Vertebral osteomyelitis due to Shigella boydii.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
W R Wilson
Publications and source records attributed to W R Wilson.
Effective treatment of multidrug-resistant enterococcal experimental endocarditis with combinations of cell wall-active agents.
The efficacy of treatment with a combination of ampicillin, imipenem, and vancomycin was compared with that of two-drug combinations or monotherapy in a model of experimental endocarditis using a strain of Enterococcus faecium with high-level resistance to vancomycin and moderate intrinsic resistance to ampicillin and imipenem. In vitro time-kill synergy studies demonstrated bactericidal synergistic activity only for the triple combination. In vivo, monotherapy with vancomycin was not effective. Treatment with either ampicillin or imipenem alone or in combination with vancomycin resulted in <4 log10 reduction in colony-forming units (cfu) per gram of vegetation. The combination of ampicillin with imipenem was highly active (an additional 5 log10 reduction in cfu per gram of vegetation compared with the most active single agent), but efficacy was not increased by the addition of vancomycin to ampicillin and imipenem. Therapy with the combination of ampicillin and imipenem may be effective for some strains of multidrug-resistant enterococcal infections.
Ampicillin↗
India-born immigrants in Australia and Canada: a comparison of selected characteristics.
"This article examines the Indian component of Asian immigration to Canada and Australia, reviews briefly the historical background of Indian immigration, discusses the characteristics of India-born immigrants and explores their social impact upon both nations. A comparative approach is adopted to highlight similarities and differences." (SUMMARY IN FRE AND SPA)
Americas↗
N-methyl-D-aspartate-stimulated increases in intracellular calcium exhibit brain regional differences in sensitivity to inhibition by ethanol.
This study compared N-methyl-D-aspartate (NMDA)-stimulated increases in intracellular calcium in fura-2-loaded neurons dissociated from newborn rat brainstem (EC50 in microM; 6.4), cerebellum (9.5), forebrain (6.3), and hippocampus (10.6). Ethanol inhibition of the response to 25 microM NMDA differed among the regions. The NMDA response in hippocampus was inhibited by 20 mM ethanol; cortex and cerebellum responses were inhibited by 80 mM ethanol, and no inhibition was seen in the brainstem. Addition of glycine (15 microM) failed to attenuate ethanol inhibition of the NMDA response. These results demonstrate that ethanol inhibition of NMDA-stimulated responses varies according to brain region. In contrast to previous findings from this laboratory using dissociated neurons from whole brain, the addition of glycine did not reverse the inhibitory effects of ethanol on NMDA-stimulated responses.
Animals↗
Effect of gentamicin dosing interval on efficacy of penicillin or ceftriaxone treatment of experimental endocarditis due to penicillin-susceptible, ceftriaxone-tolerant viridans group streptococci.
The efficacy of ceftriaxone or penicillin alone or combined with gentamicin at different dosing intervals was evaluated in experimental endocarditis due to a penicillin-susceptible, ceftriaxone-tolerant strain of Streptococcus sanguis I. The difference between monotherapy with ceftriaxone and procaine penicillin approached statistical significance (P = 0.052). Ceftriaxone combined with gentamicin administered as a single daily dose was less effective than was procaine penicillin combined with gentamicin administered in a single daily dose or in three divided doses.
Animals↗
Prospective evaluation of the utility of molecular techniques for diagnosing nosocomial transmission of multidrug-resistant tuberculosis.
OBJECTIVE: To compare molecular techniques with conventional diagnostic methods for evaluating nosocomial transmission of multidrug-resistant tuberculosis (MDR-TB). DESIGN: We conducted a 12-week postexposure inception cohort study of health-care personnel who had been exposed to a patient with MDR-TB. MATERIAL AND METHODS: In addition to baseline and follow-up tuberculin skin tests and chest roentgenography, weekly pulmonary specimens were evaluated by (1) auramine-rhodamine fluorescent staining, (2) culture for mycobacteria, and (3) polymerase chain reaction (PCR) to amplify IS6110, a nucleic acid insertion sequence unique to the Mycobactrium tuberculosis complex. RESULTS: The index patient's isolate of M. tuberculosis showed a mutation in codon 531 of the RNA polymerase beta subunit (rpoB) gene of M. tuberculosis, which is associated with rifampin resistance and considered a marker for this MDR-TB strain. All pulmonary and gastric specimens from study participants had negative auramine stains and cultures for mycobacteria, One person, however, had separate specimens with repeatedly positive PCR results for IS6110 sequences, but the specimens contained a wild-type M. tuberculosis rpoB codon 531 dissimilar from the index patient's strain. CONCLUSION: Although both molecular and conventional testing showed that no exposed person was infected with the MDR-TB strain, molecular test results were available sooner and seemed more sensitive for detecting M. tuberculosis in one exposed person, presumably in a preinfection or "colonized" stage. Molecular methods provided information that helped distinguish this person's M. tuberculosis strain from the index patient's MDR-TB strain. Additional prospective studies should assess the value of these molecular techniques in similar clinical settings.
