Pitolisant 40 mg for excessive daytime sleepiness in obstructive sleep apnea patients treated or not by CPAP: Randomised phase 3 study.

Obstructive sleep apnea (OSA) syndrome commonly leads to excessive daytime sleepiness (EDS). Pitolisant, a selective histamine-3 receptor antagonist, is efficacious at doses up to 20 mg once daily in OSA treated or not with continuous positive airway pressure (CPAP). We assessed the efficacy and safety of pitolisant at doses up to 40 mg once daily in patients with moderate to severe OSA treated or not with CPAP therapy. In this phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial, patients with OSA were assigned 2:1 to receive pitolisant (according to an individual up-titration scheme, 10, 20 or 40 mg once daily) or placebo for 12 weeks. The primary endpoint was a change in the Epworth Sleepiness Scale (ESS) score from baseline to week 12. Secondary endpoints included a change in reaction time using the Oxford Sleep Resistance test (OSleR), Clinical Global Impression of Change (CGI-C), and Patient's Global Opinion of the Effect (PGOE) of study treatment. Overall, 361 patients (mean age 52.4 years, 77.3% male; mean apnea-hypopnea index [AHI] 27.0 events/h) were randomised to receive pitolisant (n = 242; 50% received CPAP) or placebo (n = 119; 48.7% CPAP). After the dose-adjustment phase (week 3), 88.8% of patients received pitolisant 40 mg. Compared with placebo, pitolisant produced a significant reduction in the ESS score at week 12 (least square mean difference -2.6 (95% CI: -3.4; -1.8; p < 0.001)) irrespective of CPAP use; and improved the reaction time on OSleR, CGI-C, and PGOE at week 12. Pitolisant was well tolerated; no new safety signals were identified. In conclusion, pitolisant up to 40 mg once daily was an effective treatment for EDS in patients with moderate to severe OSA irrespective of CPAP use.

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Risk factors for lung diseases after renal transplantation.

BACKGROUND: Lung diseases are one of the major causes of morbidity and mortality after renal transplantation. The aim of the study is to define the risk factors for infectious and noninfectious pulmonary complications in kidney transplant patients. MATERIALS AND METHODS: We prospectively studied 267 patients after renal transplantation. The kidney recipients were followed-up for the development of pulmonary complications for a period of 7 years. Different noninvasive and invasive diagnostic tests were used in cases suspected of lung disease. RESULTS: The risk factors associated with the development of pulmonary complications were diabetes mellitus (odds ratio [OR] = 4.60; P = 0.001), arterial hypertension (OR = 1.95; P = 0.015), living related donor (OR = 2.69; P = 0.004), therapy for acute graft rejection (OR = 2.06; P = 0.038), immunosuppressive regimens that includes mycophenolate (OR = 2.40; P = 0.011), azathioprine (OR = 2.25; P = 0.023), and tacrolimus (OR = 1.83; P = 0.041). The only factor associated with the lower risk of complications was a positive serology test for Cytomegalovirus of the recipient before transplantation (OR = 0.1412; P = 0.001). CONCLUSION: The risk factors can be used to identify patients at increased risk for posttransplant lung diseases. Monitoring of higher-risk patients allow timely diagnosis and early adequate treatment and can reduce the morbidity and mortality after renal transplantation.

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP: A Randomized Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety. RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported. INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.

Obstructive sleep apnea syndrome and depressive symptoms.

A strong body of evidence has emerged over the recent years suggesting a relationship between obstructive sleep apnea (OSA) and depressive symptoms. The frequent co-occurrence of the two conditions makes it necessary that their co-morbidity and the pathogenetic relations between them should be studied in detail. Most of the studies to date have found a significant correlation between depressive symptoms and OSA. The basic pathogenetic mechanisms involved are disturbed neurotransmission, synaptic remodeling and neuronal death (neuroplasticity). Further longitudinal studies are needed to completely elucidate the OSA-depression relationship. Better knowledge of the problem may significantly improve diagnostics and therapeutical options in that group of patients.

Pericardial Effusion in Obstructive Sleep Apnea without Pulmonary Arterial Hypertension and Daily Hypoxemia - is it Unusual?

