Biomedical subjects

T C Jenkins

Publications and source records attributed to T C Jenkins.

At least 145 records · Page 8Linked to original sources

PubMed1989

Molecular modelling of DNA-antitumour drug intercalation interactions: correlation of structural and energetic features with biological properties for a series of phenylquinoline-8-carboxamide compounds.

The crystal structure of the experimental antitumour compound N-(2-dimethylaminoethyl)-2-phenylquinoline-8-carboxamide has been determined. The geometry and conformation have been used as starting points for molecular modelling of the intercalative interactions with DNA shown by the parent compound and analogues with the phenyl ring located at alternative positions on the quinoline chromophore. A molecular mechanics force field program was used for energy minimization and calculation of intermolecular (enthalphic) binding energies. The parent quinoline-8-carboxamide and derivatives with a phenyl substituent at the 4- or 5-position were judged to be poor intercalators in both structural and energetic terms. By contrast, the 2-, 3-, and 6-phenyl derivatives all had high calculated binding energies with the phenyl groups involved in stacking with DNA base pairs. The order of energies calculated for this series of compounds has been found to correlate well with both the order of experimentally derived free energies and with the in vitro cytotoxic activity.

Antineoplastic Agents↗

PubMed1989

3-Nitro-1,2,4-triazoles as hypoxia-selective agents.

A series of 1-alkyl-3-nitro-1,2,4-triazoles has been prepared and assessed in vitro as radiosensitizers of hypoxic cells and as bioreductive cytotoxins. The differential hypoxic:aerobic cytotoxicities of representative compounds have been determined and compared with analogous 2-nitroimidazoles. It is found that the 3-nitrotriazoles are considerably less effective than the corresponding 2-nitroimidazole derivatives. This result includes dual-function nitrotriazoles where potential alkylating moieties have been incorporated into the molecule. In contrast, the 3-nitrotriazoles show similar or slightly improved radiosensitizing efficiency, in accord with their redox behaviour, and significantly lower chronic aerobic toxicity compared with the corresponding 2-nitroimidazoles. On the basis of a derived in vitro therapeutic ratio, 1-(3-nitro-1,2,4-triazol-l-yl)-3-piperidino-2-propanol (8) has been identified as particularly active and warrants further evaluation as a hypoxic cell radiosensitizer in vivo.

Animals↗

PubMed1988

Structures of the anticancer compounds N-(2-hydroxyethyl)-2-(3-nitro-1,2,4-triazol-1-yl)-acetamide (RB-6110) and 5-(1-aziridinyl)-3-nitro-1-(3-oxo-1-butyl)-1,2,4- triazole (RB-6162).

RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.

Antineoplastic Agents↗

PubMed1988

1-Methoxy-3-(2-nitro-1-imidazolyl)-2-propanol (misonidazole).

C7H11N3O4, Mr = 201, monoclinic, P2(1)/c, a = 6.997 (1), b = 7.862 (1), c = 17.024 (3) A, beta = 97.06 (2) degrees, U = 929.4 (5) A3, Z = 4, D chi = 1.44 Mg m-3, lambda(Cu K alpha) = 1.5418 A, mu = 0.916 mm-1, F(000) = 424, ambient temperature, R = 0.049 for 1324 unique reflections. All bond lengths and angles have normal values and the planes of the nitro group and imidazole ring form a dihedral angle of 7.9 (1) degrees.

Hydrogen Bonding↗

PubMed1988

An objective VER assessment of visual acuity compared with subjective measures.

Visual acuity was estimated by making amplitude measurements of the transient visually evoked response (VER) wave to pattern reversal using check sizes of 5.5, 7.5, 8.5, and 9.5 min arc. As in previous studies the 5.5 min arc check produced a response which reflected the visual acuity of the high acuity subjects, but often failed to produce a VER wave at the low acuity end. The proposal is made that where the 5.5 min arc check produces an acceptable wave (amplitude greater than 1.5 microV) then the regression line for the 5.5 check can be used to predict visual acuity. Where the VER amplitude is below 1.5 microV for this small check size then a second recording must be made using the 9.5 min arc check and the visual acuity predicted from the 9.5 check regression line.

Adolescent↗

PubMed1988

Amplitude variability of the transient visual evoked response.