Antitubercular Agents↗
Multicellular membranes as an in vitro model for extravascular diffusion in tumours.
Efficient extravascular diffusion is a critical requirement for hypoxic cell radiosensitisers, bioreductive drugs and hypoxic cell markers that must reach cells distant from functional blood vessels in tumours. The diffusion of simple nitroimidazoles with neutral (misonidazole, miso) and basic (pimonidazole, pimo) side chains, as well as 2-nitroimidazoles with acridine (NLA-1) and phenanthridine (2-NLP-3) DNA intercalating moieties was investigated using multicellular membranes (MMs), a new in vitro model for the extravascular compartment of tumours. The diffusion of miso through V79 MMs was concentration independent over the range 0.1-10 mM. Mathematical modelling of the flux kinetics provided a diffusion coefficient in MMs (DMM) of 5.5 x 10(-7) cm2 s-1 which was approximately 13-fold lower than in culture medium. Flux was little affected by the extent of hypoxia in MMs, indicating that hypoxic metabolism does not compromise diffusion of miso over distances in the order of 200 microns. The DMM for pimo was similar to miso, while those for 2-NLP-3 and NLA-1 were both lower. The results demonstrate compromised extravascular diffusion for DNA-intercalating nitroimidazoles, but indicate that this problem is more severe for the basic acridine derivative, NLA-1, than for the phenanthridine, 2-NLP-3. The MM model appears to be well suited to quantitative determination of drug diffusion in a multicellular environment.
Acridines↗
Recent developments in the design of bioreductive drugs.
Explore the source record for details and available documents.
Animals↗
Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N.
Tertiary amine N-oxides of DNA intercalators with alkylamino sidechains are a new class of bioreductive drugs. N-oxidation masks the cationic charge of the amines, forming prodrugs with low DNA binding affinity and low toxicity which can be activated selectively by metabolic reduction under hypoxic conditions. This study compares three intercalator N-oxides (NC-NO, DACA-NO and AQ4N), which, respectively, give nitracrine (NC), DACA and AQ4 on reduction. In aerobic cell culture all three N-oxide were much less toxic than the corresponding amines, and showed large increases in cytotoxicity under hypoxia. The topoisomerase poisons DACA and AQ4 (and their N-oxides) were less active against non-cycling than cycling cells. However, only AQ4N was active against the mouse mammary tumour MDAH-MCa-4. This dialkylaminoanthraquinone-di-N-oxide has activity at least as great as the reference bioreductive drug RB 6145 against this tumour, both with and without radiation and when combined with the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA). It is suggested that the high in vivo activity of AQ4N relative to the other topoisomerase-targeted N-oxide, DACA-NO, may be in part due to release in hypoxic cells of an intracalator with sufficiently high DNA binding affinity that it is retained long enough to kill non-cycling cells when they eventually re-enter the cell cycle.
Acridines↗
Pulse radiolysis studies on the hypoxia-selective toxicity of a colbalt-mustard complex.
The kinetic basis for the in vitro hypoxia-selective cytotoxicity (HSC) of the Co(III)-nitrogen mustard complex SN 24771 (NSC 675352) has been investigated using pulse radiolysis. The rate constants for the one-electron reduction of SN 24771 by model reductants exhibited a marked dependence on the one-electron reduction potential of the reductant, with values up to several orders of magnitude slower than for the nitroimidazole drug misonidazole. Following one-electron reduction to form the Co(II) complex (species I) consecutive conversion to further transient species (II and III) occurs with first order rate constants of 120 +/- 10 s-1 and 10 +/- 2 s-1 and are associated with release of ligands. Neither of these subsequent processes are inhibited by the addition of O2 up to a concentration of 0.5 mmol l-1 suggesting that the HSC action of SN 24771 most likely arises from a mechanism other than simple redox cycling between the Co(III) and Co(II) forms by O2. If the measured low rate constants of one-electron reduction by model reductants of SN 24771 (as compared to the reduction of nitroaromatics), is mirrored by biological reductants, then it is proposed that HSC may occur through competition between SN 24771 and O2 for these reductants.
