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Biomedical subjects

K M O'Connor

Publications and source records attributed to K M O'Connor.

At least 19 recordsLinked to original sources
PubMed2001

Preparation and characterisation of a range of diclofenac salts.

Physicochemical properties of diclofenac salts prepared using eight different counterions and including five novel salts, obtained with the bases 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanol, tert-butylamine, benzylamine and deanol, were compared. Four of the bases used to prepare these salts were related in their chemical structure, differing only in the number of hydroxy groups. Characterisation techniques included X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, thermomicroscopy, Karl Fischer titration, FT-IR spectroscopy and elemental analysis. In the case of salts prepared from 2-amino-2-methylpropanol and benzylamine, two polymorphic forms of each salt were identified. For the 2-amino-2-methyl-1,3-propanediol salt, a pseudopolymorphic form was identified. The aqueous solubilities of the salts studied ranged from 3.95 mM (tris(hydroxymethyl)aminomethane salt) to 446 mM (deanol salt), corresponding to a 113-fold difference in solubility. The solubility of diclofenac deanol was higher than the solubilities for diclofenac salts reported earlier. Correlation was found between the inverse of the salt melting point and the logarithm of salt solubility. A log-log relationship was observed between salt solubility and hydrogen ion concentration in the salt solution. Relationships between the properties of the salt-forming agents and those of the resulting diclofenac salts were explored. Reasonable correlation was found between the free base melting point and the salt melting point.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac.

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have very low aqueous solubilities and consequently salt formation may be used to enhance solubility and dissolution rate. In this study, we examined the physicochemical properties of three diclofenac salts, diclofenac sodium (DNa), diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) and diclofenac diethylamine (DDEA), and their different solid state forms to determine the influence of salt form on solubility, dissolution rate and membrane transport. The equilibrium solubility of DDEA at 25 degrees C was determined as 33 mM, lower than the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported (Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP previously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ratios of the hydrated and anhydrous forms. The monohydrate form of DHEP was found to be 1.8 times less soluble than the anhydrate, whereas DDEA anhydrate was approximately 1.7 times as soluble as the monohydrate form. On investigation of the pH-solubility profile (25 degrees C) of DDEA, appreciable supersaturation (76 mM) relative to the theoretical profile, was detected at the pH(max). This contrasts with values of >800 and 67 mM for DHEP and DNa, respectively. The transport of salt solutions through a porous membrane (Visking) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solutions. The mass transfer coefficient determined for DHEP was lower than that for the other two salts. Nevertheless, the maximum transport rate obtained for DHEP is almost six times higher than that obtained for DDEA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Distributive spirals: negotiation impasses and the moderating role of disputant self-efficacy.

Negotiations do not always end in agreements. Yet, we know little about impasses and how they affect negotiators. In three studies, we compare how negotiators experience impasses and agreements, paying particular attention to the moderating role of disputant self-efficacy. Specifically, we propose and find that negotiators who impasse find themselves caught in a distributive spiral-they interpret their performance as unsuccessful, experience negative emotions, and develop negative perceptions of their counterpart and the process. In terms of their future behavioral intentions, they are less willing to work together in the future, plan to share less information, plan to behave less cooperatively, and they lose faith in negotiation as an effective means of managing conflicts. As predicted, negotiators with relatively high levels of self-efficacy were insulated from some of these negative outcomes.

Journal Article↗
PubMed2001

Typological predictions in developmental phonology.

Two common and seemingly independent error patterns, namely consonant harmony and gliding, are examined for their typological characteristics based on cross-sectional and longitudinal evidence from young children's developing phonologies. Data are drawn from the published literature and from the developmental phonology archives at Indiana University. An asymmetry is observed such that the occurrence of harmony is found to imply the occurrence of gliding, but not vice versa. While this finding would be unexpected within contemporary derivational theories, it can be shown to follow within optimality theory from a fixed universal ranking relationship among certain constraints. Optimality theory is also argued to offer a viable developmental account with clinical implications that can serve as a further test of the theory.

Child Language↗
PubMed2001

ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE.

