethyl-1-aziridinyl) methyl)-1-oxo-3,4-dihydro-6-nitro-1-H-pyrrolo [2,1-c] oxazine (22) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25) showed significant bioreductively-activated cytotoxicity, with differentials of 3.5. Although these differential toxicities were coupled with significantly lower aerobic toxicity compared with similar 2-nitroimidazoles, this series was not deemed effective enough to warrant further evaluation. The electron affinity and radiosensitization could be manipulated by chemical design but hypoxia-selectivity was not clearly related to these properties.

Animals↗
PubMed1990

Energy exchange in downhill and uphill walking: a calorimetric study.

Energy balance can be written as 1) M = sigma Q +/- W +/- S, expressed as power (W), where M is the rate of metabolic energy transformation, sigma Q the rate of heat loss, W the work rate, and S the rate of body heat storage. When submaximal treadmill exercise continues long enough, body temperature stops changing, S becomes zero, and the heat storage term is dropped from equation 1. For uphill walking the equation becomes 2) M = sigma Q + Wvert, and for downhill walking it becomes 3) M = sigma Q - Wvert. This study tested the energy balance equations with direct measurements of heat exchange using a suit calorimeter and M from standard measurements of respiratory gas exchange. Ten healthy men walked on a motor driven treadmill at 1.5 m.s-1 at grades of 0, 5, 10, -5, and -10% for 70-90 min to ensure a thermal steady state. As expected, +Wvert was identified as a power output, whereas -Wvert was accounted for as a power input, totally transformed to heat in the downhill walking subject. There also appeared to be a quantity of non-thermal energy, Wwalk, needed to satisfy the energy balance equation. This was significant at 0, 5, and 10% grades (P less than 0.01) but not significant at -5 and -10% grades (P greater than 0.05). The data confirm previous results for level walking and extend them to include uphill walking. While it had been suggested that Wwalk represents an externalization of energy at the foot, the present data suggest an alternative explanation.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry↗
PubMed1989

Water referencing for spectroscopic imaging.

A water referencing algorithm for addressing the spectroscopic imaging problems of low SNR and main field inhomogeneities is proposed. Using the location of the water peak from each voxel and additional a priori information results in a parametric estimation problem. Optimum estimates of the desired metabolite concentration can then be computed and displayed in an image format. The algorithm is shown to be very stable in the presence of noise and is insensitive to Bo inhomogeneity. A detailed error analysis as well as extensions to the basic data model are also discussed. Results from both 1H and 31P experiments are presented to verify the predicted good performance even with extremely low signal-to-noise ratio data.

Algorithms↗
PubMed1989

A fast spectroscopic imaging method using a blipped phase encode gradient.

Many methods of chemical shift imaging have been described recently. In most cases, these methods couple resolution and imaging time. The most flexible methods use time-varying gradients to cover a large region of k space on each excitation. We present here a new time-varying gradient method that offers a decrease in scan time (when SNR is sufficient), simplifies the reconstruction problem by retaining an essentially rectilinear sampling grid, and makes efficient use of scan time by minimizing gradient reversals. Implementation on a standard high-field imaging system (GE Signa) is discussed, and experimental results are shown. An application of the method to the generation of water reference data sets is described.

Fourier Analysis↗
PubMed1989

Effects of dietary fish oil or pectin on blood pressure and lipid metabolism in the DOCA-salt hypertensive rat.

This study investigated the effects of diets containing fish oil or pectin on blood pressure and lipid metabolism in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. Three groups (8 rats/group) of unilaterally nephrectomized rats were fed for 21 d one of three purified diets: a) 8% fish oil + 2% safflower oil + 5% alpha cellulose (fish oil diet), b) 10% safflower oil + 5% pectin (pectin diet), or c) 10% safflower oil + 5% alpha cellulose (control diet). Each of the diets contained 6% NaCl and all rats received DOCA (30 mg/kg body wt, subcutaneously) twice weekly. Systolic blood pressure of rats fed fish oil was significantly lower (P less than 0.05) than that of rats fed the control diet; there was no significant difference between the pectin and control groups. Plasma renin activity and net sodium and potassium balances were similar among the three groups. Plasma total cholesterol, LDL cholesterol and HDL cholesterol were significantly lower (P less than 0.05) in the group fed the fish oil diet than in the group fed the control diet. Total, LDL and HDL cholesterol did not differ between rats fed the pectin and rats fed the control diet. Plasma triglyceride concentration did not differ among the three groups. Thus, dietary fish oil attenuated the development of DOCA-salt hypertension, unrelated to alterations of net sodium balance. Fish oil feeding also lowered total, LDL and HDL cholesterol, but did not alter the HDL/LDL ratio. In contrast, dietary pectin exerted no effect on blood pressure or lipid metabolism.

Animals↗
PubMed1989

Influence of inducers and inhibitors on the metabolism in vitro and neurochemical effects in vivo of MDMA.

(S)-(+)- and (R)-(-)-3,4-methylenedioxymethamphetamine (MDMA) were metabolized in vitro by rat liver microsomes via N-demethylation to 3,4-methylenedioxyamphetamine (MDA). Whereas no difference was found in the biotransformation of the two enantiomers in the male rat or in the phenobarbital (PB) treated animals of either sex, more than twice as much MDA was formed from (S)-(+)- than from (R)-(-)-MDMA in the untreated female rat. Although 3-methylcholanthrene (3MC) pretreated rat liver microsomes were less active than those from the untreated rats of the same sex, they formed more MDA from (+)- than from (-)-MDMA. The enantioselective metabolism thus appears to be associated with the relative abundance of individual cytochrome P-450 isozymes. (S)-(+)- and (R)-(-)-MDMA.HCl (20 mg/kg) were about equipotent in depleting serotonin (5-HT) levels in the frontal cortex at 3 hrs and 1 wk following oral administration to female rats. Pretreatment of rats with SKF-525A attenuated and that with PB enhanced the 5-HT depleting potential of either isomer at 3 hrs. The 5-HT depleting potency of (+)-MDMA was significantly greater than that of its (-)-antipode at 3 hr in PB pretreated, but not in SKF-525A pretreated animals. The results suggest that the neurochemical effects of MDMA are caused by the formation of an active metabolite in vivo, and since both enantiomers were N-demethylated in vitro to approximately the same extent by PB pretreated rat liver microsomes, the active metabolite may be other than MDA.

3,4-Methylenedioxyamphetamine↗