Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

Rationale Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). Objective Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. Methods The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. Results Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. Conclusions The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs

Biodegradable Polymer Versus Permanent Polymer Drug-Eluting Stents and Everolimus- Versus Sirolimus-Eluting Stents in Patients With Coronary Artery Disease 3-Year Outcomes From a Randomized Clinical Trial

ObjectivesThe aim of this study was to compare the 3-year efficacy and safety of biodegradable polymer with permanent polymer stents and of everolimus-eluting stents (EES) with sirolimus-eluting stents (SES).BackgroundBiodegradable polymer drug-eluting stents (DES) offer potential for enhanced late outcomes in comparison with permanent polymer stents. In addition, there is increasing interest in the comparison of EES (Xience, Abbott Vascular, Abbott Park, Illinois) versus SES (Cypher, Cordis Corporation, Miami Lakes, Florida).MethodsThe ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4) was a randomized clinical trial with broad inclusion criteria, enrolling 2,603 patients at 2 clinics in Munich, Germany. Patients were randomized to either biodegradable polymer (n = 1,299) or permanent polymer stents (n = 1,304); patients treated with permanent polymer stents were randomly allocated to EES (n = 652) or SES (n = 652). The primary endpoint was the composite of cardiac death, target vessel-related myocardial infarction, or target lesion revascularization.ResultsClinical events continued to accrue at a low rate out to 3 years in all groups. Overall, there was no significant difference between biodegradable polymer and permanent polymer DES with regard to the primary endpoint (20.1% vs. 20.9%, hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.80 to 1.13; p = 0.59). Rates of definite/probable stent thrombosis were also similar in both groups (1.2% vs. 1.7%, respectively; HR: 0.71, 95% CI: 0.37 to 1.39; p = 0.32). In patients treated with permanent polymer stents, EES were comparable to SES with regard to the primary endpoint (19.6% vs. 22.2%, respectively; HR: 0.87, 95% CI: 0.68 to 1.11; p = 0.26) as well as definite/probable stent thrombosis (1.4% vs. 1.9%, HR: 0.75, 95% CI: 0.32 to 1.78; p = 0.51).ConclusionsBiodegradable polymer and permanent polymer DES are associated with similar clinical outcomes at 3 years. In addition, EES are comparable to SES in terms of overall clinical efficacy and safety. (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting STents [ISAR-TEST 4]: Prospective, Randomized Trial of 3-limus Agent-eluting Stents With Different Polymer Coatings; NCT00598676