OBJECTIVE: To compare the relative efficacy of electroconvulsive therapy (ECT) in psychotic and nonpsychotic patients with unipolar major depression. METHODS: The outcome of an acute ECT course in 253 patients with nonpsychotic (n = 176) and psychotic (n = 77) unipolar major depression was assessed in the first phase of an ongoing National Institute of Mental Health-supported four-hospital collaborative study of continuation treatments after successful ECT courses. ECT was administered with bilateral electrode placement at 50% above the titrated seizure threshold. The remission criteria were rigorous: a score <or=10 on the 24-item Hamilton Rating Scale for Depression (HRSD) after 2 consecutive treatments, and a decrease of at least 60% from baseline. RESULTS: The overall remission rate was 87% for study completers. Among these, patients with psychotic depression had a remission rate of 95% and those with nonpsychotic depression, 83%. Improvement in symptomatology, measured by the HRSD, was more robust and appeared sooner in the psychotic patients compared with the nonpsychotic patients. CONCLUSION: Bilateral ECT is effective in relieving severe major depression. Remission rates are higher and occur earlier in psychotic depressed patients than in nonpsychotic depressed patients. These data support the argument that psychotic depression is a distinguishable nosological entity that warrants separate treatment algorithms.

Adult↗
PubMed1997

The costs of managing advanced colorectal cancer: a broad perspective.

Cancer care is expensive, consuming between 5 and 10% of health-care resources in industrialized countries. Therefore increasing emphasis is being placed on the value of treatment interventions. Colorectal cancer is the second most common cancer in the Western world and nearly two-thirds of patients will require palliative treatment. Only limited data are available on the cost of palliative chemotherapy for patients with advanced disease. The profile of raltitrexed ('Tomudex', formerly ZD1694) suggests that it may reduce costs associated with the administration of chemotherapy. Recent studies demonstrate that the total monthly cost of raltitrexed is lower or about the same as a variety of commonly used 5-fluorouracil-based regimens and offers potential savings for hospitals in terms of demand on specialist facilities, physician, nursing and pharmacy time, and overnight bed occupancy. The personal cost borne by patients and their carers for travelling and time off work is reduced with raltitrexed compared with the widely used Mayo regimen. However, there may be disincentives within certain national health-care systems to the introduction of a more resource-efficient drug such as raltitrexed. Physicians will need information on both the benefits and costs of drug treatments to be able to make informed decisions on the provision of high quality, cost-effective patient care, and it is likely that health economic assessment will be incorporated into increasing numbers of clinical trials.

Antimetabolites, Antineoplastic↗
PubMed1997

Unweighting accelerates tidemark advancement in articular cartilage at the knee joint of rats.

Morphologic development of articular cartilage is influenced by biologic adaptation to functional demands. It has been theorized that intermittent stresses generated by load bearing and motion determine cartilage thickness by controlling advancement of the subchondral mineralization front. The mineralization front is comprised of two interfaces, the tidemark and chondroosseus junction, each of which advances through a different biologic process. This study was designed to evaluate the influence of one month of hind limb unweighting, with and without concurrent restriction of joint motion, on mineral apposition at the tidemark and vascular invasion at the chondroosseus junction in the knee joints of young adult rats. In mobile joints, hind limb unweighting induced a 2-fold increase in the tidemark mineral apposition rate (p = 0.0001) at the primary weight bearing region, resulting in a thinning of the uncalcified cartilage layer and a concurrent thickening of the calcified layer. Cast immobilization negated the effect of unweighting at the tidemark while it activated subchondral vascular encroachment into the calcified cartilage (p = 0.001). These findings suggest that cartilage thinning associated with the elimination of weight bearing is mediated through a different biological mechanism than cartilage loss associated with restriction of joint motion.

Adaptation, Physiological↗
PubMed1995

Effects of microgravity on bone healing in a rat fibular osteotomy model.

Bone healing was investigated histologically in a rat fibular osteotomy model subjected to microgravity (shuttle flight STS-29) and the tail suspension microgravity simulation model. Exposure to microgravity or tail suspension occurred during the last 5 days of a 10-day healing period. Periosteal osteogenesis and the development of vascular channels in both experimental groups were similar to that observed in a weightbearing control group. Chondrogenesis was more advanced in weightbearing rats than in either flight or tail-suspended rats. Angiogenesis in the osteotomy gap was more advanced in weightbearing and tail-suspended rats than in the flight group. These findings suggest that bone healing may be impaired during space travel. Interpretation of the findings is complicated by observations that flight and suspended rats lost weight during the flight period and that suspended rats consumed less water than control rats. Tail suspension did not produce the same pattern of healing as spaceflight; therefore, long-term studies of bone healing, conducted entirely in the microgravity environment, are needed to distinguish metabolic from mechanical influences and to determine whether effective fracture consolidation will occur in the absence of gravitational forces.

