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Biomedical subjects

W R Wilson

Publications and source records attributed to W R Wilson.

At least 127 records · Page 7Linked to original sources
PubMed1994

The morphological effects of the anti-tumor agents flavone acetic acid and 5,6-dimethyl xanthenone acetic acid on the colon 38 mouse tumor.

Flavone acetic acid and 5,6-dimethyl xanthenone acetic acid have a broad spectrum of anti-tumor activity in mice, and act by stimulating immune cells and inhibiting tumor blood flow, resulting in hemorrhagic necrosis within 24 hrs. To study the evolution of hemorrhagic necrosis, subcutaneous Colon 38 tumors were examined by light and electron microscopy from 30 min to 24 hrs after treatment with these agents, and measurements of tumor energy metabolites made. The results show that both agents cause apoptosis beginning at 30 min, and that by 4 hrs necrosis supervenes, accompanied by rupture of tumor blood vessels. The absence of early endothelial cell damage or thrombosis suggests that vessel rupture, and consequent loss of blood flow and energy metabolite depletion, is caused by loss of extravascular mechanical support by the tumor parenchyma.

Adenocarcinoma↗
PubMed1994

Failure of time-kill synergy studies using subinhibitory antimicrobial concentrations to predict in vivo antagonism of cephalosporin-rifampin combinations against Staphylococcus aureus.

Results of in vitro time-kill synergy studies using subinhibitory, inhibitory, or suprainhibitory concentrations of bactericidal agents were compared with treatment outcomes of experimental infective endocarditis due to a methicillin-susceptible strain of Staphylococcus aureus. For rifampin-cephalosporin combinations, in vitro synergy testing using recommended fractions of the MIC failed to predict antagonism in vivo while concentrations above the MIC corresponded with antagonism in vivo.

Animals↗
PubMed1994

Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents.

To determine whether xanthenone acetic acid (XAA) analogues of flavone acetic acid (FAA) have similar ischemic and nonischemic mechanisms of antitumor action to FAA, a series of such compounds was evaluated in vivo and in vitro. Necrotising activity and changes in tumor blood flow were measured in Colon 38 tumors, and morphological changes assessed in immune cell-infiltrated EMT6 tumor cell spheroids, after treatment with FAA, XAA and its derivatives (5-methyl XAA, 5,6-dimethyl XAA, 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid). FAA, XAA and the 5-methyl and 5,6-dimethyl analogues of XAA were active in inducing tumor necrosis, falls in tumor perfusion and characteristic morphological changes in multicellular spheroids. The other XAA analogues lacked these activities. 5-methyl XAA and 5,6-dimethyl XAA were more potent than FAA or XAA. The results suggest that XAA and its analogues have the same mechanisms of action as FAA, and that both the vascular and the immune effects of these compounds are mediated via a common biochemical receptor.

Adjuvants, Immunologic↗
PubMed1994

Magnetic resonance imaging evidence of a focal pontine ischemia in sudden hearing loss and seventh nerve paralysis.

Sudden sensorineural hearing loss (SSHL) has been associated with many etiologies. However, determining the exact cause of SSHL remains elusive. Recent reports have demonstrated the usefulness of magnetic resonance imaging in identifying the site of lesion in SSHL. This report presents the case of a 68-year-old male who presented with right-sided SSHL associated with right-sided facial paralysis. Magnetic resonance imaging demonstrated a focal area of increased signal on T2-weighted image within the right inferior pons, suggestive of a postischemic edematous focus. Magnetic resonance imaging is becoming important in establishing the etiology of SSHL. Magnetic resonance imaging findings in cases of hearing loss are discussed.

Aged↗
PubMed1993

Hypoxia-selective antitumor agents. 7. Metal complexes of aliphatic mustards as a new class of hypoxia-selective cytotoxins. Synthesis and evaluation of cobalt(III) complexes of bidentate mustards.

