Pharmacodynamic monitoring of the immunosuppressive therapy in patients after heart transplantation: whole blood flow cytometric analysis of lymphocyte function

Despite therapeutic monitoring and daily measurements of blood concentrations (pharmacokinetics) of immunosuppressive medications, immunosuppressive therapy remains still a challenge after heart transplantation (HTx) due to drug interactions, toxicities and individual responses to drug effects. We established whole blood flow cytometric assays of lymphocyte function to assess the pharmacodynamics of immunosuppressive therapy and investigated both pharmacokinetic and pharmacodynamic approaches after HTx. Our results showed that pharmacodynamic measurements provide a more direct assessment of the functional activity of immunosuppressants on immune cells compared to drug level monitoring alone. The information from both pharmacokinetic and pharmacodynamic monitoring has the potential to increase the efficacy and safety of individual immunosuppressive therapy after HTx.     

Individuals With Chronic Neck Pain Have Lower Neck Strength Than Healthy Controls: A Systematic Review With Meta-Analysis

ObjectiveThe aim is to verify whether there is difference in neck strength between healthy individuals and individuals with chronic neck pain.MethodsThe PubMed, Embase, and Scopus databases were searched. Two independent reviewers selected relevant full articles comparing neck strength between healthy individuals and individuals with chronic neck pain. Two independent reviewers extracted the data from the full articles selected. A meta-analysis was used to assess standardized mean differences in neck strength based on a random-effects model (Prospero number CRD42017081502).ResultsThe search returned 3554 results; 15 articles were included. The chronic neck pain group showed lower neck strength compared with healthy individuals. The standardized mean difference was -0.90 (95% confidence interval [CI] = -1.13 to -0.67) for flexion, -0.79 (95% CI = -0.99 to -0.60) for extension, -0.74 (95% CI = -1.03 to -0.45) for right lateral flexion, and -0.75 (95% CI = -1.04 to -0.46) for left lateral flexion.ConclusionBased on this meta-analysis with a 3a level of evidence, individuals with chronic neck pain have lower neck strength for flexion, extension, and the lateral flexion of the neck than healthy controls.     

Desipramine prevents cardiac gap junction uncoupling

Background and purpose

Uncoupling of cardiac gap junction channels is an important arrhythmogenic mechanism in ischemia/reperfusion. Antiarrhythmic peptide AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH₂) has been shown to prevent acidosis-induced uncoupling and ischemia-related increase in dispersion. Previous structure–effect investigations and subsequent computer modeling studies indicated that the tricyclic antidepressant desipramine may exert similar effects as AAP10.

Methods

We assessed the binding of ¹⁴C-AAP10 to membranes of rabbit cardiac ventricles and its displacement with desipramine in a classical radioligand binding and competition study. Gap junction currents were measured between isolated pairs of human atrial cardiomyocytes under normal and acidotic (pH 6.3) conditions with or without 1?μmol/l desipramine using dual whole-cell voltage clamp. The effect of 1?μmol/l desipramine was assessed in isolated rabbit hearts (Langendorff technique) undergoing local ischemia by coronary occlusion with 256-channel electrophysiological mapping and subsequent analysis of connexin43 (Cx43) expression, phosphorylation (Western blot), and subcellular localization (immunohistology).

Results

We found saturable ¹⁴C-AAP10 binding to cardiac membranes (K _D, 0.29?±?0.11?nmol/l; B _max, 42.5?±?7.2 pmol/mg) which could be displaced by desipramine with a K _D.High?=?0.14?μmol/l and a K _D.Low?=?22?μmol/l. Acidosis reduced the gap junction conductance in human cardiomyocyte pairs from 24.1?±?4.7 to 11.5?±?2.5 nS, which could be significantly reversed by desipramine (26.6?±?4.8 nS). In isolated hearts, ischemia resulted in significantly increased dispersion of activation–recovery intervals, loss of membrane Cx43, and dephosphorylation of Cx43, which all could be prevented by desipramine.

Conclusion

Desipramine seems to prevent the uncoupling of cardiac gap junctions and ischemia-related increase in dispersion.