Animals↗
PubMed1989

The effect of beta-adrenergic blockade on vulnerability to ventricular fibrillation and inducibility of ventricular arrhythmia in short- and long-term feline infarction models.

Previous investigation, predominantly in the short-term canine model, has documented a potent antifibrillatory effect of beta-adrenergic blockade. To determine whether the protection afforded by beta blockade is species- and model-specific, we studied 23 chloralose-anesthetized cats. Eight animals were studied over a short term and underwent serial determinations of the ventricular fibrillation (VF) threshold prior to and 1 minute after occlusion of the left anterior descending coronary artery (LAD) and immediately following reperfusion of a 10-minute occlusion. Beta-blocking doses of intravenous propranolol (P) (0.5 mg/kg) attenuated the fall in VF threshold during acute ischemia. Increasing the dose of P to 1 mg/kg did not provide further protection, nor did P protect against reperfusion VF. The other 15 animals underwent a preliminary surgical procedure during which the LAD was completely and irreversibly occluded (nine animals) or in which a sham procedure was performed (six animals). Two weeks later, we measured ventricular refractoriness at several left ventricular sites, ventricular inducibility using programmed electrical stimulation, and VF thresholds both before and after administration of intravenous P (1 mg/kg). Ventricular refractory periods in the infarcted zones were significantly increased compared with normal sites and with values obtained in sham-operated animals. In addition, VF thresholds in the infarcted animals were lower than those obtained in the sham-operated group. Before treatment, a reproducible sustained ventricular tachyarrhythmia was induced by means of programmed stimulation in seven of the nine chronically infarcted animals but in none of the sham-operated animals (p less the 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effect of thromboxane inhibition on vulnerability to ventricular fibrillation in the acute and chronic feline infarction models.

Inhibition of the enzyme that synthesizes thromboxanes may protect against the development of ventricular fibrillation (VF) during acute myocardial ischemia. This study was carried out to test this hypothesis with a new thromboxane synthetase inhibitor, and to extend the studies to alternative animal models of myocardial infarction. In a series of acute experiments, 19 cats were pretreated with 10 mg/kg of U-63557A (a dose that produced greater than 75% reduction in thromboxane B2 [TxB2] levels) or saline before abrupt left anterior descending coronary artery occlusion. Seven of the nine control animals suffered spontaneous VF associated with a 77% fall in VF threshold compared with the treated animals, of which 2 of 10 had spontaneous VF and in which VF threshold fell by only 45% (p less than 0.025). Despite a similar extent of TxB2 inhibition in another set of nine animals, U-63557A failed to protect against a fall in VF threshold during coronary reperfusion. Finally, chronic changes in VF threshold and inducibility of sustained ventricular tachycardia by programmed stimulation were assessed in a group of eight animals. The lowering of VF threshold and inducibility of ventricular tachycardia seen in the control state were not influenced by treatment with U-63557A. Thus protection against infarct-related VF by TxB2 inhibition is a property shared by more than one pharmacologic agent. Arrhythmias generated by reperfusion or induced in a more chronic setting may not be thromboxane-dependent. These results have important implications for the planning of studies designed to assess the antiarrhythmic potential of drugs that inhibit thromboxane synthesis.

Acute Disease↗
PubMed1989

Electrophysiologic effects of left ventricular hypertrophy in the intact cat.