Antineoplastic Agents↗
Oxygen dependence of the cytotoxicity of the enediyne anti-tumour antibiotic esperamicin A1.
The enediyne anti-tumour antibiotics are extremely potent cytotoxins, apparently because of their conversion to diradical species which induce DNA double strand breaks with high efficiency. The potency of enediynes suggests their possible utility as effector units for prodrugs which can be activated selectively in tumours, such as bioreductive drugs (BD) or radiation-activated cytotoxins (RAC). However, the similarity of the radical-induced DNA breakage reactions of the enediynes to those caused by ionising radiation suggested that resistance of hypoxic cells might be a potential problem. Experiments with AA8 cells in culture demonstrated that the enediyne antibiotics neocarzinostatin and esperamicin A, (ESP) are much less toxic under hypoxic than aerobic conditions. Sensitivity to ESP (concentration for 90% cell kill 10 pM) decreased 15-fold under hypoxia, and was partially restored by simultaneous exposure to misonidazole. ESP induced chromosome breakage (micronucleus formation) with an efficiency similar to gamma radiation at equivalent cell kill, suggesting a clastogenic mechanism of cytotoxicity. In contrast, little micronucleus formation was evident after exposure to ESP under hypoxia, even at concentrations giving equivalent cell killing. These findings suggest that resistance of hypoxic cells may limit the utility of enediynes as cytotoxic effectors for BD or RAC prodrug development, and that further investigation of enediynes as anti-tumour agents should include strategies capable of eliminating hypoxic cells.
Aminoglycosides↗
Nitroimidazole-based "extruded mustards' designed as reductively activated hypoxia-selective cytotoxins.
A new class of nitroimidazole alkanoic acid amides, designed to extrude para-aminophenyl mustard (3a) by intramolecular cyclization following reduction of the nitro group, have been prepared and evaluated for their ability to function as bioreductively activated prodrugs. The mechanism of activation following (bio) reduction was studied using the model compounds (8a-e, 18 and 23a,b) and the related mustard analogues (11a-c and 26a,b). However, the reduced forms of these compounds were found to be relatively stable and not susceptible to intramolecular cyclization. This is in contrast to the corresponding 2-nitrophenylalkyl amides, where the hydroxylamino or amino reduction products (e.g. 27) undergo intramolecular cyclization via a tetrahedral intermediate, resulting in cleavage of the amide and release of an activated aromatic mustard. One of the 2-nitroimidazole mustards (11b) had 20-fold greater toxicity towards aerobic AA8 cells than RB 6145 (4), and a 51-fold greater toxicity towards UV4 cells (which are defective in DNA cross-link repair and thus hypersensitive to cross-linking agents). The cytotoxicity of 11b against AA8 cells was enhanced 3.3-fold under hypoxic conditions, but the compound was inactive against the hypoxic subfraction of cells in KHT tumours in vivo.
Animals↗
Synthesis and evaluation of 4-substituted analogues of 5-[N,N-bis (2-chloroethyl)amino]-2-nitrobenzamide as bioreductively activated prodrugs using an Escherichia coli nitroreductase.
2,4-Dinitrobenzamide mustards, exemplified by the parent compound SN 23862 (2) are activated under aerobic conditions by an Escherichia coli nitroreductase enzyme (NR2) via selective reduction of the 2-nitro group, and are thus of interest as prodrugs for antibody-directed enzyme-prodrug therapy (ADEPT). A series of related compounds 12a-12d, where the 4-nitro group of 2 was replaced by other substituents of varying electronic properties, were prepared and evaluated as potential ADEPT prodrugs. One-electron reduction potentials of the compounds correlated well with the substituent sigma m values, with the exception of the unsubstituted (4-H) analogue 13, which had a much lower value than expected on electronic grounds, due to a coplanar conformation of the mustard. The cytotoxicities of the compounds towards aerobic UV4 cells correlated positively with the electron-donating ability of the 4-substituent (measured by sigma p values), indicating that the cytotoxicities of the compounds in the absence of the NR2 enzyme are due substantially to the parent (unreduced) compounds. A positive, although less strong, correlation was seen between the electronic properties of the 4-substituent and their cytotoxicities in the presence of the NR2 enzyme, suggesting that, in this closely related series, the degree of activation by the enzyme is significantly dependent on the reduction potential of the 2-nitro group. While the 4-SO2Me derivative 12d was the next most preferred substrate after the parent 2, it was considerably less so (degree of activation as measured by IC50 ratio of 26 compared with 145), despite the similar electronic properties of the two 4-substituents.
