Expression and activity of transglutaminase II in spontaneous tumours of dogs and cats.

Tissue transglutaminase II (TGase II) is a dual function protein with both transamidating and guanidine triphosphate (GTP)-binding capabilities. Previous studies have implicated TGase as a pro-apoptotic molecule; however, our recent findings indicate that TGase II may act as a survival factor in various cell types. The purpose of this study was to survey TGase II expression in normal tissue and spontaneous tumours of dogs and cats, by Western blotting and immunohistochemistry. Bladder, liver and adrenal gland exhibited prominent expression of TGase II while other tissues, including mammary gland, displayed limited expression and activity. TGase II GTP-binding in normal tissues was proportional to the level of expression in all tissues examined. Normal mammary tissue and that showing benign hyperplasia did not express TGase II. However, 11/25 (44%) of canine mammary carcinomas and 10/12 (83%) of feline mammary carcinomas strongly expressed TGase II in either a stromal, cellular or combined pattern. The pattern of expression was not related to the classification of mammary carcinoma (solid, tubulopapillary, complex or anaplastic), except that two anaplastic canine mammary carcinomas showed prominent TGase II expression. Two canine mammary carcinoma cell lines showed prominent TGase expression, and when the TGase activity was inhibited, the cells became more sensitive to doxorubicin-induced cell death. Thus, TGase II was significantly expressed in mammary cancers from dogs and cats and immunoreactivity of TGase II was similar to that reported in humans beings. The pro-survival effect of TGase II in canine mammary carcinoma cell lines was similar to that previously reported in humans patients.

Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats.

Intravenously administered docetaxel (DT) is problematic in cats because of the requirement for premedication to ameliorate acute vehicle-induced hypersensitivity reactions. Previously we have revealed that therapeutic plasma concentrations of DT can be achieved in normal and tumor-bearing dogs when DT is administered PO in combination with oral cyclosporin A (CSA). The purpose of this study was to identify the maximally tolerated dosage and characterize the pharmacokinetic disposition of oral DT combined with CSA in cats with tumors. Eighteen tumor-bearing cats were enrolled in this phase I dose escalation and pharmacokinetic study. DT was administered by gavage with CSA (5 mg/kg) twice over a 3-week period. The starting dose of DT was 1.0 mg/kg. Based on the clinical toxicity profile, with gastrointestinal adverse effects and hematologic toxicity the maximal tolerated dose of oral DT was 1.75 mg/kg in combination with 5 mg/kg CSA. Additional studies are necessary to determine the efficacy of DT/CSA in cats with epithelial tumors.

Use of insulation to reduce extremity temperature nonuniformity during whole body hyperthermia in dogs.

Previously we have shown in dogs that tibial bone marrow and s.c. tissue temperatures are lower than rectal temperature during the plateau phase of whole body hyperthermia with the use of a radiant heating device. In an attempt to increase thermal dose to these sites during whole body hyperthermia, we applied insulation to an extremity prior to the plateau phase of heating. We found that extremity insulation during whole body hyperthermia resulted in increased s.c. tissue and tibial bone marrow temperatures. With insulation, tibial bone marrow and rectal temperature were nearly equal but s.c. tissue temperature, although greater than without insulation, remained lower than rectal temperature. High efficiency extremity insulation or supplemental heating techniques may be necessary during whole body hyperthermia with the use of the radiant heat device in order to assure that extremities receive the prescribed thermal dose.

Determination of continuous atracurium infusion rate in dogs undergoing whole-body hyperthermia.

Infusion rates for atracurium were calculated from multiple bolus injection data for normothermic (38 degrees C; n = 4) and hyperthermic (42 degrees C; n = 14) dogs anesthetized with thiopental and oxymorphone while undergoing whole-body hyperthermia treatment. The calculated infusion rate for atracurium at 38 degrees C was 6.2 +/- 0.3 micrograms/kg/min and the calculated infusion rate at 42 degrees C was 8.5 +/- 0.4 micrograms/kg/min. Infusion of atracurium at the calculated infusion rate of 8.5 micrograms/kg/min produced an estimated 90-100% neuromuscular blockade during heating from 38-42 degrees C and at 42 degrees C. Following discontinuation of the infusion and cooling to 38 degrees C, neuromuscular function returned to normal within 20 min with no evidence of recurarization. Atracurium infusion rates appear to be linear and related to body temperature from 26-42 degrees C. Clinically useful neuromuscular blockade in dogs may be obtained during whole-body hyperthermia by utilizing the 42 degrees C atracurium infusion rate throughout the 38-42 degrees C heating phase.