Electrophysiologic abnormalities have been described in isolated, hypertrophied left ventricular tissue removed from animals exposed to a chronic pressure load. However, changes in electrical properties of intact hypertrophied hearts have not been described. To study this question, 15 cats underwent supraventricular aortic banding and five underwent a sham procedure. After ten weeks, the animals were anesthetized and instrumented using paired transmural plunge electrodes and endocardial quadripolar pacing catheters. Measurement of pacing threshold, refractoriness, inducibility of ventricular arrhythmias (using programmed electrical stimulation), and vulnerability to ventricular fibrillation (ventricular fibrillation threshold) were made in both groups. Mean left ventricular mass was significantly greater in the banded compared with sham-operated animals (2.5 +/- 0.9 v 2.1 +/- 0.5 g/kg body weight; P less than .05). Pacing thresholds and refractory periods measured at multiple left and right ventricular sites were similar in both groups, and there was no difference in the extent of site-to-site differences in refractoriness (dispersion). Six banded but no sham animals had inducible ventricular tachycardia or fibrillation using programmed stimulation. Furthermore, left ventricular mass was significantly greater in animals with inducible arrhythmias compared with those noninducible (P less than .05). Ventricular fibrillation thresholds, measured in milliamperes (mA), in the banded animals were significantly lower in the left ventricle (13.5 +/- 1.3 mA) than in the right (21.7 +/- 3.2 mA; P less than .05) and was also lower than the thresholds obtained in either the left or right ventricle of the sham-operated animals (18.3 +/- 1.9 mA and 20.1 +/- 1.1 mA, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Acute electrophysiologic effects and antiarrhythmic/antifibrillatory activity of intravenous amiodarone in a chronic feline infarction model.

In animal studies, amiodarone has substantial and immediate antiarrhythmic/antifibrillatory action during acute myocardial ischemia. The magnitude of this effect is discordant with the minor degree of prolongation of ventricular action potential duration (APD) and refractoriness which occurs immediately after acute drug administration. However, amiodarone's early onset of antiadrenergic activity and inhibition of inward slow calcium channel currents may be important when arrhythmogenesis is dependent on increased sympathetic tone. Because ventricular arrhythmia substrate may differ in acute and chronic ischemic heart disease, we investigated the acute electrophysiologic and antiarrhythmic/antifibrillatory effects of intravenously (i.v.) administered amiodarone in nine chronically infarcted cats. Amiodarone caused significant decreases (-17%) in mean heart rate (HR) and increases (+10%) in mean ventricular effective refractory period (ERP), which occurred promptly after drug administration. Increases in mean ventricular fibrillation (VF) threshold also occurred (11 +/- 3.4 and 12.5 +/- 2.4 mA for right and left ventricular sites before drug as compared with 45.5 +/- 13.2 and 42 +/- 13.9 mA after drug). Despite these changes, no significant reduction in the incidence of malignant ventricular arrhythmias induced by programmed stimulation was noted (63% of animals with arrhythmia induced before drug were still inducible after drug). In addition, no change in the increased degree of mean dispersion of refractoriness between infarcted and normal myocardial sites occurred following amiodarone (22.8 +/- 3.9 ms before vs. 30.2 +/- 2.5 ms after drug). In chronic myocardial infarction without superimposed acute ischemia, early onset of amiodarone's antiadrenergic and calcium channel blocking activities may play only a minor role in preventing ventricular arrhythmias inducible by programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1986

Effect of thromboxane synthetase inhibition on vulnerability to ventricular arrhythmia following coronary occlusion.

Release of thromboxane (TXA2) during acute myocardial infarction may be an important contributing factor in the genesis of ventricular fibrillation (VF). We assessed the effect of selective TXA2 inhibition on vulnerability to VF after total occlusion of the anterior descending coronary artery in chloralose-anesthetized cats. Animals were pretreated with vehicle or with CGS-13080, a TXA2 synthetase inhibitor, 3.0 or 9.0 mg/kg intravenously. There was an apparent dose-dependent protective effect following CGS-13080 administration, in which the decrease in VF threshold following coronary occlusion was attenuated. Also, the incidence of spontaneous ventricular arrhythmia in the first 30 minutes after occlusion was reduced by two thirds in the 9.0 mg/kg CGS-13080 group compared to the vehicle-treated animals. This protective effect does not appear to be due to a change in hemodynamics, effective refractory periods, or extent of ischemia. TXA2 released during coronary occlusion appears to be arrhythmogenic, and inhibiting its synthesis may be protective.

Animals↗
PubMed1985

The effect of bretylium and clofilium on dispersion of refractoriness and vulnerability to ventricular fibrillation in the ischemic feline heart.

