Evaluation of Chelating Drugs on the Toxicity, Excretion, and Distribution of Nickel in Poisoned Rats

Evaluation of Chelating Drugs on the Toxicity, Excretion, andDistribution of Nickel in Poisoned Rats. ATHAR, M., MISRA, M.,AND SRIVASTAVA, R. C. (1987). Fundam. Appl. Toxicol. 9,26–33.The effects of various doses of two macrocyclic drugs, namely,1,4,8,11-tetraazacyclotetradecane (Cyclam) and 5,7,7', 1 2,14,14'-hexamethyl-1,4,8,11-tetraazacyclotetradecane (Cyclam s), on the toxicity, distribution,and excretion of nickel were evaluated in nickel-poisoned ratsand compared with the linear counterpart triethylenetetraamine(TETA) and a tripeptide, glutathione (GSH). Cyclam and Cyclams revealed a higher order of efficacy against the lethal responseof nickel even at a lower dose. These drugs significantly enhancedthe urinary and biliary excretion of nickel and restored thealtered levels of trace metals (viz., Cu, Zn, Fe, Mn) comparedto TETA and GSH. The efficacy of these drugs in vivo may berelated to their ability to transport nickel across an artificiallipid membrane, a phenomenon was not exhibited by TETA or GSH.     

Clinical Experience with the Intertach 262-12 Pulse Generator in Patients with Recurrent Supraventricular and Ventricular Tachycardia

FROMER, M., ET AL.: Clinical Experience with the Intertach 262-12 Pulse Generator in Patients with Recurrent Supraventricular and Ventricular Tachycardia. An antitachycardia pulse generator, the Intermedics Intertach 262-12 was implanted in 16 patients (14 patients with supraventricular tachycardia of various origins and two patients with recurrent ventricular tachycardia), who were not responsive to various antiarrhythmic drug regimens. The follow-up was from 6–49 months (mean 30.9 ± 13.8). Five patients had a follow-up of over 3 years. The device was used in all patients. One patient with ventricular tachycardia died from a nonarrhythmic cause. Loss of responsiveness to burst pacing was observed in 1/14 patients with supraventricular tachycardia and nontolerance of antitachycardia pacing in one patient. Overall clinical success of pacing was observed in 13/16 patients = 81%. The pacemaker proved to be a versatile system with reliable tachycardia detection and termination functions.     

Atrioventricular Nodal Conduction and Refractoriness Following Abrupt Changes in Cycle Length

The properties of the atrioventricular (AV) nodal conduction and effective refractory period in man are generally evaluated at a constant basic cycle length (CL) and, in most cases, they demonstrate an inverse relationship to the drive cycle. The response of AV node to abrupt change in CL is less defined. We therefore studied the effects of abrupt changes in CL on AV nodal conduction time and refractoriness in 18 patients. AV nodal conduction time, and effective and functional refractory periods were measured during: (1) a constant long CL, (2) a constant short CL, and (3) after an abrupt increase in CL just prior to the introduction of extrastimuli. In 10 of the 18 patients a constant long CL of 600 ms, a constant short CL of 400 ms and a sudden short-to-long change in CL (400 to 600 ms) were tested. AV nodal conduction times (A2H2) were measured at the shortest and longest comparable A1A2 intervals. The mean value of the shortest A2H2 intervals for constant CL of 600 ms was 144 +/- 18 ms; for a constant CL of 400 ms it was 162 +/- 17 ms; after a sudden short-to-long change in CL (400 to 600 ms) it was 142 +/- 14 ms. The mean value of the longest A2H2 intervals at a constant CL of 600 ms was 185 +/- 18 ms; at a constant CL of 400 ms it was 236 +/- 26 ms (p less than 0.01) and after a short-to-long change in CL (400 to 600 ms) 199 +/- 21 ms. AV nodal effective refractory periods measured at the same three CLs had mean values of 279 +/- 13 ms; 300 +/- 15 ms and 294 +/- 13 ms, respectively. Similar results were obtained when other CLs such as 700 to 900, 500 to 900, and 400 to 700 ms were tested. The data suggest that after abrupt short-to-long changes in CL, AV nodal function curves shift from long constant CL toward short constant CL as the coupling intervals decrease, indicating a cumulative pattern. Although the return to baseline conduction time after the fast basic rate is known to be slow, the limitation of this effect to the very early premature beat in the human has not been reported previously.     