Benzamides↗
Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. American Heart Association.
OBJECTIVE: To provide guidelines for the treatment of endocarditis in adults caused by the following microorganisms: viridans streptococci and other streptococci, enterococci, staphylococci, and fastidious gram-negative bacilli of the HACEK group. PARTICIPANTS: An ad hoc writing group appointed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young. EVIDENCE: Published studies of the treatment of patients with endocarditis and the collective clinical experience of this group of experts. CONSENSUS PROCESS: The recommendations were formulated during meetings of the working group and were prepared by a writing committee after the group had agreed on the specific therapeutic regimens. The consensus statement was subsequently reviewed by standing committees of the American Heart Association and by a group of experts not affiliated with the working group. CONCLUSIONS: Sufficient evidence has been published that recommendations regarding treatment of the most common microbiological causes of endocarditis (viridans streptococci, enterococci, Streptococcus bovis, staphylococci, and the HACEK organisms) are justified. There are insufficient published data to make a strong statement regarding the efficacy of specific therapeutic regimens for cases of endocarditis due to microorganisms that uncommonly cause endocarditis. As a useful aid to the practicing clinician, the writing group developed a consensus opinion regarding management of endocarditis caused by the most commonly encountered microorganisms and regarding those cases due to infrequent causes of endocarditis.
Adult↗
Bioactivation of dinitrobenzamide mustards by an E. coli B nitroreductase.
A nitroreductase isolated and purified from Escherichia coli B has been demonstrated to have potential applications in ADEPT (antibody-directed enzyme prodrug therapy) by its ability in vitro to reduce dinitrobenzamides (e.g. 5-aziridinyl 2,4-dinitrobenzamide, CB 1954 and its bischloroethylamino analogue, SN 23862) to form cytotoxic derivatives. In contrast to CB 1954, in which either nitro group is reducible to the corresponding hydroxylamine, SN 23862 is reduced by the nitroreductase to form only the 2-hydroxylamine. This hydroxylamine can react with S-acetylthiocholine to form a species capable of producing interstrand crosslinks in naked DNA. In terms of ADEPT, SN 23862 has a potential advantage over CB 1954 in that it is not reduced by mammalian DT diaphorases. Therefore, a series of compounds related to SN 23862 has been synthesized, and evaluated as potential prodrugs both by determination of kinetic parameters and by ratio of IC50 against UV4 cells when incubated in the presence of prodrug, with and without the E. coli enzyme and cofactor (NADH). Results from the two studies were generally in good agreement in that compounds showing no increase in cytotoxicity in presence of enzyme and cofactor were not substrates for the enzyme. None of the analogues were activated by DT diaphorase isolated from Walker 256 carcinoma cells. For those compounds which were substrates for the E. coli nitroreductase, there was a positive correlation between kcat and IC50 ratio. Two compounds showed advantageous properties: SN 25261 (with a dihydroxypropylcarboxamide ring substituent) which has a more than 10-fold greater aqueous solubility than SN 23862 whilst retaining similar kinetic characteristics and cytotoxic potency; and SN 25084, where a change in the position of the carboxamide group relative to the mustard resulted in an increased cytotoxicity ratio and kcat compared with SN 23862 (IC50 ratios 214 and 135; kcat values of 75 and 26.4 sec-1, respectively). An analogue (SN 25507) incorporating both these structural changes had an enhanced kcat of 576 sec-1. This study elucidates some of the structural requirements of the enzyme and aids identification of further directions in the search for suitable prodrugs for an ADEPT nitroreductase system.
Aniline Mustard↗
Efficient redox cycling of nitroquinoline bioreductive drugs due to aerobic nitroreduction in Chinese hamster cells.
Nitroquinoline bioreductive drugs with 4-alkylamino substituents undergo one-electron reduction in mammalian cells, resulting in futile redox cycling due to oxidation of the nitro radical anion in aerobic cultures, and eventual reduction to the corresponding amines in the absence of oxygen. Rates of drug-induced oxygen consumption (R) due to redox cycling in cyanide-treated AA8 cell cultures were determined for 17 nitroquinolines. There was a linear dependence of log R on the one-electron reduction potential at pH 7 (E(7)1 with a slope of 7.1 V-1, excluding compounds with substituents ortho to the nitro group. The latter had anomalously low rates of oxygen consumption relative to E(7)1, suggesting that interaction with the active site of nitroreductases is impeded sterically for such compounds. Absolute values of R (and the observed E(7)1 dependence) were well predicted by a simple kinetic model that used rates of net nitroreduction to the amines under anoxia as a measure of the rates of one-electron reduction in aerobic cells. This indicates that redox cycling of 4-alkylaminonitroquinolines occurs at high efficiency in aerobic cells, suggesting that there are no quantitatively significant fates of nitro radical anions in cells other than their reaction with oxygen (or their spontaneous disproportionation under hypoxia).
