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Biomedical subjects

R L Page

Publications and source records attributed to R L Page.

At least 37 records · Page 2Linked to original sources
PubMed2000

Selective parasympathetic denervation following posteroseptal ablation for either atrioventricular nodal reentrant tachycardia or accessory pathways.

Baroreflex gain and coronary sinus norepinephrine and epinephrine levels were measured before and immediately after radiofrequency ablation in the posteroseptal region in 9 patients with atrioventricular nodal reentrant tachycardia or posteroseptal accessory pathways. Arterial baroreflex gain was significantly reduced after radiofrequency ablation (p = 0.046), whereas coronary sinus epinephrine and norepinephrine levels did not change significantly compared with preablation levels.

Baroreflex↗
PubMed2000

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.

PURPOSE: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Animals↗
PubMed2000

Increased sympathetic activity after atrioventricular junction ablation in patients with chronic atrial fibrillation.

OBJECTIVES: The aim of this study was to determine the changes in sympathetic nerve activity (SNA) after atrioventricular junction (AVJ) ablation in patients with chronic atrial fibrillation (AF). BACKGROUND: Polymorphic ventricular tachycardia (PMVT) has been reported after AVJ ablation in patients paced at a rate of < or =70 beats/min. We hypothesized that AVJ ablation results in sympathetic neural changes that favor the occurrence of PMVT and that pacing at 90 beats/min attenuates these changes. METHODS: Sympathetic nerve activity, 90% monophasic cardiac action potential duration (APD90), right ventricular effective refractory period (ERP) and blood pressure measurements were obtained in 10 patients undergoing AVJ ablation. Sympathetic nerve activity was analyzed at baseline and during and after successful AVJ ablation for at least 10 min. Data were also collected after ablation at pacing rates of 60 and 90 beats/min. The APD90 and ERP were measured before and after AV block during pacing at 120 beats/min. RESULTS: Sympathetic nerve activity increased to 134 +/- 16% of the pre-ablation baseline value (p < 0.01) after successful AVJ ablation plus pacing at 60 beats/min and decreased to 74 +/- 8% of baseline (p < 0.05) with subsequent pacing at 90 beats/min. Both APD90 and ERP increased significantly. CONCLUSIONS: 1) Ablation of the AVJ followed by pacing at 60 beats/min is associated with an increase in SNA. 2) Pacing at 90 beats/min decreases SNA to or below the pre-ablation baseline value. 3) Cardiac APD and ERP increase after AVJ ablation. The increase in SNA, along with the prolongation in APD, may play a role in the pathogenesis of ventricular arrhythmias that occur after AVJ ablation.

Action Potentials↗
PubMed2000

Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose-response. Azimilide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators.

OBJECTIVES: The purpose of this study was to assess the effectiveness of azimilide, a class III antiarrhythmic drug, in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation, atrial flutter or both. BACKGROUND: Atrial fibrillation is an increasingly common disorder of the heart rhythm, and most patients with this problem are identified because they have symptoms associated with their arrhythmia. New antiarrhythmic therapies are needed to treat patients with this problem. METHODS: A total of 384 patients with a history of atrial fibrillation, atrial flutter or both were randomly assigned to receive once daily doses of placebo or azimilide; recurrent symptomatic arrhythmias were documented using transtelephonic electrocardiogram (ECG) recording. Azimilide 50 mg, 100 mg or 125 mg was tested; the primary efficacy analysis compared the time to first symptomatic recurrence in the combined azimilide 100 mg and 125 mg dose groups with that in the placebo group using the log-rank test. RESULTS: In the primary efficacy analysis, the time to first symptomatic arrhythmia recurrence was significantly prolonged in the combined azimilide 100 mg and 125 mg daily dose group compared with the placebo group (chi-square 7.96, p = 0.005); the hazard ratio (placebo: azimilide) for this comparison was 1.58 (95% confidence interval [CI] = 1.15, 2.16). In comparisons between individual doses and placebo, the hazard ratio for the 50 mg daily dose was 1.17 (95% CI = 0.83, 1.66; p = 0.37); for the 100 mg group, dose was 1.38 (95% CI = 0.96, 1.98; p = 0.08), and for the 125 mg group, dose was 1.83 (95% CI = 1.24, 2.70; p = 0.002). CONCLUSIONS: Azimilide significantly lengthened the symptomatic arrhythmia-free interval in patients with a history of atrial fibrillation, atrial flutter or both.