Bundle Branch Reentrant Ventricular Tachycardia:

Sustained Bundle Branch Reentrant Tachycardia. introduction: The clinical, electrophysiologic features and follow-up of 48 patients with inducible bundle branch reentrant (BBR) tachycardia are presented. Methods and Results: Forty-eight patients were identified in whom a diagnosis of BBR tachycardia was made during electrophysiologic evaluation. The clinical presentation was syncope or sudden death in 38 patients, and sustained palpitations during wide QRS complex tachycardia in 5 patients. Electrophysiologic studies were performed in 5 additional patients for various other reasons. Structural heart disease was present in 45 patients. Idiopathic dilated cardiomyopathy and coronary artery disease were the anatomical substrates in 19 (39%) and 24 (50%) patients, respectively, severe aortic regurgitation was present in 2 patients, and no organic heart disease was identified in 3. All 48 patients had evidence of His-Purkinje system disease. BBR tachycardia with left and right bundle branch block morphologies was induced in 46 and 5 patients, respectively, and interfascicular BBR tachycardia was initiated in 2 patients. Ventricular tachycardia of a myocardial origin was induced in 11 patients. Management of BBR tachycardia included transcatheter bundle branch ablation in 28 patients, and antiarrhythmic drug therapy in 16 patients. Four patients were treated with implantablc defibrillators. After a mean follow-up of 15.8 months in 42 patients, there were 13 deaths due to congestive heart failure, 4 sudden cardiac deaths, 3 nonsudden cardiac deaths, and 3 noncardiac related deaths. Conclusion: Sustained BBR, a form of monomorphic ventricular tachycardia, is a highly malignant arrhythmia usually seen in patients with structural heart disease. Three different types of BBR tachycardia are described. If distinguished from ventricular tachycardia of a myocardial origin, catheter ablation of the right bundle branch can be easily performed and effectively eliminates BBR. During follow-up, congestive heart failure is the most common cause of death in this population.     

Anticancer efficacy of 3-(4-isopropyl) benzylidene-8-ethoxy, 6-methyl,chroman-4-one (SBL-060), a novel,dual, estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells

Estrogen receptor (ER) α is expressed in a subset of patient-derived acute myeloid leukemia (AML) cells,whereas Akt is predominantly expressed in most types of AML. Targeting AML with dual inhibitors is a novelapproach to combat the disease. Herein, we examined a novel small molecule, 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one (SBL-060), capable of targeting AML cells by inhibiting ERα and Akt kinase. The chemicalproperties of SBL-060 were identified by proton nuclear magnetic resonance (¹H-NMR), ¹³C-NMR, and massspectroscopy. In silico docking was performed using an automated protocol with AutoDock-VINA. THP-1 and HL-60cell lines were differentiated using phorbol 12-myristate 13-acetate. ERα inhibition was assessed using ELISA. TheMTT assay assessed cell viability. Flow cytometry was performed for cell cycle, apoptosis, and p-Akt analyses.Chemical analysis identified the compound as 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one, whichshowed high binding efficacy toward ER, with a ΔG_binding score of −7.4 kcal/mol. SBL-060 inhibited ERα, exhibitingIC₅₀ values of 448 and 374.3 nM in THP-1 and HL-60 cells, respectively. Regarding inhibited cell proliferation, GI₅₀values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells, respectively. In addition, a dose-dependentincrease in sub G₀/G₁ phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in bothcell types. SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells.Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Aktkinase, warranting further preclinical evaluations.     

