Rapid Administration of High-Dose Human Antibody Fab Fragments to Dogs: Pharmacokinetics and Toxicity

Rapid Administration of High-Dose Human Antibody Fab Fragmentsto Dogs: Pharmacokinetics and Toxicity. Keyler, D. E., Salerno,D. M., Murakami, M. M., Ruth, G., and Pentel, P. R. (1991).Fundam. Appl Toxicol 17, 83-91. The treatment of drug overdosewith drug-specific antibody fragments may require very highantibody doses. To address the feasibility of this therapy,we studied the pharmacokinetics and toxicity of high-dose humannonspecific Fab fragments in beagles. Three dogs received 5.3g/kg Fab iv over 1 hr. Because nephrotoxicity was observed,three subsequent dogs received 3.2 g/kg. The fraction of theFab dose excreted in urine (10 ± 6%%) was lower thanreported values for either high or low doses of Fab in otherspecies. The terminal serum elimination half-life (42 hr forthe higher and 48 hr for the lower dose) was also longer thanreported values for other species, due to lower renal and nonrenalFab clearance. Fab administration was tolerated without adversehemodynamic effects. One of three dogs at each dose developedtransient oliguria. All dogs developed a transient but markedincrease in the serum creatinine concentration. At 2 weeks creatinineclearance had returned to normal. Urinary protein and albuminexcretion at 2 weeks were within the normal range for dogs butwere increased over their baseline values. The histology ofall organs was normal at 3 weeks by light microscopy, and renalhistology by electron microscopy was also normal. The mechanismof Fab nephrotoxicity, not observed previously with high-doseFab in rats or lower doses of Fab in other species includingdogs, is not clear. These data suggest that further study ofthe potential toxicity of high-dose Fab, and its reversibility,is needed to assess the feasibility of treating drug overdosewith this antibody fragment The long terminal half-life of high-doseFab in the dog and its low renal clearance contrast with valuesobserved with lower doses of Fab in other species but wouldnot be expected to preclude the use of high-dose Fab for drugoverdose.     

Safety and Effectiveness of Transvenous Lead Extraction in Octogenarians

Transvenous Lead Extraction . Introduction: As the population ages, the number of elderly patients with implantable cardiac devices referred for transvenous lead extraction will dramatically increase in Western countries. The safety and effectiveness of lead extraction in elderly patients has not been well evaluated. We report the safety and effectiveness of transvenous lead extraction in octogenarians. Methods and Results: From January 2005 to January 2011, we reviewed data from consecutive patients ≥ 80 years referred to our institutions for transvenous lead extraction because of cardiac device infection or lead malfunction. Clinical characteristics, procedural features, and periprocedural major and minor complications were compared between octogenarians and younger patients. Out of 849 patients undergoing lead extraction in the participating institutions during the study period, 150 (18%) patients were octogenarians (mean age 84 years; range 80–96; 64% males). A significantly higher percentage of octogenarians presented with chronic renal failure (55% vs 26%; P < 0.001), history of malignancy (22% vs 6%; P < 0.001), and chronic obstructive pulmonary disease (46% vs 19%; P < 0.001). Complete lead extraction rates were similar in the 2 age groups (97% in octogenarians vs 96% in patients <80 years; P = 0.39). Periprocedural death occurred in 2 (1.3%) patients ≥80 years and in 5 (0.72%) patients <80 years (P = 0.45 for comparison). No differences in terms of other periprocedural major and minor complications were found between the 2 age groups. Conclusion: Despite presenting with a significantly higher rate of comorbidities, transvenous lead extraction can be performed safely and successfully in octogenarians. (J Cardiovasc Electrophysiol, Vol. 23 pp. 1103‐1108, October 2012)     

Pancreatic amylase release in chronically pilocarpine-treated rats

The neuronal and glial release of (³H)-GABA from rabbit retina has been studied. The results indicate, that neither are there any glutamate, aspartate or glycine receptors on the GABA accumulating neurons, nor any GABA autoreceptors. (³H)-GABA was found to be released by 40 mM K⁺ from retinal neurons, but not from glia, and the release was not dependent on extracellular Ca⁺⁺. This indicates a release from a non vesicular transmitter pool. Ouabain has been proposed as a pharmacological tool for studying the release of (³H)-GABA located in neuronal cytoplasm. However, it induced an increased release of (³H)-GABA from both neurons and glia and it is therefore unlikely that it can be used for the specific purpose of studying release from neuronal cytoplasm.     

The Efficacy of Propafenone for Treatment of Ventricular Ectopic Depolarizations

Propafenone is an effective agent for suppression of chronic ventricular ectopic depolarizations. Complete elimination of nonsustained ventricular tachycardia is achieved in most patients treated with propafenone. The efficacy of propafenone is best correlated with its prolongation of the PR and QRS intervals whereas its plasma level is a poor predictor of therapeutic efficacy. Although serious side effects do occur with propafenone therapy and the drug must be discontinued in some patients, successful therapy of patients for up to four years has been reported.     