Aged↗
PubMed2000

Azimilide dihydrochloride: a new class III anti-arrhythmic agent.

Azimilide dihydrochloride (Stedicor) is a new class III anti-arrhythmic agent that is being developed by Proctor & Gamble to treat supraventricular and ventricular arrhythmias. Development of this agent is being undertaken due to the high prevalence of atrial fibrillation and the lack of satisfactory therapy for this arrhythmia, along with the desire to develop therapy to reduce the risk of life-threatening ventricular arrhythmias in patients following myocardial infarction. The mechanism of action of azimilide is to block both the slowly conducting (I(Ks)) and rapidly conducting (I(Kr)) rectifier potassium currents in cardiac cells. This differs from other class III agents that block I(Kr) exclusively or in combination with sodium, calcium, or transient outward (I(to)) potassium current channels. Azimilide is distinguished by a relative lack of reverse use-dependence, excellent oral absorption, no need for dose titration, an option for out-patient initiation, no need for adjustment associated with renal or liver failure and a lack of interaction with warfarin or digoxin. It carries some risk of torsade de pointes and rarely, neutropoenia. Azimilide has shown dose-related efficacy in prolonging the time to recurrence of atrial fibrillation. A large trial examining the impact of azimilide on mortality in high-risk patients following myocardial infarction has completed enrolment and should yield data in the next couple of years and further studies are planned. Even if this trial fails to show a survival benefit, a neutral effect on mortality will make the agent attractive for atrial arrhythmias.

Animals↗
PubMed2000

The pharmacokinetics and pharmacodynamics of GW395058, a peptide agonist of the thrombopoietin receptor, in the dog, a large-animal model of chemotherapy-induced thrombocytopenia.

GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimulates megakaryocytopoiesis and has previously been shown to increase platelet counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 were characterized using a randomized, crossover study in a large-animal model (dog) of chemotherapy-induced thrombocytopenia. Nine beagle dogs received i.v. carboplatin (350 mg/m(2)) on day 0 and day 28. GW395058 (1.31 mg/kg) (n = 6) or vehicle control (n = 3) was administered on day 1 and day 29 either as an i.v. bolus or s.c. injection. After i.v. administration, peak concentrations of GW395058 occurred rapidly, while the half-life averaged approximately 56 h. Bioavailability (+/- standard deviation) of GW395058 given s.c. was 78.2% (20.9%). GW395058 (i.v. and s.c.) ameliorated the platelet nadir (p = 0.0086) and resulted in a shorter time to recovery compared to the control group. The mean nadir platelet counts following carboplatin administration were 197,000 cells/microl (80,000) for the i.v. GW395058-dose group, 183,000 cells/microl (72,000) for the s.c.-dose group and 71,000 cells/microl (38,000) for the vehicle-alone group. GW395058 reduced the thrombocytopenic effects of carboplatin in dogs. No GW395058-related adverse side effects were observed.

Animals↗
PubMed2000

The relationship between intracellular and extracellular pH in spontaneous canine tumors.

Recently, it has been suggested that the cellular uptake of chemotherapeutic drugs may be dependent on the pH gradient between the intracellular (pHi) and extracellular (pHe) compartments. It has been demonstrated in murine tumor models that the extracellular environment is acidic, relative to the intracellular environment, thus favoring preferential accumulation of drugs that are weak acids into cells. However, concomitant measurements of pHi and pHe in spontaneous tumors have not been reported, so it is not certain how well the murine results translate to the clinical scenario. In this study, both types of measurements were performed in dogs with spontaneous malignant soft tissue tumors. On average, pHe was more acidic than pHi, with maintenance of a more physiologically balanced intracellular tumor environment. However, the magnitude of the gradient varied widely, and individual tumors had both positive and negative pH gradients (pHi - pHe). These data suggest that the magnitude and direction of the pH gradient may need to be measured for individual patient tumors and/or that manipulation of pHe may be required if exploitation of the pH gradient is to be achieved for tumor-selective augmentation of intracellular drug delivery.

