Effect of propranolol on ventricular repolarization and refractoriness: Role of beta-blockade versus direct membrane effects

Summary The purpose of this study was to define the role of beta-adrenergic blockade and direct membrane effects in the ability of dl-propranolol to alter ventricular repolarization and refractoriness in the intact heart. The effective refractory period (ERP) and the local Q-T interval were measured at an epicardial site in the left ventricle in 14 open-chest dogs anesthetized with alpha-chloralose. Beta-adrenergic influences were eliminated in seven dogs (group 1) by stellate transection and nadolol (0.5 mg/kg IV), and enhanced in seven dogs (group 2) by stellate transection and stimulation of the left ansae subclavia. Each dog received an initial beta-blocking dose of propranolol (0.5 mg/kg) followed by a second, cumulative dose of 5.0 mg/kg. In group 1 dogs, there was no significant change in either the ERP or local Q-T interval in response to the first dose of propranolol. In group 2 dogs, left stellate stimulation significantly shortened the ERP (20±2 msec) and the local Q-T interval (17±4 msec). The first dose of propranolol prolonged these parameters to values not different from prestimulation control values. There was no change in the H-V interval, QRS complex duration, or diastolic threshold (DT) in either group after the initial propranolol dose. The second dose of propranolol significantly shortened the ERP (5±1 msec) and the local Q-T interval (11±2 msec) in both groups. This dose also significantly increased the DT, H-V interval, and QRS complex duration. In three additional nadolol-treated dogs, a single 5 mg/kg dose of propranolol shifted the entire strength-interval curve 4 to 7 msec earlier into electrical diastole. The data indicate that a beta-blocking dose of propranolol prolongs repolarization and refractoriness only when adrenergic input is elevated. In the absence of beta-adrenergic influences, high doses of propranolol shorten repolarization and refractoriness. This latter effect may be due to a direct membrane effect of the drug.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Monocytoid B-cell lymphoma: its evolution and relationship to other low- grade B-cell neoplasms

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.     

A National Study of Australian Nurse Practitioners’ Organizational Practice Environment

The nurse practitioner (NP) workforce in Australia plays a vital role in helping the country meet the current demand for health care. Data from Australian NPs using the Nurse Practitioner Primary Care Organizational Climate Questionnaire demonstrated that one-seventh of the overall Australian NP population completed the study. The response was overwhelmingly positive in the area of practice; 71.6% of NPs had no restriction on their practice and felt valued by their organization. The results of this study enable a benchmark for ongoing national evaluations in addition to international comparative data.     

Targeting virulence not viability in the search for future antibacterials

New antibacterials need new approaches to overcome the problem of rapid antibiotic resistance. Here we review the development of potential new antibacterial drugs that do not kill bacteria or inhibit their growth, but combat disease instead by targeting bacterial virulence.