Background: Pericardial effusion in chronic hypoxemic lung diseases, such as Obstructive Sleep Apnea syndrome, usually occurs after the development of severe pulmonary arterial hypertension. However, data about the frequency of pericardial effusions in Obstructive Sleep Apnea syndrome without pulmonary arterial hypertension and/or daytime hypoxemia are still scarce, and their pathogenesis is unclear. Aims: To assess the prevalence of pericardial effusions and their volume and location in patients with obesity and Obstructive Sleep Apnea syndrome without pulmonary arterial hypertension and/or hypoxemia. Study Design: Cross-sectional study. Methods: We included 279 consecutive patients (162 males) with newly diagnosed Obstructive Sleep Apnea syndrome having a mean age of 42.8±12.4 years and a mean body mass index of 37.3±7.8 kg/m2. Obstructive Sleep Apnea syndrome was confirmed by polysomnography. Main exclusion criteria were concomitant inflammatory diseases, thyroid dysfunction, daytime hypoxemia, nephrotic syndrome, left ventricular systolic dysfunction and pulmonary arterial hypertension. Results: Pericardial effusion was found in 102 (36.56%) -all of them with moderate to severe obstructive Sleep Apnea syndrome. The mean effusion volume was mild to moderate (up to 250 mL). In 36 patients (35.3%) the pericardial effusion was diffuse, in 42 (41.2%), the pericardial effusion was located in front of the right atrium and the right ventricle, and in 24 (23.5%) the pericardial effusion was situated in front of the right cardiac cavities and the left atrium. We found a significant positive correlation between the presence of pericardial effusion and apnea-hypopnea index (r=0.374, p<0.001), body mass index (r=0.473, p<0.001), and desaturation time during sleep (r=0.289, p<0.001). Conclusion: Pericardial effusion in patients with obesity and moderate to severe Obstructive Sleep Apnea syndrome without daily hypoxemia and/or pulmonary hypertension is a relatively common finding. The occurrence of pericardial effusions is dependent mostly on the grade of Obstructive Sleep Apnea syndrome, degree of obesity, and duration of sleep desaturation.

Cognitive Impairment and Affective Disorders in Patients With Obstructive Sleep Apnea Syndrome.

Sleep-related breathing disorders could be accompanied by or caused by a variety of medical conditions. They are considered to be a significant medical and social problem. Together with excessive daytime sleepiness, patients with obstructive sleep apnea experience neuropsychological symptoms such as anxiety, attention deficits, cognitive impairment, depressive symptoms and other psychological disturbances leading to social adjustment difficulties. Patients diagnosed with obstructive sleep apnea demonstrate a decline in a wide spectrum of cognitive abilities, including memory, attention, psychomotor speed, executive, verbal and visual-spatial skills. The aim of this study is to investigate the cognitive functioning and affective disorders among patients with obstructive sleep apnea syndrome and to examine the frequency and severity of cases in comparison with a control group consisting of healthy volunteers. Our research has shown that there is a relation between sleep apnea and cognitive impairments and affective changes. This relation can be explained by the direct effect of the syndrome on the patient, where the main connecting factor is the severity and the distribution of excessive daytime sleepiness. Along with treatment of the somatic medical condition, it is extremely important that the patient's mental state is treated as well. Trial Registration: 57/2013, Medical University - Sofia, Bulgaria.

Assessment of the expectancy, seriousness and severity of adverse drug reactions reported for chronic obstructive pulmonary disease therapy.