Animals↗
PubMed1999

Effect of radiofrequency ablation on atrial mechanical function in patients with atrial flutter.

Atrial stunning, as assessed by left atrial appendage emptying and increased spontaneous echo contrast, is known to occur following direct-current cardioversion of atrial fibrillation (AF) and atrial flutter (AFI). Little is known on atrial mechanical function and the time course of atrial recovery following radiofrequency ablation of AFI. Fourteen patients undergoing radiofrequency ablation of persistent typical counterclockwise AFI were enrolled. Two-dimensional and pulse Doppler transesophageal echocardiography (TEE) were performed before ablation and immediately following restoration of sinus rhythm. Left atrial spontaneous echo contrast grades, left atrial appendage emptying fractions, and peak left atrial appendage emptying velocities were measured. Transthoracic echocardiography (TTE) was performed immediately after ablation, then repeated after 1 day, 1 week, and 6 weeks to measure peak transmitral velocities and percent atrial contribution to ventricular filling. Left atrial appendage emptying velocities decreased significantly following AFI termination (44 +/- 23 cm/s before ablation vs 25 +/- 14 cm/s after ablation, p = 0.01). Left atrial appendage emptying fractions also decreased significantly (0.48 +/- 0.1 preablation vs 0.34 +/- 0.17 postablation, p = 0.02). New spontaneous echo contrast developed in 4 patients (29%) after ablation. Four patients had complete atrial standstill after ablation, and 1 patient developed a new left atrial appendage thrombus. The percent atrial contribution to ventricular filling recovered progressively over 6 weeks with significant improvement in peak transmitral velocities at day 7. Thus, atrial stunning occurs after catheter ablation of AFI and may lead to rapid formation of thrombus in the left atrial appendage. Significant improvement in left atrial function occurs in 7 days.

Aged↗
PubMed1999

Reflex control of sympathetic activity during simulated ventricular tachycardia in humans.

BACKGROUND: Ventricular tachyarrhythmias present a unique set of stimuli to arterial and cardiopulmonary baroreceptors by increasing cardiac filling pressures and decreasing arterial pressure. The net effect on the control of sympathetic nerve activity (SNA) in humans is unknown. The purpose of this study was to determine the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during ventricular pacing in humans. METHODS AND RESULTS: Two experiments were performed in which SNA and hemodynamic responses to ventricular pacing were compared with nitroprusside infusion (NTP) in 12 patients and studied with and without head-up tilt or phenylephrine to normalize the stimuli to either the arterial or cardiopulmonary baroreceptors in 9 patients. In experiment 1, the slope of the relation between SNA and mean arterial pressure was greater during NTP (-4.7+/-1.4 U/mm Hg) than during ventricular pacing (-3.4+/-1.1 U/mm Hg). Comparison of NTP doses and ventricular pacing rates that produced comparable hypotension showed that SNA increased more during NTP (P=0.03). In experiment 2, normalization of arterial pressure during pacing resulted in SNA decreasing below baseline (P<0.05), whereas normalization of cardiac filling pressure resulted in a greater increase in SNA than pacing alone (212+/-35% versus 189+/-37%, P=0. 04). Conclusions--These data demonstrate that in humans arterial baroreflex control predominates in mediating sympathoexcitation during ventricular tachyarrhythmias and that cardiopulmonary baroreceptors contribute significant inhibitory modulation.

Action Potentials↗
PubMed1999

Baroreflex gain predicts blood pressure recovery during simulated ventricular tachycardia in humans.