Experience with Two Different Nonthoracotomy Systems for Implantable Defibrillator in 170 Patients

Implantation of a nonthoracotomy system (Medtronic PCD or CPI Endotak) was attempted in 170 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) not requiring concomitant cardiac surgery. A nonthoracotomy system could be successfully implanted in 95 of the 115 patients with the PCD system and 49 of 55 patients receiving the Endotak lead system. In 26 patients with failed nontboracotomy system because of defibrillation threshold (DFT) > 25 joules (J), an epicardial system was implanted at the same setting. Patients receiving the two lead systems were comparable with regard to age, sex, and ejection fraction. However, since tbe PCD system offers tiered therapy multiprogrammable options, all attempts were made to implant tbis lead system in patients with VT that could be pace terminated. Mean DFT(15 ± 4.7 vs 17 ± 4.6 J;P = 0.03) and implant time (2.5 ± 0.6 vs 3.3 ± 0.7 hours; P = 0.02) were less with the Endotak lead system. There was no perioperative mortality. During a mean follow-up of 20 ± 4 months, there were eight instances of lead dislodgment in patients receiving the PCD system. Tbere were four nonsudden cardiac deaths and one sudden death in the Endotak group and three nonsudden deaths in the PCD group. Sudden cardiac death and total survival using the intention-to-treat analysis during this follow-up period were 99% and 95%, respectively. In conclusion, successful implantation, perioperative mortality, and survival rate are comparable with both lead systems; however, incorporating two defibrillating electrodes in one lead minimizes lead dislodgment and reduces implant time.     

Clinical Experience with a New Software-Based Antitachycardia Pacemaker for Recurrent Supraventricular and Ventricular Tachycardias

The Intermedics Intertach 262-12 tachycardia reversion pulse generator was implanted in 14 patients (six male, eight female, mean age at implantation 45 +/- 16 years) with recurrent symptomatic tachycardias. Six patients had atrioventricular (AV) nodal reentrant tachycardia, three patients had orthodromic tachycardia with Wolff-Parkinson-White syndrome, two had circus movement tachycardia via a concealed bypass tract, two had ventricular tachycardia, one patient had atrial flutter. Mean duration of symptoms before implantation was 8 +/- 4 years and mean number of antiarrhythmic drug trials was 3.5 +/- 1. The primary tachycardia response made consisted of autodecremental pacing in one patient, burst pacing in two patients, and adaptive scanning of the initial delay or burst cycle length in eleven patients. The secondary tachycardia response mode consisted of autodecremental pacing in four patients, burst pacing in three patients and burst scanning in four patients. Tachycardia response was automatic in all but one patient with ventricular tachycardia. During a follow-up period of 30.5 +/- 10.6 months, one patient with ventricular tachycardia died from a nonarrhythmic cause. Reinterventions were necessary due to electrode fracture in one patient and due to pacemaker software defect in another one. Two patients underwent surgical cure of their arrhythmia: one patient with atrial flutter and one patient with AV nodal reentry tachycardia, 24 months and 11 months postpacemaker implantation, respectively. Four patients required digitalis to prevent pacing induced atrial fibrillation. Other proarrhythmic effects were not encountered. The pacemaker proved to be a versatile system with reliable tachycardia detection and termination functions. It provided a valuable adjunctive therapy in these selected patients.     

Implantable Cardioverter Defibrillator for Prevention of Sudden Cardiac Deatb in Patients with Ventricular Tachycardia and Ventricular Fibrillation: ICD Therapy In Sudden Cardiac Death

Among the various therapy options for survivors of ventricular tachycardia-ventricular fibrillation (VT-VF), the implantable cardioverter defibrillator (ICD) seems most promising. It reliably terminates VT-VF and thus significantly impacts sudden cardiac death (SCD) survival. It is more effective than any of the known antiarrhythmic drugs in prevention of SCD, particularly among survivors of cardiac arrest. Compared to VT surgery, the ICD therapy can be offered to a larger pool of patients and can be placed at a lower surgical risk. With proper patient selection, ICD therapy is of major benefits to its recipients since it markedly reduces the chances of VT-VF relaled mortality; the main cause of premature death in this population. The ICD therapy is cost effective when compared to other medical interventions and could be more so if the implant is carried out early in the course of VT-VF management.