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C J O'Connor

Publications and source records attributed to C J O'Connor.

At least 19 recordsLinked to original sources
PubMed1999

N-Substituted 2-(2,6-dinitrophenylamino)propanamides: novel prodrugs that release a primary amine via nitroreduction and intramolecular cyclization.

A series of N-dinitrophenylamino acid amides [(4-CONHZ-2, 6-diNO2Ph)N(R)C(X,Y)CONHPhOMe] were prepared as potential bioreductive prodrugs and reduced radiolytically to study their rates of subsequent intramolecular cyclization. Compounds bearing a free NH group (R = H) underwent rapid cyclization in neutral aqueous buffers (t1/2 < 1 min) following 4-electron reduction, with the generation of a N-hydroxydihydroquinoxalinone and concomitant release of 4-methoxyaniline. Amine release from analogous N-methyl analogues (R = Me) was relatively slow. These results are consistent with intramolecular cyclization of a monohydroxylamine intermediate. The high rates of cyclization/extrusion by these very electron-deficient hydroxylamines suggest that the process is greatly accelerated by the presence of an H-bonding "conformational lock" between the anilino NH group and the adjacent o-nitro group (Kirk and Cohen, 1972). Changes in the phenylcarboxamide side chain or in C-methylation in the linking chain had little effect on the rate of cyclization. The model compounds had 1-electron reduction potentials in the range appropriate for cellular reduction (-373 mV for a measured example) and appeared suitable for development as prodrugs that release amine-based effectors following enzymic or radiolytic reduction. Prodrug examples containing 4-aminoaniline mustard and 5-amino-1-(chloromethyl)benz[e]indoline alkylating units were evaluated but were not activated efficiently by cellular nitroreductases. However, cell killing by the radiation-induced reduction of the latter prodrug was demonstrated.

Amides↗
PubMed1999

The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass.

UNLABELLED: Aprotinin is a serine protease inhibitor that undergoes metabolism in the kidney. Because elimination is almost entirely renal, the clearance of aprotinin may be reduced in patients with renal insufficiency. Unfortunately, there are no data regarding aprotinin pharmacokinetics in cardiac surgical patients with renal insufficiency or end-stage renal disease (ESRD) undergoing cardiopulmonary bypass (CPB). We, therefore, determined the clearance (ApCl) and elimination half-life (T1/2) of aprotinin in 26 cardiac surgical patients with normal and abnormal renal function (creatinine clearance [CrCl] 0-122 mL/min) undergoing CPB. Subjects were given a 2 million kallikrein inhibiting unit (KIU) initial dose of aprotinin, followed by a 0.25 million KIU/h infusion. No aprotinin was added to the pump prime. Plasma aprotinin concentrations were sampled at 30 min after completion of the loading dose, 30 and 60 min after the onset of CPB, at the end of CPB, and at 8, 24, and 32 h after completion of the loading dose. ApCl was directly related and the elimination T1/2 inversely related to CrCl (r = 0.75 and 0.42, respectively). In patients with a CrCl >50 mL/min, the T1/2 and ApCl were 7.8 h and 53 mL/min, respectively, compared with 19.9 h and 25 mL/min (P < 0.05, P < 0.002, respectively) for patients with ESRD. In conclusion, ApCl is reduced, and T1/2 is prolonged in patients with renal insufficiency or ESRD undergoing CPB. Dosing modifications may be necessary for patients with abnormal renal function undergoing cardiac surgery. IMPLICATIONS: Because aprotinin is metabolized and eliminated in the kidney, its clearance may be reduced in patients with renal insufficiency. Our data suggest that aprotinin clearance is reduced, and aprotinin half-lives are prolonged in patients with renal insufficiency undergoing CPB. Dosing modification may therefore be indicated when aprotinin is administered to these patients for cardiac surgery.

Aged↗
PubMed1998

Comparative mutational spectra of the nitrogen mustard chlorambucil and its half-mustard analogue in Chinese hamster AS52 cells.