BACKGROUND: Despite similar degrees of left ventricular dysfunction and similar tachycardia or pacing rate, blood pressure (BP) response and symptoms vary greatly among patients. Sympathetic nerve activity (SNA) increases during sustained ventricular tachycardia (VT), and the magnitude of this sympathoexcitatory response appears to contribute to the net hemodynamic outcome. We hypothesize that the magnitude of sympathoexcitation and thus arterial baroreflex gain is an important determinant of the hemodynamic outcome of VT. METHODS AND RESULTS: We evaluated the relation between arterial baroreflex sympathetic gain and BP recovery during rapid ventricular pacing (VP) in patients referred for electrophysiological study. Efferent postganglionic muscle SNA, BP, and central venous pressure (CVP) were measured in 14 patients during nitroprusside infusion and during VP at 150 (n=12) or 120 (n=2) bpm. Arterial baroreflex gain was defined as the slope of the relationship of change in SNA to change in diastolic BP during nitroprusside infusion. Recovery of mean arterial pressure (MAP) during VP was measured as the increase in MAP from the nadir at the onset of pacing to the steady-state value during sustained VP. Arterial baroreflex gain correlated positively with recovery of MAP (r=0.57, P=0.034). No significant correlation between ejection fraction and baroreflex gain (r=0.48, P=0.08) or BP recovery (r=0.41, P=0.15) was found. When patients were separated into high versus low baroreflex gain, the recovery of MAP during simulated VT was significantly greater in patients with high gain. CONCLUSIONS: These data strongly suggest that arterial baroreflex gain contributes significantly to hemodynamic stability during simulated VT. Knowledge of baroreflex gain in individual patients may help the clinician tailor therapy directed toward sustained VT.

Adult↗
PubMed1999

Interaction of a commercial heart rate monitor with implanted pacemakers.

Dry-electrode heart rate monitors allow display of heart rate by transmitting a signal to the receiving device, which typically is on the wrist or exercise machine, but due to the potential for electromagnetic interference, their use has been contraindicated in patients with pacemakers. In 12 patients, we found no adverse effect on pacemaker function; in addition, the monitors generally were accurate in measuring heart rate during pacing.

Contraindications↗
PubMed1999

Effects of repeated electrical defibrillations on cardiac troponin I levels.

Multiple endocardial countershocks applied during intraoperative endocardial implantable cardioverter-defibrillator testing for the purpose of defibrillation threshold determination resulted in detectable myocardial injury in 5 of 12 patients, as indicated by elevations in cardiac troponin I levels. This injury was not associated with acute changes on the surface electrocardiogram.

Adult↗
PubMed1999

Phase I and pharmacokinetic analysis of high-dose tamoxifen and chemotherapy in normal and tumor-bearing dogs.

PURPOSE: To determine whether tamoxifen plasma concentrations capable of blocking P-glycoprotein (Pgp) in vitro can be safely achieved in dogs and whether doxorubicin pharmacokinetic alterations occur when tamoxifen is coadministered. METHODS: Tamoxifen dose escalation studies were conducted in 7 normal dogs and in 19 tumor-bearing dogs receiving full-dose chemotherapy. Plasma tamoxifen and serum doxorubicin disposition were analyzed for putative drug interactions. RESULTS: Steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen (NDMT) were 5-10 microM following oral tamoxifen administration at 600 mg/m2 every 12 h for 7 days to normal and tumor-bearing dogs. Mild-moderate gastrointestinal toxicity (diarrhea, anorexia) and reversible neurotoxicity were observed in dogs receiving chemotherapy plus high-dose tamoxifen. Myelosuppression was not affected by combined treatment in tumor-bearing dogs. High-dose tamoxifen decreased the clearance and volume of distribution of full-dose doxorubicin. CONCLUSIONS: Concentrations of tamoxifen/ NDMT sufficient to inhibit Pgp may be achieved in dogs receiving full-dose chemotherapy with a moderate but acceptable increase in gastrointestinal toxicity. Tamoxifen affects doxorubicin metabolism in dogs at high doses resulting in increased serum exposure. Pharmacologic manipulation of Pgp expression or function in normal and tumor tissue in dogs may facilitate investigation of novel anticancer treatment strategies in humans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Management of ventricular arrhythmias: a trial-based approach.