Nitrogen mustards coordinated to Co(III) are potential hypoxia-selective cytotoxins, since one-electron reduction to the Co(II) complexes greatly labilizes the Co-N bonds, causing the release of activated aliphatic mustards which can act as diffusible cytotoxins. Two series of Co(III) complexes of the bidentate bisalkylating nitrogen mustard ligands N,N'-bis(2-chloroethyl)-ethylenediamine (BCE) and N,N-bis(2-chloroethyl)ethylenediamine (DCE) have been synthesized and evaluated for their hypoxia-selective cytotoxicity against AA8 cells in vitro. The complexes also bear two 3-alkylpentane-2,4-dionato (acac) auxiliary ligands; cyclic voltammetry studies show that variation of the alkyl group in the auxiliary ligands alters the reduction potentials of the complexes (within a series) over a range of about 150 mV. In both series, the patterns of cytotoxicities of the cobalt complexes were broadly similar to those of the respective free ligands, suggesting that the cytotoxicity of these compounds is due to release of the free ligands. The nonsymmetrical ligand DCE and its cobalt complexes were 1 order of magnitude more cytotoxic than the corresponding BCE compounds. Although the unsubstituted acac/DCE complex showed no hypoxic selectivity against repair-deficient UV4 cells in a stirred suspension culture assay, the methyl and ethyl analogues showed substantial selectivity. The results may indicate a narrow range of acceptable reduction potential, with an optimum close to that for the methyl analogue (E1/2 = -305 mV). The methyl analogue also shows hypoxic selectivity against repair-proficient cell lines (e.g., AA8 and EMT6) and has high activity against EMT6 cells in intact spheroids, suggesting that the released DCE is capable of back-diffusion from the hypoxic core of the spheroid. This work shows that metal complexes of nitrogen mustards have significant hypoxia-selective cytotoxicity toward mammalian cells in cell culture and are a new general class of hypoxia-selective cytotoxins.

Animals↗
PubMed1993

Bioreducible mustards: a paradigm for hypoxia-selective prodrugs of diffusible cytotoxins (HPDCs).

Existing hypoxia-selective cytotoxins (HSCs) are designed to kill only the hypoxic subpopulation in tumours, and to be used in conjunction with other therapies (e.g., radiation). A new class of drugs, hypoxia-activated prodrugs of diffusible cytotoxins (HPDCs) are proposed. These are designed to exploit, rather than merely deal with, tumour hypoxia, by releasing diffusible cytotoxins on bioreduction in hypoxic regions. Such diffusible cytotoxins are required to be much more cytotoxic than the parent prodrug, to be sufficiently stable (half lives from 0.1 to 10 min) to allow them to diffuse up to 200 microns from the hypoxic regions, and to be equally effective against all major tumour cell subpopulations, including non-cycling cells. Nitrogen mustards, which show little cell cycle specificity, which kill cells by a well-understood mechanism (DNA cross-links), and which have stabilities and reactivities able to be predictably controlled by structural variations, are proposed as suitable candidates fur such diffusible cytotoxins. Design parameters for two classes of potential HPDCs are discussed; nitro-deactivated aromatic mustards, and cobalt (III) complex-deactivated aliphatic mustards. Examples of both classes show greater cell-killing activity against intact compared with dissociated multi-cellular spheroids. This suggests they may indeed function as HPDCs, by penetrating to the hypoxic core of the spheroid and there releasing potent cytotoxins which diffuse out to kill surrounding cells at lower oxygen tensions.

Animals↗
PubMed1993

Candidemia from a urinary tract source: microbiological aspects and clinical significance.

