Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and Myelination

Several clinical conditions are associated with white matter injury, including periventricular white matter injury (PWMI), which is a form of brain injury sustained by preterm infants. It has been suggested that white matter injury in this condition is due to altered oligodendrocyte (OL) development or death, resulting in OL loss and hypomyelination. At present drugs are not available that stimulate OL proliferation and promote myelination. Evidence suggests that depolarizing stimuli reduces OL proliferation and differentiation, whereas agents that hyperpolarize OLs stimulate OL proliferation and differentiation. Considering that the drug diazoxide activates K(ATP) channels to hyperpolarize cells, we tested if this compound could influence OL proliferation and myelination.Studies were performed using rat oligodendrocyte precursor cell (OPC) cultures, cerebellar slice cultures, and an in vivo model of PWMI in which newborn mice were exposed to chronic sublethal hypoxia (10% O(2)). We found that K(ATP) channel components Kir 6.1 and 6.2 and SUR2 were expressed in oligodendrocytes. Additionally, diazoxide potently stimulated OPC proliferation, as did other K(ATP) activators. Diazoxide also stimulated myelination in cerebellar slice cultures. We also found that diazoxide prevented hypomyelination and ventriculomegaly following chronic sublethal hypoxia.These results identify KATP channel components in OLs and show that diazoxide can stimulate OL proliferation in vitro. Importantly we find that diazoxide can promote myelination in vivo and prevent hypoxia-induced PWMI

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Characteristics and health care utilization of otherwise healthy commercially and Medicaid-insured preterm and full-term infants in the US

Kimmie K McLaurin,1 Sally W Wade,2 Amanda M Kong,3 David Diakun,3 Ifedapo R Olajide,1 Jane Germano4 1US Medical Affairs, AstraZeneca, Gaithersburg, MD, USA; 2Wade Outcomes Research and Consulting, Salt Lake City, UT, USA; 3IBM Watson Health, Cambridge, MA, USA; 4Department of Pediatrics, MedStar Georgetown University Hospital, Washington, DC, USA Purpose: This study examined health care utilization and costs during the first year of life for preterm and full-term infants in the US. Subjects and methods: Preterm (&lt;37 weeks gestational age [GA]) and full-term infants born&nbsp;2003 to 2012 without complex medical conditions were identified in the MarketScan&reg; Commercial&nbsp;and Multi-State Medicaid claims databases using ICD-9-CM diagnosis and diagnosis-related&nbsp;grouping codes. Inpatient and outpatient claims from birth through the first year were&nbsp;analyzed for preterm and full-term subgroups. Results were stratified by payer. Results: There were 1,692,935 commercially insured infants (12.5% preterm) and 1,873,324 Medicaid-insured infants (13.9% preterm). The majority (&gt;75%) of preterm infants were admitted to the neonatal intensive care unit during their birth hospitalization. Generally, mean length of stay and costs for birth hospitalizations increased with decreasing GA. The average cost of a birth hospitalization was US $62,931 (SD$134,347) for commercially insured preterm infants and $43,858 (SD$115,412) for Medicaid-insured preterm infants compared to $2,401 (SD$7,399) and $1,894 (SD$5,444) for commercially insured and Medicaid-insured full-term infants, respectively. Post-neonatal hospitalization rates increased as GA decreased (in full-term&nbsp;to &lt;29 weeks GA: commercial =3.3%&ndash;19.5%; Medicaid =6.1%&ndash;26.2%). Preterm infants had&nbsp;greater average numbers of outpatient office visits and pharmacy claims than full-term infants.&nbsp;Following birth discharge, mean monthly health care costs per infant increased as GA decreased&nbsp;commercial = $334 to$3,126; Medicaid = $205 to$2,473).&nbsp;Conclusion: During the first year of life, post-neonatal hospitalization rates, outpatient office visits, pharmacy claims, and monthly costs increased as GA decreased. Keywords: claims database, premature, birth hospitalization, health care costs &nbsp