Sudden cardiac death accounts for approximately 300,000 deaths annually in the U.S., and most of these are secondary to ventricular tachycardia (VT) and fibrillation in patients with coronary artery disease. Most patients with cardiac death die before reaching the hospital, which brought about a tremendous amount of research focused at identifying patients at high risk. Several trials were initiated to test the effectiveness of various therapeutic measures in these high-risk patients. A history of myocardial infarction, depressed left ventricular function and nonsustained VT have all been identified as independent risk factors for future arrhythmic death. Similarly, patients with a history of sustained VT or a history of sudden cardiac death are a high-risk group and should be aggressively evaluated and treated. The purpose of this article is to discuss risk stratification and primary prevention of sustained ventricular arrhythmias. We also review the recent secondary prevention trials and discuss the options available in the management of patients with sustained ventricular arrhythmias.

Arrhythmias, Cardiac↗
PubMed1999

The effect of biphasic defibrillation on the immediate pacing threshold of a dedicated bipolar, steroid-eluting lead.

It is apparent that pacing threshold increases following an ICD shock, although the degree of change observed is dependent on the method used to assess pacing and the lead design used. We previously demonstrated a rise in postshock pacing threshold using a lead with integrated bipolar pacing in which the distal shocking coil also serves as the pacing anode. In this study, we sought to investigate whether the postshock pacing threshold increased significantly in an endocardial, steroid-eluting lead with dedicated bipolar pacing electrodes. Twenty patients (16 men, 4 women; median age 73, ejection fraction [EF] 0.17-0.58) were studied during pectoral ICD implantation (Medtronic active can model 7221Cx or 7223Cx with model 6932-65 lead). The diastolic pulse width pacing threshold at 1 or 2 V was determined. Pacing rate was set > or = 100/min at twice diastolic threshold output to assess pacing immediately following the first DFT test shock. For subsequent shocks, the output was adjusted to establish postshock thresholds as 1, 2, 3, or 4 times the diastolic threshold. The postshock threshold was defined as the output yielding 100% capture > or = 2.5 seconds following a shock. In 8 of 20 patients (ratio 0.40 +/- 0.11), a rise in the post-shock threshold was shown by failure of consistent capture when pacing at 2 times diastolic threshold > or = 2.5 seconds after a DFT test shock. Two of these patients failed at 3 times threshold, but none failed at 4 x threshold. Five of 12 patients with successful capture of 2 times threshold failed to capture at threshold. The postshock threshold increased by a mean factor of 2.83 +/- 0.83 in the group of patients with a threshold rise. Following ICD shock in an active can, steroid-eluting lead system with dedicated bipolar pacing, the post-shock threshold increases significantly. Our studies suggest a need for postshock pacing to be set at least 4 x threshold regardless of the lead design.

Adult↗
PubMed1999

Potentiation of warfarin by dong quai.

Dong quai is a Chinese herbal supplement touted for treatment of menstrual cramping, irregular menses, and menopausal symptoms. Phytochemical analyses found it to consist of natural coumarin derivatives, as well as constituents possessing antithrombotic, antiarrhythmic, phototoxic, and carcinogenic effects. A 46-year-old African-American woman with atrial fibrillation stabilized on warfarin experienced a greater than 2-fold elevation in prothrombin time and international normalized ratio after taking dong quai concurrently for 4 weeks. No identifiable cause was ascertained for the increase except dong quai. The patient's coagulation values returned to acceptable levels 1 month after discontinuing the herb. One animal study suggests a pharmacodynamic interaction between the product and warfarin, but the true mechanism remains unknown. Practitioners should be aware of the possibility of such an interaction and should inform patients of potential hazards of taking the two together.

Angelica sinensis↗