The amplitude repeatability of pattern reversal visual evoked response using a 5.5 and 40' arc check was investigated in twelve subjects with each subject recording ten 64 sweep runs. The variability by visual inspection or by analysis of variance suggests that a single run will provide a representative amplitude for a 40' arc check whereas the 5.5' check will require more runs merged together before the amplitude is stable. The larger spread of error encountered with the 40' arc check may point to a visual component contributing to more amplitude variability. The possibility of making some assessment of the level of noise present during recording is discussed.

Adolescent↗

PubMed1988

Effect of propionate level in a volatile fatty acid salt mixture fed to lambs on weight gain, body composition and plasma metabolites.

Chopped hay supplemented with a volatile fatty acid salt mixture at 20% of metabolizable energy (ME) was fed to 30 Suffolk X Corriedale lambs (mean wt 29.6 kg) to determine the effects of dietary propionate on weight gain, body composition and plasma metabolites. Propionate accounted for 0, 25, 50, 75 or 100% of the salt mixture energy, and acetate accounted for the remainder. Each diet was fed at two levels of daily intake (158.7 and 130.6 kcal ME/W.75). Lambs on the high level of intake lost more (P less than .05) energy in feces, lost less (P less than .05) energy in CH4 and had carcasses with more (P less than .10) water and fat than lambs on the low intake level. Percentage of propionate in the salt mixture had no effect on ME or body composition of lambs. Increasing the percentage of propionate in the salt mixture increased plasma propionate in blood samples taken at 1 and 2 h after feeding (linear, P less than .05). Empty body weight gain per megacalorie of ME above maintenance increased as the percentage of propionate in the salt mixture increased, but not until propionate reached 75% of the salt mixture (linear, P less than .05; cubic, P less than .05). These results show that propionate in the blood has a positive, but nonlinear, effect on weight gain, even when energy intake is held constant.

Animals↗

PubMed1987

Effects of substituted 2-nitroimidazoles and related compounds on unscheduled DNA synthesis in rat hepatocytes and in non-transformed (BL8) and transformed (JB1) rat liver epithelial derived cell lines.

1. Using unscheduled DNA synthesis as an index, the possible interaction of a number of substituted nitroimidazoles, e.g. misonidazole, with cellular DNA has been investigated. Transformed (JB1), non-transformed (BL8) rat liver epithelial derived cell lines and freshly prepared rat hepatocytes have been used. 2. Under anaerobic or aerobic conditions, relative to cells exposed to a nitroquinoline-N-oxide standard, misonidazole and related nitroimidazoles were very poor at stimulating unscheduled DNA synthesis in JB1 or BL8 cells or in hepatocytes, even at the highest concentrations tested (10 mM). Under anaerobic conditions, metabolic activation did occur as judged from the time-dependent depletion of cellular reduced glutathione in all three cell types. 3. It was concluded that in hypoxic cells an important mode of action of such nitroimidazoles as chemotherapeutic sensitisers may be by their interaction with cellular thiols rather from their interaction with DNA. 4. Functionalisation of the nitroimidazole ring with a side chain containing an aziridine function, e.g. RSU-1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol), results in the induction of unscheduled DNA synthesis in cells exposed under both aerobic and anaerobic conditions. On a molar basis, however, this induction was not so great as that caused by the simple monofunctional alkylating agent 1-aziridineethanol itself. Methyl-substitution of the aziridine ring in RSU-1069 reduced the extent of unscheduled DNA synthesis. 5. With all the compounds tested, unscheduled DNA synthesis was greater in JB1 cells than in BL8s or in hepatocytes.

Animals↗

PubMed1987

Induction of DNA crosslinks in vitro upon reduction of the nitroimidazole-aziridines RSU-1069 and RSU-1131.

The interaction of the nitroimidazole-aziridines RSU-1069 and RSU-1131, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH 7 results in strand breakage. The yields of DNA single strand breaks (ssb), "alkali-labile" damage and DNA crosslinks induced by these alkylating agents have been assessed. It is shown that DNA crosslinks are induced only by the reduced nitro-compounds. RSU-1069, as parent or reduced compound, is more efficient at producing these effects than the equivalent form of RSU-1131. Further, RSU-1069 is about 2 X more susceptible to nucleophilic attack by inorganic phosphate and deoxynucleotides than RSU-1131. RSU-1069 also shows greater selectivity for reaction with the nucleotide base moiety than does the less-reactive monomethyl analogue, RSU-1131. The yields of ssb and "alkali-labile" damaged sites induced by the two agents reflect their respective chemical reactivities and appear largely to determine their aerobic cytotoxicities. In contrast, the yield of DNA crosslinks induced by the reduced compounds appears to correspond rather better with the observed hypoxic cytotoxicities. From these findings it is suggested that the induction of DNA crosslinks by these agents may play a major role in their effectiveness as hypoxia-selective cytotoxins.