Nitrogen mustards play an important role in current cancer chemotherapy. The most effective antitumour agents are those carrying two alkylating functions, probably through their ability to form interstrand cross-links in DNA. Such lesions appear to create more of a block in DNA replication and are more difficult to repair than are most monoadducts. Although there were early reports that monofunctional drugs were more mutagenic than the bifunctional drugs, this has not been formally proved using structurally related drugs in a mutagenicity assay capable of detecting a range of different events. We have studied both the mutagenic potency and spectrum of events caused by treatment with the clinical agent, chlorambucil, compared with its half-mustard analogue, in Chinese hamster ovary (CHO)-AS52 cells. Although both drugs caused comparable increases in mutation frequency at doses killing 90% of cells (from around 9x10-6 to around 9x10-5 mutant cells), the nature of events differed significantly between the drugs. By far the majority of mutations caused by the half-mustard were transversion mutations, and almost all of these could be interpreted in relation to the DNA adducts that are known to be formed. In contrast, the majority of chlorambucil-induced mutations were major deletions, and point mutations were only identified from a few clones. Parallel micronucleus assays verified that chlorambucil has a stronger ability to break chromosomes than the half-mustard. These two drugs are thought to form similar monoadducts, but only the full mustard can form interstrand cross-links. The data suggest that DNA cross-links, although only a minor fraction of the total lesions, dominate the mutagenic spectrum and lead to gross changes at the chromosome level that can not be readily associated with individual lesions produced by the drug.

Animals↗
PubMed1998

The effect of pH on the inhibition of bacterial growth by physiological concentrations of butyric acid: implications for neonates fed on suckled milk.

Butyric acid is released from milk by pre-intestinal lipases during suckling. It is also known to inhibit bacterial growth. To investigate whether butyric acid may be a significant factor in controlling bacterial growth in the stomach of pre-weaned animals, the ability of butyric acid to inhibit growth of selected bacteria was tested over physiological ranges of pH and butyric acid concentrations. Six enteric and environmental strains of bacteria were used: two strains of Escherichia coli, Klebsiella pneumoniae, Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus. At pH 4.5 and 5.0, the growth of all organisms was significantly inhibited in the presence of butyrate, and in some cases growth was completely arrested. At pH 6.0, butyric acid did not affect bacterial growth until the concentration reached 40 mM. The maximum concentration of butyric acid available in cow's milk after incubation with pre-gastric lipase is approximately 16 mM, which would be sufficient to prevent growth of the organisms tested at pH values occurring in the stomach. Therefore, butyric acid inhibition of bacterial growth may explain in part, the role of pre-intestinal lipases in young animals' natural defenses against bacteria in ingested food prior to weaning.

Animals↗
PubMed1998

Mono- and dysfunctional nitrogen mustard analogues of the DNA minor groove binder pibenzimol. Synthesis, cytotoxicity and interaction with DNA.

Two series of mono- and dysfunctional aniline mustards linked to a bisbenzimidazole minor groove binder have been prepared using a new method (polyphosphate ester-mediated direct coupling of appropriate mustard acids with a preformed advanced phenylenediamine intermediate). As the linker chain attaching the mustard was lengthened the binding site size of the compounds to calf thymus DNA remained essentially constant at 2.6 nucleotides, but reversible binding strength declined by a factor of 2. Analogues with longer linker chains alkylated DNA much more rapidly than those with shorter chains, consistent with the electronic factors. The short chain analogues also failed to alkylate a 120 bp HindIII to Bg/II fragment of the gpt gene, as measured by gel electrophoresis cleavage assays. The longer chain analogues (both mono- and dysfunctional mustards) showed patterns of DNA alkylation that varied with chain length. In particular, while most compounds showed substantial N7 alkylation at many guanine residues, the analogue with a (CH2)3 linker chain showed strong alkylation at adenine sites in poly-AT regions. For the longer chain analogues, the bifunctional mustards were substantially (10- to 20-fold) more cytotoxic than the corresponding monofunctional analogues.

Alkylation↗
PubMed1997

Saccular outpouchings of an ascending aortic aneurysm: transesophageal echocardiographic appearance.

The differential diagnosis of cavities in the ascending aorta includes pseudoaneurysms, intimal flaps, and abscesses. We describe the transesophageal echocardiographic and pathologic appearance of a fusiform ascending aortic aneurysm that contained atypical outpouchings that were initially confused with an intimal flap. Awareness of this unreported abnormality and its echocardiographic features will avoid the misdiagnosis of more serious aortic pathology such as acute aortic dissection or infective endocarditis.

Abscess↗
PubMed1997

Hydrolysis characteristics of bovine milk fat and monoacid triglycerides mediated by pregastric lipase from goats and kids.