INTRODUCTION: Adverse drug reactions can cause increased morbidity and mortality, and therefore information needs to be studied systematically. Little is known about the adverse drug reactions for chronic obstructive pulmonary disease therapy. The goal of this study is to assess the expectedness, seriousness and severity of adverse drug reactions during chronic obstructive pulmonary disease therapy based on their reporting in the national pharmacovigilance system. METHODS: This was a prospective, observational, 1-year, real-life study about the pharmacotherapy of a sample of 390 chronic obstructive pulmonary disease patients. Prescribed medicines were systematized and national pharmacovigilance databases were searched for reported adverse drug reactions. The expectedness was evaluated through the review of the summary of product characteristics, the seriousness was evaluated by the clinicians based on the life threatening nature of the adverse drug reactions, and the severity was evaluated through Hartwig's Severity Assessment Scale. Descriptive statistics of the reported adverse drug reactions was performed and the relative risk of developing an adverse drug reaction with all international non-proprietary names included in the analysis was calculated. RESULTS: Results confirm that the chronic obstructive pulmonary disease is a disease with high appearance of adverse drug reactions, and causes many additional costs to the healthcare system. Unexpected and severe adverse drug reactions are frequent. A total of 4.8% of adverse drug reactions were evaluated as life threatening. Majority of adverse drug reactions are classified in Levels 1 (32.6%), 2 (26.4%) and 3 (19%) according to Hartwig's Severity Assessment Scale. Approximately 22% of reported adverse drug reactions affect people's everyday life to a greater extent and require additional therapy which might further increase the risk. The relative risk of developing an adverse drug reaction was highest for novphyllin (relative risk = 0.65), followed by aclidinium bromide (relative risk = 0.09). Both indacaterol and salbutamol are with a relative risk of 0.07. CONCLUSION: In conclusion, the medicines for chronic obstructive pulmonary disease cause many serious adverse drug reactions, most of them were unexpected, lacking in the short product characteristics. Appropriate reporting of adverse drug reactions is necessary to decrease the risk of patients and healthcare system.

8-isoprostanes and resistin as markers of vascular damage in non-hypersomnolent obstructive sleep apnoea patients.

BACKGROUND: Oxidative stress and inflammation are assumed as the main pathological triggers for vascular damage in hypersomnolent obstructive sleep apnoea (OSA) patients, whereas their exact role in less symptomatic population is currently unknown. AIM: To determine whether oxidative stress (urinary 8-isoprostane concentration) and inflammation (plasma resistin levels) are associated with vascular damage in non-hypersomnolent (Epworth Sleep Score <11) OSA patients. METHODS: A total of 325 consecutive patients have undergone standard polysomnography, and 256 of them were diagnosed with OSA. Excessive daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS). Only 86 patients with ESS <11 participated in the study. The control group was presented by 45 subjects without OSA. Endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation (FMD). Intima-media thickness (IMT) and ankle-brachial index (ABI) were determined by ultrasonography. Urinary 8-isoprostanes (Cayman Chemical, USA) were measured, applying mass spectrometry. Resistin (RayBio_ Human ResistinCat#:ELH-Resistin-001) plasma levels were detected by ELISA. RESULTS: In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (4·62% ±1·9) and (7·1% ±2·8), respectively (P: 0·013). The prevalence of plaques in a.carotis communis was higher in OSA (16% versus 4%). The same is observed regarding a.tibialis posterior (81% vs. 29%). The average IMT and ABI in OSA and in the control group were, respectively, (IMT - 800 µm versus. 666 µm); (ABI -1·06 versus 1·20). Urinary isoprostanes were higher in OSA patients (0·091 versus 0·078) and correlated negatively to FMD (r: -0·825, P: 0·00), IMT (r: -0·324, P: 0·003) and ABI (r: -0·226, P: 0·043). No association between resistin and the degree of vascular injury was found. CONCLUSIONS: In comparison with the control group, increased prevalence of endothelial dysfunction and vascular damage was established in OSA patients without excessive daytime sleepiness. Urinary 8-isoprostanes (oxidative stress markers) are closely associated with FMD (endothelial dysfunction), IMT and ABI (vascular damage). Resistin plasma levels correlated neither to FMD, nor to IMT or ABI.

Resistin - the link between adipose tissue dysfunction and insulin resistance in patients with obstructive sleep apnea.