Electroanatomic Mapping and Ablation of Macroreentrant Atrial Tachycardia: Comparison Between Successfully and Unsuccessfully Treated Cases

Ablation of Macroreentrant Atrial Tachycardia. Introduction: Ablation of macroreentrant atrial tachycardia (MRAT) is demanding and identification of predictors of failure may be of help in patient management. This study compares the characteristics of successfully versus unsuccessfully treated patients undergoing electroanatomic mapping (EAM) and ablation of MRAT. Methods and Results: Consecutive patients undergoing EAM and ablation of MRAT were included. Ablation was linearly placed at the mid‐diastolic isthmus (MDI) to achieve arrhythmia interruption and conduction block. Variables were analyzed for predictors of both procedural failure and cumulative failure (procedural failure + early recurrences). Fifty‐two patients (37 M; age 64 ± 16 years) with 56 MRATs were considered. The MRAT was in the right atrium in 25 morphologies (45%) and 32 (57%) showed a double‐loop reentry. Fifty‐one morphologies (91%) in 47 patients were successfully treated; 3 patients had early recurrences of the same MRAT. None of the clinical variables considered significantly differed in the successfully treated group as compared to the unsuccessfully treated. Conversely, there was a significant difference as to the EAM characteristics: successfully treated cases showed a narrower target isthmus with a lower voltage amplitude and slower conduction velocity (CV). In the MDI, a CV >60 cm/sec and a width >40 mm were the strongest predictors of procedural failure and cumulative failure, respectively. Conclusions: In this patient population, while the clinical variables did not differ significantly, there was a significant difference in the EAM characteristics between successfully and unsuccessfully treated cases. CV and width of the isthmus target for ablation were the strongest independent predictors of procedure outcome. (J Cardiovasc Electrophysiol, Vol. 21, pp. 155‐162, February 2010)     

Part IV: Class II,Class III,and Class IV Antiarrhythmic Drugs,Comparative Efficacy of Drugs,and Effect of Drugs on Mortality — A Review of Their Pharmaco kinetics,Efficacy, and Toxicity*

Part IV: Class II, Class III, and Class IV antiarrhythmic drugs, comparative efficacy of drugs, and the effect of drugs on mortality — review of their pharmacokinetics, efficacy, and toxicity. This part reviews the Class II antiarrhythmic agents that share the property of beta adrenergic antagonism, but include several drugs with other unique features. Also reviewed are the Class III agents, which prolong the action potential duration, with a focus on amiodarone. The Class IV agents, which antagonize the calcium channel, are reviewed. Finally, this part reviews the comparative efficacy of antiarrhythmic agents for treatment of ventricular ectopic depolarizations and examines their effect on mortality.     

Review article: Luminex technology for HLA antibody detection in organ transplantation

Since its inception in the early 1960s, the serologically based complement-dependent cytotoxicity (CDC) assay has been the cornerstone technique for the detection of human leucocyte antigen (HLA) antibodies, not only in pre-transplant renal patients, but also in other forms of organ transplantation. Recently, solid phase assays have been developed and introduced for this purpose, and in particular the Flow-based bead assays such as the Luminex system. This latter assay has proved to be far more sensitive than the CDC assay and has revealed pre-sensitization in potential transplant recipients not detected by other methods of HLA antibody detection. However, the clinical implications of this increased sensitivity have not been convincingly demonstrated until recently. This technology for HLA antibody detection permits the evaluation of the clinical importance of antibodies directed at, for example, HLA-DPB1 and HLA-DQA1, which has not been possible to date. There are Luminex issues, however, requiring resolution such as the ability to distinguish between complement fixing and non-complement fixing antibodies and determination of their relative clinical significance. Luminex technology will permit a re-evaluation of the role of HLA antibodies in both early and late antibody-mediated rejection.     

Serum Electrolytes and Catecholamines After Cardioversion From Ventricular Tachycardia and Atrial Fibrillation

We have observed hypokalemia after cardioversion from spontaneous out-of-hospital ventricular fibrillation and induced ventricular tachycardia. To test the hypothesis that the hormone response to the hemodynamic stress of the arrhythmia initiated the change in potassium, we compared the electrolytes and hormones in three groups of patients. We observed a decrease in serum potassium and magnesium after cardioversion from ventricular tachycardia induced by programmed Stimulation but not after normal programmed stimulation of the ventricle or after cardioversion from stable atrial fibrillation. These changes were preceded first by a rise in norepinephrine and epinephrine then a rise in glucose, followed by a rise in insulin. The stimulus for these changes was probably the hypotension associated with ventricular tachycardia. The sequence of changes suggests that the decrease of potassium and magnesium after ventricular tachycardia was due to a shift of the electrolytes into cells related to the insulin-mediated movement of glucose from the blood into cells.