Commercial extracts from oro-pharyngeal tissues of goats and kids have been used as the source of pregastric lipase and have been processed to yield partially purified samples of the primary pregastric lipase. The activity of these lipases against tributyrylglycerol has been determined over a range of pH and temperatures. Optimum pH conditions for pregastric lipase ranged from pH 5.6 to 6.5 for goats and from pH 5.5 to 6.2 for kids, respectively; the optimum temperature ranged from 43 to 60 degrees C. Optima for kid lipase extended slightly below pH 5.5 and higher than 60 degrees C; which were the limits of the test conditions. The enzymes were also used as catalysts for the hydrolysis of monoacid triglycerides (C4:0 to C12:0) at 40 degrees C and pH 6.5; activity was maximum against tributyrylglycerol (C4:0). Values for the Michaelis-Menten constant, increased as carbon chain length of the carboxylic moiety on the triglycerides increased, but values were identical for pregastric lipases of both goats and kids. Anhydrous milk fat was hydrolyzed by the commercial extracts of pregastric lipases of goats and kids, and the resulting profiles for free fatty acids were very similar to one another and to the corresponding profile for a commercial sample of Parmesan cheese. There appear to be no significant differences in activity between the enzyme preparations from goats and kids.

Animals↗
PubMed1996

The effect of esmolol pretreatment on the incidence of regional wall motion abnormalities during electroconvulsive therapy.

Electroconvulsive therapy (ECT) is associated with dramatic increases in arterial blood pressure and heart rate (HR) that may precipitate new left ventricular regional wall motion abnormalities (RWMAs) suggestive of myocardial ischemia. The purpose of this study was to investigate the effect of pretreatment with esmolol on the incidence of RWMAs after ECT. Thirteen patients served as their own controls and, in a random fashion, received a standard succinylcholine/methohexital anesthetic for one of two ECT sessions, and an identical anesthetic with esmolol 1 mg/kg for their other ECT session. Systolic (SBP), diastolic (DBP), mean arterial pressures (MAP) and HR were recorded after drug administration and before ECT and at 1-, 2-, 4-, 5-, 10-, and 15-min intervals after ECT. Echocardiograms were obtained at baseline, after drug administration, 1 min after ECT, and at recovery 15 min later. All patients had significant increases in SBP, DBP, and MAP at 1, 2 and 4 min after ECT versus baseline, whereas HR was significantly faster at all times in the control sessions. HR was significantly slower after anesthetic induction until 2 min after ECT in the esmolol versus the control group (P < 0.05). New RWMAs were seen in only 1 of 26 (4%) ECT sessions, despite the presence of baseline RWMAs in 31% of the patients. We conclude that contrary to previously reported data, new RWMAs after ECT are uncommon. Consequently, this study was unable to demonstrate any beneficial effect of pretreatment with esmolol on the incidence of ECT-induced RWMAs.

Adrenergic beta-Antagonists↗
PubMed1996

Aspirin does not increase allogeneic blood transfusion in reoperative coronary artery surgery.

While preoperative aspirin (ASA) therapy does not increase allogeneic transfusion in elective primary coronary artery bypass grafting (CABG) operations, the impact of ASA consumption on transfusion in cardiac operations with greater risk of bleeding has not been investigated. We examined the influence of ASA consumption on mediastinal drainage and allogenic transfusion in 317 patients undergoing reoperative CABG surgery. Patients receiving ASA or ASA containing medications within 7 days preoperatively (n = 215) had similar perioperative characteristics but were older and had smaller red cell volumes than control patients not receiving ASA (n = 102). All patients received aminocaproic acid, but autotransfusion of mediastinal blood or platelet rich plasma, aprotinin, or desmopressin were not used. No significant differences were observed between ASA and control groups with respect to postoperative hematocrit, mediastinal drainage, frequency of reexploration for excessive bleeding, amount of allogeneic packed red blood cell, fresh frozen plasma, platelet concentrate or cryoprecipitate transfusion, or the fraction of patients receiving any allogeneic blood product. There was no difference in mediastinal drainage when stratified by timing of most recent ASA ingestion. Multiple linear regression identified duration of cardiopulmonary bypass (CPB), internal mammary artery harvesting, chronic preoperative steroid therapy and use of an intraaortic balloon pump (IABP) as significant predictors of mediastinal drainage. Logistic regression demonstrated that female gender, prolonged duration of CPB, advanced age, use of IABP, and a negative history of smoking were significant independent predictors of blood product transfusion. There was no significant interaction of preoperative heparin therapy with ASA on transfusion demonstrated by univariate or multivariate analyses. These results indicate that preoperative ASA ingestion is not an important determinant of mediastinal drainage or allogeneic transfusion, even after repeat CABG operations, and that surgical and patient characteristics are more important predictors of these outcomes.

Age Factors↗
PubMed1995

Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards.

A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.

Alkylation↗