ABSTRACT
PURPOSE: Gabapentinoids are currently the mainstay of pharmacological treatments for patients with neuropathic pain. Little is known about the effects of this therapy on the integrity of neuronal networks, especially in patients with an already-damaged nervous system. Since gabapentinoids can worsen cognitive functions and recent studies have shown alterations in the brains of patients with neuropathic pain, it may be possible that these drugs have neurotoxic effects. METHODS: Rat clonal PC12 pheochromocytoma (autonomic) and primary sensory dorsal-root ganglion (DRG) neurons from newborn Wistar rats were employed for this study. To mimic neuronal damage, cells were exposed to cytotoxins using either hydrogen peroxide (H2O2) or vincristine. RESULTS: No direct cytotoxic effects were observed after incubating PC12 cells for 24 hours with increasing concentrations of gabapentin or pregabalin using MTT cytotoxicity assays. Even a 7-day incubation did not cause cellular damage. Furthermore, in preinjured PC12 and DRG neurons, neither gabapentin nor pregabalin prevented or enhanced the cytotoxic effects of H2O2 or vincristine after incubation for 24 hours and 7 days, respectively. Cell morphology and integrity of the cytoskeleton assessed by employing immunostaining of cytoskeletal proteins (α-tubulin, neurofilament L) remained intact and were not altered by gabapentinoids. CONCLUSION: Based on these results, gabapentinoids are unlikely to be neurotoxic in cultured autonomic (PC12) and sensory DRG cells, even when cells are preinjured. These results are of high clinical relevance, as it seems unlikely that the morphological changes recently observed in the brains of neuropathic pain patients are caused or worsened by gabapentinoids.
ABSTRACT
BACKGROUND: Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence. METHODS AND RESULTS: Rhythm histories of 647 patients (mean AF burden, 0.12±0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM (P<0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity (P<0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged-duration IRM to achieve the same sensitivity as in low-density AF (P<0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence. CONCLUSIONS: IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00806689.