Animals↗
Hypoxia-selective antitumor agents. 10. bis(nitroimidazoles) and related Bis(nitroheterocycles): development of derivatives with higher rates of metabolic activation under hypoxia and improved aqueous solubility.
A series of analogues of the previously described compound N-[2-(2-methyl-5-nitroimidazol-1H-yl)ethyl]-4-(2-nitroimidazol- 1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitization in vitro. The new derivatives were designed to overcome the low aqueous solubility of 4 and its slow kinetics of killing under hypoxia. The nitroheterocycle unit had a significant effect on solubility, with 3-nitrotriazoles being about 6-fold more soluble than the corresponding 2-nitroimidazoles. Analogues with a range of neutral linker chains (polyhydroxy, alkanesulfonamide, and bisamide) showed only slightly improved solubility and were unable to be fully evaluated. However, a series of analogues with cationic amine linkers had adequate aqueous solubility (up to 280 mM). The amine analogues could not be prepared by direct reduction of precursor amides such as 4 and were most conveniently synthesized by aza-Wittig condensation of the appropriate azide and aldehyde components. The amine-linked compounds were more cytotoxic than 4, with the symmetrical bis(2-nitroimidazole) derivatives (13 and 14) up to 9-fold more potent. They showed hypoxic selectivities comparable to that of 4 (ca. 200-fold) but had much more rapid kinetics of killing under hypoxia, resulting in high hypoxic selectivity at early times in culture. The nature of the mechanism of cytotoxicity of these compounds remains unclear but appears not to be DNA cross-linking, with the compounds showing a lack of hypersensitivity toward repair-deficient UV4 cells. The enhanced solubility and hypoxia-selective cytotoxicity (at early times) of 13 compared with 4 represent significant potential advantages.
Animals↗
Reductive chemistry of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide.
5-[N,N-Bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (1; SN 23862) is a novel bioreductive drug whose selective toxicity for hypoxic cells appears due to oxygen-inhibited enzymatic reduction of one of the nitro groups to the corresponding amine or hydroxylamine. Radiolytic reduction of 1 using up to four reducing equivalents in 1 N sodium formate was shown to proceed via electron addition to the 4-nitro group, thereby identifying this substituent as the most electron-affinic site in the molecule. The initially-formed 4-hydroxylamine and its N-hydroxytetrahydroquinoxaline half-mustard cyclization product (formed by intramolecular reaction with one arm of the adjacent mustard group) are reduced to the corresponding 4-amines upon further addition of electrons, although reduction of the 2-nitro group leading to 2,4-diamino products begins after addition of only six electron equivalents. Radiolytic reduction of the structurally similar 5-(aziridin-1-yl)-2,4-dinitrobenzamide (2; CB 1954) with six electron equivalents also occurs at the 4-nitro group to give the 4-hydroxylamine and 4-amine. The product mixture from reduction of 2 is less complex, largely because the corresponding 4-hydroxylamine and 4-amine are stable. The major reduction products of 1 were chemically synthesized by unequivocal routes to provide authentic samples for identification of the products of radiolytic reduction and to allow determination of their cytotoxicities. The 2- and 4-amino derivatives of 1 are significantly more cytotoxic than the parent drug, although the toxicity of the 4-amine is moderated by its facile conversion to the corresponding less toxic tetrahydroquinoxaline half-mustard. Although the 2- and 4-hydroxylamino derivatives were prepared by chemical reduction of 1, their toxicity could not be evaluated because of their instability. The 4-hydroxylamine reacts intramolecularly with the 5-mustard group somewhat more rapidly than does the 4-amine, while the 2-hydroxylamine is converted into a 2,2'-azoxy dimer following aerial oxidation to the 2-nitroso derivative. The fully reduced 2,4-diamino derivative of 1 is 10-fold more cytotoxic again than the 2-amine and, surprisingly, does not undergo spontaneous intramolecular alkylation. This elucidation of the reduction chemistry of 1 will facilitate further investigations of the toxic products generated from this compound both by hypoxic tumor cells and by ADEPT enzymes.
Aniline Mustard↗