Twenty-six cases of candidemia associated with a well-defined urinary tract source were retrospectively identified and reviewed. Urinary tract abnormalities were present in 23 of 26 patients (88%), 19 (73%) of whom had urinary tract obstruction. Nineteen patients had undergone urinary tract procedures before the onset of candidemia. Episodes of candidemia were brief and low-grade in intensity (median duration, 1 day; median colony count, 1.5 cfu/10 mL of blood). Only eight patients (31%) received > or = 500 mg of amphotericin B. There were five in-hospital deaths (19%); two of these deaths were attributed to candidiasis. No late complications of candidemia were documented for the surviving patients. Patients with urologic pathology and candiduria who undergo surgery or manipulation of the urinary tract are at significant risk for candidemia, and further studies should examine the issue of administration of prophylaxis to this group.

Adolescent↗
PubMed1993

Relative efficacies of broad-spectrum cephalosporins for treatment of methicillin-susceptible Staphylococcus aureus experimental infective endocarditis.

The effects of treatment with broad-spectrum parenterally administered cephalosporins and cefuroxime, cefazolin, or nafcillin were compared in an experimental model of Staphylococcus aureus infective endocarditis, and the results in vivo were compared with the activities of the study drugs in vitro. After 3 days of treatment, all antimicrobial agents tested were more effective than no treatment in reducing the number of surviving bacteria in cardiac valve vegetations. Nafcillin was the most effective agent studied and was significantly more active than was ceftizoxime, ceftriaxone, cefotaxime, cefoperazone, cefuroxime, or cefazolin (P < or = 0.05). Cefpirome and ceftazidime were the most effective broad-spectrum cephalosporins. The outcome of treatment with cefpirome or ceftazidime was similar to that of treatment with nafcillin and significantly better than that of treatment with ceftizoxime or cefotaxime (P < or = 0.05). Treatment outcome correlated closely with the MICs of the antimicrobial agents for the study strain with the exception of ceftazidime, which was significantly more active in vivo in comparison with other agents than predicted by its MIC (P < or = 0.0003). When ceftazidime was excluded as an outlier, treatment outcome correlated with the MICs of the remaining study drugs (Spearman's correlation coefficient, 0.95; P < or = 0.0004), as well as with the estimated percentage of time during which the concentration of total drug (correlation coefficient, -0.85; P < or = 0.007) or free drug (correlation coefficient, -0.90; P < or = 0.003) exceeded the MIC. A consideration of total or free drug concentrations in relation to MICs did not significantly improve the correlation with outcome observed with the MICs alone.

Animals↗
PubMed1993

Animal models of alcoholism: genetic strategies and neurochemical mechanisms.

Evidence from human studies indicates that response to alcohol consumption and the probability of developing alcoholism have a heritable basis. The involvement of several genes encourages the application of classical genetics to elucidate the genetic basis of alcohol abuse. Quantitative genetics can provide evidence for modes of inheritance and estimates of gene number. Therefore, inbred strains and selective breeding programmes have been used to demonstrate a genetic basis for the physiological and behavioural effects of ethanol in rodents. Neurochemical studies have shown that ethanol has effects on membrane fluidity, and on membrane receptors, ion channels and enzymes (Fig. 1). Comparison of these in animal lines selected for a particular response (or lack of response) to ethanol has disclosed differences in membrane composition (notably in polysialogangliosides), and in the functioning of NaK-ATPase, Na+ channels and gamma-aminobutyric acid (GABAA) receptors. Not all of these effects were observed at relevant ethanol concentrations, but differences in the properties of GABAA receptors between lines are the most compelling. Thus classical genetic strategies, while labour intensive with respect to the generation and maintenance of animal lines, have proven useful in dissecting the molecular, cellular and behavioural effects of alcohol and their genetic variability.

Alcoholism↗
PubMed1993

Risk factors for infective endocarditis.

The incidence of endocarditis is increased in patients with cardiac lesions causing turbulent flow. A 400-fold increase is observed in patients with prosthetic valves and a prior history of endocarditis. Other high risk lesions include rheumatic valvular disease, cyanotic congenital heart disease, and degenerative valve lesions. The smaller increased incidence in patients with mitral valve prolapse is important because of the high prevalence of mitral valve prolapse in the population. In addition, intravenous drug use and nosocomial bacteremia have emerged as important factors among patients with endocarditis.