BACKGROUND: Resistin is an adipocytokine, associated with obesity and inflammation. Its exact role in insulin resistance and diabetes in the general population is still controversial. The relation between resistin plasma levels, insulin resistance and risk of impaired glucose metabolism in OSA patients has not been investigated. MATERIALS AND METHODS: Plasma levels of resistin were measured in 67 patients with OSA and impaired glucose metabolism. 34,7% (23/67) had diabetes; 40% (27/67) patients had impаired glucose tolerance(IGT); 25,3%(17/67) had normal glucose metabolism (NGM). The association between resistin, BMI, obesity, markers of insulin resistance, oxidative stress and sleep study characteristics was analysed. The different groups of patients were compared in regards to glucometabolic parameters and biomarkers of oxidative stress - isoprostanes and insulin resistance - free fatty acids (FFA). RESULTS: Plasma levels of resistin were higher in patients with diabetes (6,12 ±5,93ng/ml), compared to those with IGT (3,85±2,81ng/ml, p-0,021) and NGM (3,77±3,23, p-0,043). Resistin did not differ between patients with IGT and NGM (p-0,954). In OSA patients with BMI>40 resistin plasma levels correlated neither to the clinical parameters (BMI, IRI, HOMA-I, HbA1C, AHI, desaturation index), nor to the biomarkers of oxidative stress and insulin resistance. Free fatty acids (0,232>0,177mmol/l, p-0,037) were higher in diabetics in comparison to NGM. CONCLUSIONS: Plasma resistin levels in OSA patients with BMI>40 are independent of insulin resistance and are not associated with the parameters, characterising the oxidative stress or severity of OSA. Resistin could be used in a multiple panel of clinical and biomarkers to discern patients with diabetes from those with IGT; in OSA patients with BMI >40 resistin together with HbA1C could discern patients with diabetes from those with NGM. In OSA patients with BMI >40 FFA and HbA1C are useful clinical markers in assessing the risk of dysglycaemia among patients with normal and IGT.

The role of small heat-shock protein αB-crystalline (HspB5) in COPD pathogenesis.

BACKGROUND: αB-crystallin (HspB5) is a chaperone whose role as a marker of innate immunity activation as well as its therapeutic potential have recently been investigated in several inflammatory diseases: multiple sclerosis, myocardial ischemia, and Guillain-Barré syndrome. AIM: The aim of this study is to determine the role of αB-crystallin in chronic obstructive pulmonary disease (COPD) pathogenesis and inflammation. MATERIALS: Plasma levels of αB-crystallin were studied in 163 patients: 52 healthy non-COPD smokers; 20 COPD smokers in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-II; 43 COPD smokers in GOLD stages III-IV. Forty-eight patients were diagnosed with acute inflammatory respiratory disease. The plasma levels of αB-crystallin antibodies were determined by an enzyme-linked immunosorbent assay (Calbiochem), and were confirmed with Western blotting. Tissue expression of the protein was compared in three different groups of patients: COPD smokers, COPD nonsmokers, and in patients with age-related emphysema. RESULTS: The mean level of anti-αB-crystallin antibodies in non-COPD smokers was 0.291 nm. In COPD smokers it was 0.352 nm and, in patients with inflammatory lung diseases, 0.433 nm. There was a statistically significant difference between COPD smokers and healthy non-COPD smokers (P = 0.010). The same could be observed comparing the group of patients with acute inflammation and non-COPD healthy smokers (P = 0.007). There was no statistically significant difference between patients with mild/moderate inflammation and those with severe COPD. Tissue detection of the protein showed that it was significantly overexpressed in COPD smokers in comparison to COPD nonsmokers and was only slightly expressed in patients with age-related emphysema. CONCLUSION: αB-crystallin is increased in patients with inflammatory lung diseases. Though unspecific, it could be used in a panel of markers discerning COPD smokers from healthy nonsmokers. As αB-crystallin is a regulator of innate immunity and a therapeutic anti-inflammatory agent, its exact role in COPD pathogenesis and therapy should be explored further.

Clinical usefulness of alpha-crystallin antibodies in non-small cell lung cancer patients.