Bretylium has been shown to have a pronounced antifibrillatory effect. The purpose of this study was to examine the effects of bretylium on changes in vulnerability to ventricular fibrillation (VF) and refractoriness which occur during acute myocardial infarction. Right ventricular VF thresholds and effective refractory periods (ERP) at six left ventricular sites were measured before and serially after left anterior descending coronary occlusion in chloralose-anesthetized cats. In eight untreated animals, there was a decrease in VF thresholds of 73% (p less than 0.01) immediately after occlusion and dispersion of refractoriness (DR) (maximum difference in ERP between normal and ischemic left ventricular sites) increased from 18 +/- 4 to 50 +/- 6 msec (p less than 0.01). Five of eight animals manifested spontaneous VF within the first minutes of occlusion but none had nonsustained VF. Pretreatment with bretylium (10 to 20 mg/kg intravenously) increased resting ERP from 181 +/- 9 to 201 +/- 9 msec (p less than 0.05) and VF threshold from 32 +/- 5 to 85 +/- 7 mA (p less than 0.001). Bretylium also prevented spontaneous VF in all eight animals and abolished occlusion-related changes in VF and DR. Fourteen animals were similarly studied using clofilium, a bretylium congener which is devoid of sympatholytic effect (no effect on blood pressure response to bilateral carotid artery occlusion). Clofilium increased resting ERP and VF thresholds at both low (0.5 mg/kg intravenously) and high doses (5 mg/kg intravenously). High-but not low-dose clofilium blunted the fall in VF threshold after coronary occlusion. In addition, DR correlated with VF threshold changes at both doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Arrhythmia inducibility and ventricular vulnerability in a chronic feline infarction model.

Ventricular tachyarrhythmias are the cause of sudden cardiac death in ischemic heart disease. Reliable animal models are necessary to study techniques for identifying individuals at risk and to develop effective modes of therapy. The purpose of the present study was to evaluate the inducibility of ventricular tachyarrhythmias and vulnerability to ventricular fibrillation and to correlate these findings with changes in ventricular refractoriness in a chronic feline model. Twelve conditioned cats were randomly divided into two groups: group A, sham-operated controls (n = 5); or group B, permanent occlusion of the left anterior descending coronary artery (n = 7). Two weeks later, the following measurements were made: (1) assessment of refractory periods at several ventricular sites; (2) inducibility to ventricular tachyarrhythmias; and (3) determination of ventricular fibrillation threshold. After electrophysiologic testing, the animals were killed and the hearts were studied histologically. Ventricular fibrillation thresholds were significantly lower in group B compared with group A (13 +/- 3 vs 46 +/- 9 mA; p less than 0.01). One of the sham-operated controls had induction of nonsustained ventricular tachycardia, while six of the group B animals had reproducible, inducible ventricular tachyarrhythmias (p less than 0.01). There was a significant dispersion in effective refractory periods between normal and infarcted sites in group B (46 +/- 6 msec) not seen in group A (12 +/- 2 msec, p less than 0.01). The group A cats demonstrated minimal damage to the myocardium or cardiac architecture. Group B cats demonstrated extensive, transmural, homogeneous infarcts of approximately 30% of the anterior wall of the left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Influence of site of stimulation on measurement of ventricular vulnerability in the normal and ischemic feline heart.

Site of stimulation is an important variable in the inducibility of ventricular tachycardia in both non-human animal infarction models and in humans; that is, proximity of the stimulating electrode to the site of reentry facilitates the induction of sustained arrhythmia. Whether site of stimulation is decisive in measurement of vulnerability to ventricular fibrillation (VF) during acute coronary occlusion has not been fully evaluated. We measured VF thresholds in 9 chloralose-anesthetized cats at 2 right ventricular and 3 left ventricular sites (2 endocardial, 3 intramural) before and after abrupt occlusion of the anterior descending coronary artery. VF thresholds were measured using a single stimulus of increasing intensity delivered during ventricular drive. Although VF thresholds were lower at endocardial sites, there were no significant differences in VF threshold among any of the sites tested at control. After occlusion, VF thresholds fell to a similar extent at all 5 sites tested. The percent reduction in VF threshold at any site was not influenced by the sequence of testing. VF may be precipitated from multiple sites and, unlike ventricular tachycardia, does not represent an isolated focus of arrhythmogenicity.

Animals↗