Development and characterization of an isolated and perfused tumor and skin preparation for evaluation of drug disposition.

The purpose of this study was to develop a model in which the regional pharmacokinetics of a drug in tumor and nontumorous tissue could be evaluated under a variety of physiological conditions. To this effect, the growth of a human choriocarcinoma cell line (JAR) was evaluated in pigs immunosuppressed with 25 mg cyclosporine/kg every 24 h. During an initial study, we demonstrated that suspensions containing approximately 3 million JAR cells with and without 1 million normal human fibroblasts injected s.c. into the inguinal region of pigs resulted in the growth of tumors consisting primarily of polygonal neoplastic cells. Multinucleate tumor cells, inflammatory cells, necrotic debris, and vascular endothelial cells were also present. Maximal tumor size was noted on day 12, after which time tumor regression occurred. The coinoculation of fibroblasts resulted in significantly larger tumors. Two single pedicle, axial pattern tubed flaps were created in the inguinal area of 4 pigs. JAR cells and fibroblasts were transplanted to one flap to allow for tumor formation. The other flap served as a nontumorous control. Both flaps were removed for perfusion with a physiological solution 11 days later. Glucose utilization, lactate concentrations, lactate dehydrogenase activities, and microscopic evaluation of skin samples were used to assess flap viability. All flaps remained viable for 8 h of perfusion. The only differences detected between nontumorous and tumor flaps was the initial perfusion pressure which was significantly lower in tumor flaps (P < 0.05). The isolated perfused tumor and skin flap is unique in that it consists of a tumor surrounded by normal tissue with an intact microvascular system and can be utilized to design regional pharmacokinetic studies describing drug distribution in tumor tissue.

Unexpected toxicity associated with use of body surface area for dosing melphalan in the dog.

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m2 of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, less than 1500/mm3; and/or thrombocytopenia, less than 80,000/mm3), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively. It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

Nonuniform alteration of cis-diamminedichloroplatinum(II) tissue distribution in dogs with whole body hyperthermia.

The purpose of this study was to investigate the pharmacokinetics and tissue disposition of cisplatin (CDDP) in euthermic and hyperthermic dogs to determine if hyperthermic alteration of tissue CDDP concentration is uniform. Eighteen female beagle dogs received 20, 50, or 80 mg/m2 CDDP by constant infusion for 60 min under normothermic or hyperthermic conditions (n = 3/subgroup). Blood, plasma, and ultrafiltered plasma samples were collected during the infusion. At termination of infusion, animals were immediately sacrificed, all major tissues were collected, and platinum levels were determined by atomic absorption spectroscopy. Platinum concentrations in all blood fractions of hyperthermic dogs tended to be lower than those of normothermic dogs. The correlation between dose and blood area under the concentration-time curve was linear at both temperatures. Each tissue concentration was normalized for that individual dog's blood area under the curve. The ratio of relative extraction at 42 degrees C to that at 37 degrees C were compared for each tissue. Values of 1.0 were interpreted as indicating uniform relative tissue extraction at each temperature. Values of greater than 2.0 were obtained in lung and ileum, while values of greater than 1.5 were obtained in liver, adrenal, stomach, colon, duodenum, spleen, and pancreas. Values of less than 1.0 were obtained in skin and superficial lymph nodes. These results indicate that hyperthermia significantly alters the pattern of CDDP tissue disposition in a nonuniform manner and that pharmacokinetic data obtained at one temperature, e.g., areas under the curve, cannot be used to directly predict tissue concentrations at another temperature.

Temperature measurements in normal and tumor tissue of dogs undergoing whole body hyperthermia.