The non-invasive approach of finding biomarkers in peripheral blood of cancer patients makes it useful for clinical application and cancer screening. The aim of the study was to explore the clinical utility of alpha-crystallin antibodies as markers for diagnosis of non-small cell lung cancer (NSCLC) and screening among high-risk groups. Alpha-crystallin antibodies were detected with enzyme-linked immunosorbent assay (ELISA) in 51 NSCLC patients, 38 high-risk chronic obstructive pulmonary disease (COPD) patients and 52 age and sex matched healthy volunteers. Alpha-crystallin IgG antibodies differed significantly between the groups of cancer patients and the healthy volunteers (P<0.001). A cut-off value of 0.317 discerned NSCLC patients with sensitivity 62%, and specificity 72% among the control group. The assay was effective in distinguishing the patients with and without lymphogenic metastatic spread of the disease (P=0.045): sensitivity 60%, and specificity 70%. The clinical significance of this marker has a modest implication in lung cancer diagnosis and screening in high-risk groups. Its importance as a prognostic marker or a marker of disease recurrence and lymph node micrometastasis should be further explored.

EGFR and hTERT Expression as a Diagnostic Approach for Non-small Cell Lung Cancer in High Risk Groups.

OBJECTIVE: The early detection of NSCLC is of importance because it provides chances for better outcomes. The aim of the study was to explore the clinical utility of EGFR and hTERT mRNA expression as markers for diagnosis of NSCLC. METHODS: EGFR and hTERT mRNA were quantified by quantative reverse transcription real time polymerase chain reaction in plasma of 45 non-small cell lung cancer (NSCLC) and 40 chronic obstructive pulmonary disease (COPD) patients, selected by certain spirometric characteristics that made them at high risk of developing lung cancer in future. RESULTS: The gene expression level of each gene was calculated and given as a relative quantity-RQ. EGFR gene expression was found in all lung cancer patients. The mean level of expression was RQ = 29.39. hTERT mRNA could be detected in 88% of patients. The mean expression ratio in them was RQ = 17.31. Only 50% of the high risk patients turned to be positive for EGFR. The level of their expression was RQ = 2.09. The plasma levels of hTERT could be detected in 17 (42.5%) patients of the high risk COPD group. Their mean level of expression was RQ = 1.02. A statistically significant difference in EGFR and hTERT mRNA expression could be observed between the two groups of patients-p = 0.0001. CONCLUSION: EGFR and hTERT mRNA are potential markers for lung cancer diagnosis, whose clinical importance should be replicated in a larger cohort of patients.

Expression profile of the small heat-shock protein alpha-B-crystallin in operated-on non-small-cell lung cancer patients: clinical implication.

OBJECTIVE: Alpha-B-crystallin, a small heat-shock protein, recently gained major interest because of its differential expression during tumourigenesis and metastasis in various epithelial tumours. The purpose of this study was to investigate the expression of alpha-B-crystallin and its biologic and prognostic significance in non-small-cell lung cancer (NSCLC). METHODS: Immunohistochemical analysis was performed on a tissue microarray slide containing samples from 146 NSCLC patients who were operated on between 2004 and 2005. RESULTS: Cytoplasmic and nuclear staining was detected. Squamous cell carcinomas and adenocarcinomas had a distinctive profile of expression. The cytoplasmic staining of the tumours, however, is related to the local invasion - T-factor (p=0.044). Nuclear staining was more commonly detected in advanced stages, and was a biomarker of an aggressive tumour biology (p=0.042). Kaplan-Meier analysis showed that patients with positive nuclear staining had shorter overall survival (log-rank p=0.002). Using Cox's proportional hazards model, we performed multivariate analyses to assess the independent prognostic value of nuclear staining. The variables used included age, histology, gender and stage. Alpha-B-crystallin was an independent negative prognostic factor of survival in addition to clinical stage. CONCLUSIONS: Alpha-B-crystallin plays an essential role in NSCLC biology and its nuclear staining is an independent factor of poor survival. Its clinical application in molecular biologic substaging of NSCLC patients needs further validation.

Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study.

OBJECTIVES: Short-course therapy has been advocated for the treatment of community-acquired pneumonia (CAP). We compared the efficacy and safety of 5 and 7 day courses of gemifloxacin for outpatient treatment of mild-moderate CAP. PATIENTS AND METHODS: In a multicentre, double-blind, parallel group study, patients were randomized to receive 320 mg of oral gemifloxacin once daily for 5 or 7 days. Over 95% of all patients in each cohort had a Fine score of