DNA↗

PubMed1987

Effect of reading in low illumination on fixation disparity.

Fixation disparity has been shown to be produced by prism stress, and it has therefore been proposed that its presence constitutes a sign that binocular vision is under stress (decompensated heterophoria). Fixation disparity can be present in the absence of any other indication of stress, and therefore may have a physiological basis. This study investigates the effect on fixation disparity and visual discomfort of placing the visual system under a different type of stress, that of requiring the subject to read under conditions of inadequate illumination. In 50 young adults, it was found that fixation disparity increased under inadequate illumination and that this was accompanied by symptoms in the form of visual discomfort. After a period of rest from any near-vision task, the fixation disparity decreased and the symptoms were reduced.

Adolescent↗

PubMed1987

Visual acuity prediction using the VER--temporal aspects.

A pattern reversal stimulus (check size 5.5 min arc) was used to elicit visually evoked responses (VER's). The peak to trough amplitude of the VER wave was measured and compared to the subjective visual acuity (Landolt C) in 30 subjects. The recordings were made at 3, 6, and 12 pattern reversals per s. The correlation coefficients are reasonably high (r = 0.81) for both the 3 and 6 reversal rates with a considerably lower correlation coefficient (r = 0.54) for the 12 reversals per s stimulus. Repeatability measurements on a further 6 subjects taken over a 5-week period produced an amplitude coefficient of variation of 13% for the 6 subjects with the 3 reversals per s stimulus.

Adolescent↗

PubMed1987

Effect of fats and fatty acid combinations on ruminal fermentation in semi-continuous in vitro cultures.

Four in vitro trials were conducted to determine how ruminal fermentation is affected by source of fat, level of fat, and combinations of fatty acids. Trials I and II examined how volatile fatty acids (VFA) were changed by three sources of fat (blended animal-vegetable fat, corn oil and tallow fatty acids) each added to a hay substrate at six levels (0, 2, 4, 6, 8 and 10%). Increasing blended fat caused no changes in VFA levels except to decrease butyric acid from 12.1 to 9.9% of the total VFA (P less than .05). Corn oil and tallow fatty acids both increased propionic acid, causing the ratio of acetic to propionic acids (A/P) to decrease (P less than .01). Trial III tested different ratios of oleic/stearic and linoleic/stearic acids to determine if certain combinations were better for fermentation. There was no evidence of synergism among fatty acids since increasing the ratio of unsaturates steadily reduced A/P. Trial IV was designed to determine how changes in VFA levels reflect changes in fiber digestibility of substrates containing added fat. Volatile fatty acids having significant regressions with fiber digestibility were acetic acid (r = .648), propionic acid (r = -.670), total VFA concentration (r = .742) and A/P (r = .831). Results are interpreted to show that blended animal-vegetable fats are less toxic in the rumen than equal levels of other lipids, and the beneficial effects of blended fat cannot be attributed to a unique combination of fatty acids acting synergistically.

Animals↗

PubMed1987

Repeated oral doses of activated charcoal and the clearance of tobramycin, a non-absorbable drug.

Factors which determine the ability of activated charcoal to increase systemic drug clearance include adsorption characteristics, the extent of back diffusion, and biliary excretion into the gut. Orally absorbed drugs diffuse back into the gut, but it is not known whether non-absorbed agents also diffuse back. Tobramycin was studied with a highly activated charcoal to determine whether this occurs. Five volunteers received a single IV dose of tobramycin on two occasions. Using a randomized, crossover design, subjects received 10 g of activated charcoal (as SuperCharR suspension) 2 hr prior, and at 0, 2, 6, and 8 hr after tobramycin administration during one of the study days. In vitro, tobramycin adsorbed to charcoal at pH 5.6, but not at pH 2.6. A 20:1 charcoal:tobramycin ratio resulted in 34.9% of tobramycin adsorbed to activated charcoal. Blood (0-12 hr) and urine (0-24 hr) were collected and tobramycin concentrations determined. Urinary tobramycin recovery, renal and total drug clearance, half-life, and volume of distribution were calculated. There were no differences in these parameters between the two groups. We conclude that activated charcoal has no effect on tobramycin distribution or elimination in normal volunteers, and that back diffusion does not occur with this drug.