Temperature was measured in the left ventricle, aorta, liver, brain, lung, bone marrow, kidney, and spontaneous solid tumors in dogs undergoing whole body hyperthermia in a radiant heat device. Rectal temperature was found to be a satisfactory indicator of systemic arterial temperature during plateau temperature conditions but rectal temperature underestimated arterial temperature during heating and overestimated it during cooling. Lung temperature, based on small airway temperature, was the same as rectal temperature during plateau temperature conditions. Liver and brain temperatures were slightly higher (0.1-0.2 degree C) than rectal temperature during the plateau phase. During plateau temperature conditions, kidney temperature measurements were higher than rectal temperature when one site/kidney was measured but were lower than rectal temperature when two sites/kidney were measured suggesting invasive thermometry may have affected measured temperature values. Tibial marrow temperature was greater than rectal temperature during heating but fell below rectal temperature during plateau temperature conditions by as much as 1.3 degree C. Femoral marrow temperature was below rectal during heating but gradually exceeded it during steady state conditions, by 0.1-0.4 degree C. Temperature in solid tumors was variable, sometimes exceeding (0.6 degree C) and sometimes being less (1.8 degree C) than rectal temperature.

Effect of P-wave timing during supraventricular tachycardia on the hemodynamic and sympathetic neural response.

BACKGROUND: Previous studies have shown the importance of the timing of atrial and ventricular systole on the hemodynamic response during supraventricular tachycardia (SVT). However, the reflex changes in autonomic tone during SVT remain poorly understood. METHODS AND RESULTS: Eleven patients with permanent dual-chamber pacemakers were enrolled in the study. Arterial blood pressure (BP), central venous pressure (CVP), and peripheral muscle sympathetic nerve activity (SNA) were recorded during DDD pacing at a rate of 175 bpm (cycle length 343 ms) with an atrioventricular (AV) interval of 30, 200 and 110 ms, simulating tachycardia with near-simultaneous atrial and ventricular systole, short-RP tachycardia (RPPR). Each pacing run was performed for 3 minutes separated by a 5-minute recovery period. All patients demonstrated an abrupt fall in BP, an increase in CVP, and an increase in SNA regardless of the AV interval. The decreases in SBP, DBP, and MAP and the increase in CVP were significantly less during long-RP tachycardia (AV interval 110 ms) than during the other 2 pacing modes (P:<0.05), and the increase in SNA in 7 of the 11 patients was significantly greater during closely coupled atrial and ventricular systole than during long-RP tachycardia (P:<0.05). CONCLUSIONS: These data suggest that the superior maintenance of hemodynamic stability during long-RP tachycardia is accompanied by reduced sympathoexcitation, which is primarily mediated by the arterial baroreceptors, with a modest cardiopulmonary vasodepressor effect.

Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction.

BACKGROUND: Although there have been few studies in which the hemodynamic effects of right ventricular (RV) and left ventricular (LV) pacing were compared with those of biventricular (BV) pacing, the autonomic changes during these different pacing modes remain unknown. We hypothesized that BV pacing results in improved hemodynamics and a decrease in sympathetic nerve activity (SNA) compared with single-site pacing. METHODS AND RESULTS: Thirteen men with a mean ejection fraction of 0.28+/-0.7 were enrolled in the study. Arterial blood pressure (BP), central venous pressure (CVP), and SNA were recorded during 3 minutes of right atrial (RA)-RV, RA-LV, and RA-BV pacing at a rate 10 beats faster than sinus rhythm. BP was greater during LV (151+/-7/85+/-3 mm Hg) and BV (151+/-6/85+/-3 mm Hg) pacing than during RV pacing (146+/-7/82+/-3 mm Hg) (P:<0.05). There were no differences in CVP among all pacing modes (P:=0.27). SNA was significantly less (P:<0.02) during both LV (606+/-35 U) and BV (582+/-41 U) pacing compared with RV pacing (685+/-32 U) (P:<0.02). Although not statistically significant (P:=0. 08 to 0.14), there was a trend for patients with a narrow QRS to have a lower mean BP and higher SNA during LV pacing than during BV pacing (r=0.42 to 0.49). CONCLUSIONS: LV-based pacing results in improved hemodynamics and a decrease in SNA compared with RV pacing in patients with LV dysfunction regardless of the QRS duration.

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.

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.

Pharmacokinetics and toxicity of intraperitoneal cisplatin combined with regional hyperthermia.

Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT.

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.

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.

Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm?