Endocarditis, Bacterial↗
PubMed1992

Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: a new class of hypoxia-selective cytotoxins.

A series of isomeric 4-[[3-(dimethylamino)propyl]amino]nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratios of cytotoxicity against wild-type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of -286 mV. Structure-activity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline pKa. Two compounds of lower reduction potential, the 3- and 8-methyl analogues, showed improved selectivity (47- and 60-fold in a clonogenic assay). These two compounds also showed the highest "in vitro therapeutic indices" of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when administered at 60% of the MTD.

Animals↗
PubMed1992

Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells.

Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine. However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600 mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction. To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines. The N-[(N,N-dimethylamino)ethyl]carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the non-carboxamide compounds, were still low and little selectivity for hypoxic cells were observed. A series of carboxamides of 2,4-dinitroaniline mustard was also prepared. These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells. The most selective compounds were 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-[(N,N-dimethylamino)ethyl]carboxamide analogue. These showed selectivities of 60- to 70-fold for hypoxic UV4 cells. The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system. Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase). Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23.

Aniline Compounds↗
PubMed1992

Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain.

Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported across the rat blood-brain barrier by the large (L-system) neutral amino acid transporter in tumor-bearing brain, but no evidence for blood-brain barrier transport by the alanine-serine-cysteine system carrier was obtained in the present study. The ability of melphalan to inhibit phenylalanine uptake was compared in rats implanted with two experimental CNS tumors: the C-6 glioma (a model of primary brain tumors) and Walker carcinoma (a model of metastatic brain tumors). The melphalan concentration which caused 50% inhibition of blood-brain barrier (BBB) phenylalanine uptake (Ki) was 0.49 +/- 0.18 mM in the Walker tumor, compared with 0.46 +/- 0.19 mM in the contralateral control brain. In the ipsilateral hemisphere (Ki = 0.59 +/- 0.25 mM) and contralateral hemisphere (Ki = 0.45 +/- 0.19 mM), drug entry was also via the neutral amino acid transporter. In C-6 gliomas (Ki = 0.77 +/- 0.20 mM) and contralateral control brain (Ki = 0.84 +/- 0.29 mM), melphalan also inhibited BBB phenylalanine transport. A major finding was that, at melphalan concentrations greater than 1.0 mM, BBB permeability of radiolabeled indium (chelated to EDTA) increased in proportion to melphalan concentration. In the contralateral hemisphere of rats implanted with C-6 gliomas, brain extractions of indium-EDTA measured 3 to 4% in the absence of drug, 5 to 6% at 2.5 mM melphalan, and 9 to 10% at 5 mM melphalan. A similar phenomenon was observed in the nontumoral brain regions of rats implanted with Walker carcinoma cells. In normal (nonimplanted) rats, melphalan's inhibition (Ki = 0.29 mM) of phenylalanine and tryptophan (Ki = 0.20 mM) uptake was confirmed, and brain extraction of sucrose (a nonspecific marker which does not penetrate the intact BBB) was observed to increase in proportion to melphalan concentration. We conclude that melphalan not only enters the brain via the neutral amino acid transporter, but at higher concentrations (greater than 1 mM) may open the blood-brain barrier in a nonspecific manner.

Amino Acid Transport Systems↗
PubMed1992

Stomal seeding by percutaneous endoscopic gastrostomy in patients with head and neck cancer.

Presented is the first known case of squamous cell carcinoma that developed at the site of a "pull" type percutaneous endoscopic gastrostomy stoma. The patient had advanced squamous cell carcinoma of the pharynx when the percutaneous endoscopic gastrostomy tube was placed. This article should serve as a warning of this potential complication. Alternate techniques and other precautionary methods are described.

Carcinoma, Squamous Cell↗