Administration, Oral↗

PubMed1987

Mechanism of action of some bioreducible 2-nitroimidazoles: comparison of in vitro cytotoxicity and ability to induce DNA strand breakage.

The interaction of a series of nitroimidazole-aziridine radiosensitisers, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH7 results in strand breakage. The efficiency of strand breakage substantially increases on reduction of the nitroimidazole analogues. The rate of production of strand breaks decreases on interaction with both parent and reduced nitroimidazole analogues as the aziridine moiety is deactivated through alkyl-substitution. These variations in efficiency are reflected in changes in the toxicity towards both oxic and hypoxic cells and in the decrease in toxicity with progressive substitution of the aziridine moiety. The stabilities of these nitroimidazoles in aqueous solution at pH7 have also been determined. However, these stabilities do not parallel the variations in the alkylating efficiency of DNA by the aziridine moiety. These results have been discussed in terms of the relative reactivities of the nitroimidazoles with plasmid DNA and their ability to act as cytotoxic agents, especially following bioreduction and how the findings may relate to the radiosensitising properties of these agents.

Antineoplastic Agents↗

PubMed1987

Visual acuity prediction using the visual evoked response.

A technique is described for predicting visual acuity in adult humans by using the visually evoked response (VER). This involves using a pattern-reversal checkerboard with a small check size (5.5. min arc) as the stimulus, and measuring the peak-to-trough amplitude of the VER wave arising from it. The technique is therefore both rapid and convenient. The pattern-reversal rate was varied in order to assess the influence of the temporal modulation on the VER waves. The results suggest that a rapid pattern reversal rate produces a VER which displays a reduced association with spatial processing.

Adult↗

PubMed1987

Fixation disparity in binocular stress.

Fixation disparity has been taken as a sign of stress on binocular vision because it is established that prism stress creates fixation disparity. This paper looks at the effect on fixation disparity of the stress caused by requiring subjects to read in inadequate illumination. It is found that the reduction in illumination does not in itself immediately change the magnitude of the fixation disparity. There is, however, an increase in the mean slope of the central part of the fixation disparity curve which suggests that when the effect of reduced illumination is added to prism stress, fixation disparity is increased. The stress created by asking subjects to read in reduced illumination for half an hour resulted in the mean associated heterophoria being increased, and over half the subjects reported symptoms of stress. It is concluded that fixation disparity is changed by this type of visual stress in some subjects, and in near vision is increased to a more marked degree of exo-disparity. Most of this increase occurs in the first ten minutes.

Adolescent↗

PubMed1986

Induction of DNA strand breaks by reduced nitroimidazoles. Implications for DNA base damage.

Radiation-reduced 2-nitroimidazoles (misonidazole, RSU-1137, Ro.03-8799 and Ro.03-8800) incubated in air with plasmid DNA (pH 7.0, 310K) induce DNA strand breakage, as revealed following subsequent heat or alkali treatment. Only RSU-1137 resulted in the binding of a [2-14C] fragment and significant yields of heat-labile strand breaks (greater than 20% loss of type-I DNA after 48 hr incubation). RSU-1137 was shown to be greater than 6 times more effective than misonidazole at producing alkali-labile breaks. In fact, the efficiency of alkali-induced strand break production is in the order: misonidazole less than Ro.03-8799 approximately Ro.03-8800 less than RSU-1137. Reaction of these reduced 2-nitroimidazoles with 2'-deoxyguanosine (dG) also results in the formation of a common glyoxal-dG product, with its yield and rate of production being dependent upon the 2-nitroimidazole used. It has been demonstrated that these variations are influenced by the N-1 side-chain of the 2-nitroimidazole. Product yields are approximately 5-6 times greater with misonidazole than with RSU-1137. From the evidence presented, it is apparent that formation of glyoxal (or a glyoxal-like product) is not responsible for the DNA strand breakage seen. It is inferred that these breaks are induced by a nitro-reduction product(s) which remains unidentified.

DNA↗

PubMed1986

Convergence insufficiency in a rural population.

Convergence insufficiency represents a significant problem in optometric practice. The percentage of cases in a rural area was compared with that in a previous sample from an urban area, with respect to the general incidence, and the effects of age and taking of medicines as an indicator of health. The percentage of convergence insufficiency in the rural area was about half that in the urban area, and the percentage taking medicines was about two-thirds. The incidence of convergence insufficiency increased with age in both populations. When both samples were taken together, the incidence of convergence insufficiency was three times greater in those taking medicines.

Adolescent↗