OBJECTIVES: This study sought to examine the hemodynamic and autonomic dose response to digoxin. BACKGROUND: Previous studies have demonstrated an increase in contractility and heart rate variability with digitalis preparations. However, little is known about the dose-response to digoxin, which has a narrow therapeutic window. METHODS: Nineteen patients with moderate heart failure and a left ventricular ejection fraction < 0.45 were studied hemodynamically using echocardiography and blood pressure at baseline and after 2 weeks of low dose (0.125 mg daily) and 2 weeks of moderate dose digoxin (0.25 mg daily). Loading conditions were altered with nitroprusside at each study. Autonomic function was studied by assessing heart rate variability on 24-h Holter monitoring and plasma norepinephrine levels during supine rest. RESULTS: Low dose digoxin provided a significant increase in ventricular performance, but no further increase was seen with the moderate dose. Low dose digoxin reduced heart rate and increased heart rate variability. Moderate dose digoxin produced no additional increase in heart rate variability or reduction in sympathetic activity, as manifested by heart rate, plasma norepinephrine or low frequency/high frequency power ratio. In addition, we did not find that either low or moderate dose digoxin increased parasympathetic activity. CONCLUSIONS: We conclude that moderate dose digoxin provides no additional hemodynamic or autonomic benefit for patients with mild to moderate heart failure over low dose digoxin. Because higher doses of digoxin may predispose to arrhythmogenesis, lower dose digoxin should be considered in patients with mild to moderate heart failure.

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.

Incidence of symptomatic atrial fibrillation in patients with paroxysmal supraventricular tachycardia.

OBJECTIVES: This study was performed to determine the incidence of symptomatic, sustained atrial fibrillation in a group of patients with paroxysmal supraventricular tachycardia. The effects of the mechanism of paroxysmal supraventricular tachycardia (atrioventricular [AV] node reentry vs. AV reentry through an accessory pathway) and heart rate during the tachycardia on the occurrence of atrial fibrillation were also assessed. BACKGROUND: There is a substantial incidence of atrial fibrillation in patients with paroxysmal supraventricular tachycardia, but the precise incidence and the factors that determine it are unknown. METHODS: One hundred sixty-nine patients with paroxysmal supraventricular tachycardia were followed up by regular clinic visits and transtelephonic electrocardiographic monitoring during symptomatic episodes of arrhythmia. The Kaplan-Meier product-limit method was used to estimate the proportion of patients remaining free of atrial fibrillation during the observation period. The Cox proportional hazards model was used to assess the effect of mechanism and heart rate during paroxysmal supraventricular tachycardia on the atrial fibrillation-free period. RESULTS: Thirty-two (19%) of the 169 patients had an episode of atrial fibrillation during a mean follow-up period of 31 months. The cumulative percent of patients experiencing an episode of atrial fibrillation was 6% within 1 month, 9% within 4 months and 12% within 1 year. The mechanism of paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio corresponding to classification in the AV node reentry group was 0.8 (p > 0.6). The heart rate during paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio associated with an increase in heart rate of 50 beats/min during the tachycardia was 1.15 (p > 0.5). CONCLUSIONS: This study suggests that atrial fibrillation will develop in approximately 12% of patients with paroxysmal supraventricular tachycardia during a 1-year follow-up period. The occurrence of atrial fibrillation is not related to the mechanism or heart rate of the paroxysmal supraventricular tachycardia.

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.

Bidisomide (SC-40230), a new antiarrhythmic agent: initial study of tolerability and pharmacokinetics.

Forty-nine healthy male volunteers received the test article for bidisomide (SC-40230) in a double-blind, placebo-controlled, dose-ranging study. Intravenous doses ranged from 0.03 to 2.5 mg/kg. There was a close relationship between the dose and the peak plasma concentration. The PR, QRS, QT, RR, and QTc intervals each demonstrated a statistically significant response to the dose administered. The PR and QRS intervals lengthened and the other intervals shortened (although to a lesser degree). The compound was well tolerated, with mild symptoms only at higher doses. Bioavailability was studied in 12 male volunteers, with each receiving 2.0 mg/kg of bidisomide, both orally and intravenously, in an open-label crossover trial. After a 10-minute zero-order intravenous infusion, bidisomide plasma levels could best be described in terms of a three-compartment pharmacokinetic model with the mean half-life values of alpha, beta, and gamma phases of 0.12, 1.77, and 12.3 hours, respectively. The mean absolute oral bioavailability was 43%.