The relationship between sleep disorders and stroke

Although sleep appears to be a quiescent, passive state externally, there are a multitude of physiological changes occurring during sleep that can affect cerebral homeostasis and predispose individuals to cerebrovascular disorders. Therefore, it is not surprising that sleep-disordered breathing causes significant nocturnal perturbations, such as obstructive sleep apnea (OSA), that can lead to cerebrovascular disorders. There is evidence to suggest that OSA is a risk factor for stroke, although studies have not been able to clearly discern the absence or presence of OSA before the stroke event. Sleep-disordered breathing, such as OSA and central sleep apnea, can occur as a consequence of stroke. Fortunately, treating OSA appears to decrease morbidity and possibly mortality. Unfortunately, continuous positive airway pressure compliance in this population group is low, and significant efforts and resources may be needed to improve compliance and adherence. Various other sleep disorders, such as insomnia, fatigue, hypersomnia, and parasomnia, can occur following a stroke, and physicians treating patients following a stroke need to be aware of these disorders in order to effectively treat such patients.     

Sleep among opioid users

Use of opioids in the treatment of both acute and chronic pain has increased significantly in the past 2 decades. Recent literature suggests that chronic opioid use is related to sleep-related breathing disorders, particularly central sleep apnea of both the periodic and nonperiodic breathing pattern. The clinical significance, pathogenesis, and treatment options of these sleep-related breathing disorders are not well understood. This article summarizes the current literature on the effects of both acute and chronic opioid use on sleep, sleep-disordered breathing, and the current evidence on various treatment options for breathing disorders related to chronic opioid use.     

Vascular changes, cardiovascular disease and obstructive sleep apnea

Vascular changes related to obstructive sleep apnea (OSA) can lead to chronic cardiovascular consequences such as hypertension. The cardiovascular consequences are owing to nocturnal perturbations related to intrathoracic pressure changes, intermittent hypoxia, sympathetic neural activation, endothelial dysfunction, oxidative stress and systemic inflammation. Intermittent hypoxia due to sleep-related events in OSA activates the renin-angiotensin system and increases the levels of endothelin-1. Intermittent hypoxia also results in oxidative stress, as evidenced by elevated levels of xanthine oxidoreductase, lipid peroxidation and the presence of reactive oxygen species. There is also evidence for a decrease in antioxidant capacity. Patients with OSA may have endothelial dysfunction that resolves with continuous positive airway pressure. OSA is a state of inflammation as evidenced by elevated levels of C-reactive protein, IL-6, NF-κB, TNF-α, ICAM-1, VCAM-1 and E-selectin. This may suggest that OSA is a predisposing factor for atherogenesis. This article will discuss the role of nocturnal perturbations consequent to OSA resulting in endothelial dysfunction, oxidative stress, and inflammation and how they may subsequently play a causative role in cardiovascular disorders.     

Pathophysiologic and prognostic role of proinflammatory and regulatory cytokines as a proinflammatory and regulatory cytokine in dengue fever

PurposeCytokines are important immune-modulators and improper T-cell activation can lead to cytokine storms which are believed to result in endothelial permeability and leakage, a typical feature of Dengue disease progressing into a more severe stage. Many cytokines have been implied in causing severe Dengue manifestations among which IL-10 poses to be an important one. Inflammatory cytokines such as TNFα and IFN γ can be pointed out in Dengue pathogenesis and prognosis. Therefore, we sought to investigate the T cell activation of Dengue infected patients via these three markers and asses their levels and correlate cytokine levels with disease severity and clinical outcomes.MethodsSamples using standard blood collection techniques were obtained from patients with clinical signs suggestive of dengue. A haematological was obtained subsequently. Serological markers including IgM and NS1 were assessed using ELISA following which ELISA will be done for immunological markers including TNFα, IFN γ (markers of pro-inflammatory response and IL-10 (marker for regulatory response).ResultsThere was a significant correlation between IL10 and clinical features. There was no significant correlation between TNF alpha and clinical features. IFN gamma had a positive correlation with the clinical features. There was a positive cumulative correlation between clinical features, platelet counts, IL10 and TNF alpha but not with IFN gamma contrary to its correlation as a separate entity with just the clinical features.ConclusionsThe present study clearly indicates that IL10 is a highly sensitive marker of Severe Dengue and can be used as a screening tool in Secondary Dengue patients or those with warning signs. TNF alpha as it correlates strongly with patients with warning signs can be used for prognosis is patients presenting with symptoms. However, interferon gamma correlates strongly with low platelet counts and can be a measure to screen patients presenting with fever with thrombocytopenia.     

Galangin,a dietary flavonol inhibits tumor initiation during experimental pulmonary tumorigenesis by modulating xenobiotic enzymes and antioxidant status

The aim of present study was to elucidate anti-initiating efficacy of galangin against benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in male Swiss albino mice. Therefore, the activities of xenobiotic metabolic enzymes such as phase I and II were examined in lung as well as liver tissues (to compare the effects between target and non-target organs). Besides, the activities/levels of tissue marker enzymes, antioxidants, lipid peroxidation (LPO), cytochrome P450 1A1 (CYP1A1) expressions and histological observation of lungs were also analyzed. B(a)P (50 mg/kg body weight) was administered to male Swiss albino mice (20–25 g) to experimentally induce lung cancer. B(a)P-induced animals showed increased activity of phase I (Cytochrome P450, Cytochrome b5, NADPH Cytochrome P450 redcutase and NADH Cytochrome b5 reductase) drug metabolic enzymes, LPO levels, tissue marker enzymes and decreased activity of phase II metabolic enzymes (glutathione-S-transferase, DT-diaphorase and UDP-glucuronyl transferase) as well as antioxidant levels. Histological examination of lungs revealed severe alveolar and bronchiolar damages in B(a)P-induced mice. Immunohistochemical and western blot analysis of CYP1A1 increased significantly in lung tissues of B(a)P-induced animals. Treatment with galangin (20 mg/kg body weight) efficiently counteracted all the above anomalies and restored cellular homeostasis. Our results demonstrate that galangin can modify xenobiotic enzymes in murine model of pulmonary tumorigenesis.     

Cardiac Repolarization With Gabapentin Enacarbil in a Randomized,Double-Blind,Placebo- and Active-Controlled,Crossover Thorough QT/QTc Study in Healthy Adults

Background

Gabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome.

Objective

This study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance.

Methods

This was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18–50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups.

Results

Of 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) C_max (between-subject coefficient of variation) was 7.49 (21.2) μg/mL for GEn 1200 mg, 32.46 (23.9) μg/mL for GEn 6000 mg, and 2.08 (24.5) μg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%).

Conclusion

Single doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.