Asunaprevir for hepatitis C: a safety evaluation

Introduction: The introduction of direct-acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV) chronic infection. Non-structural 3 protease inhibitors are currently the most numerous class of DAAs on the market.

Areas covered: This review mainly focuses on the tolerability and safety profile of asunaprevir (ASV)-containing DAA regimens. ASV is a second-wave protease inhibitor currently in Phase III clinical development in most countries and already available in Japan.

Expert opinion: ASV shows potent antiviral effect and clinical efficacy on HCV genotypes 1 and 4. The all-oral combination daclatasvir/ASV reached high eradication rates in HCV genotype 1b and 4 infection, and a lower efficacy in genotype 1a infection. ASV presents a low potential for drug–drug interaction and a good tolerability as part of multiple, including all-oral, regimens. ASV is associated with a transient and usually mild increase in aminotransferase levels in a low percentage of cases. Due to the impaired pharmacokinetic profile observed in advanced liver disease, ASV use in patients with moderate or severe hepatic impairment is not allowed. In conclusion, ASV represents a powerful weapon against HCV infection and has to be considered an optimal option as a component of genotype tailored interferon-free combinations.     

Rheumatoid arthritis and myasthenia gravis: a case-based review of the therapeutic options

Clinical Rheumatology - Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients...     

A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.     

A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with newly diagnosed type 1 diabetes (IMDIAB 8)

In a pilot study, the metabolic effects of continuous subcutaneous insulin infusion (CSII) versus intensive subcutaneous insulin therapy (ISIT) started at diagnosis in patients with Type 1 diabetes and continued for a 2-year period were evaluated and compared. Twenty-three patients (between 12 and 35 years old, mean +/- SD 18.4 +/- 9 years) were randomized into two treatment groups (CSII vs. ISIT), and both received supplemental nicotinamide (NA), 25 mg/kg of body weight. CSII was started immediately after admission to the hospital. Parameters of metabolic control [insulin dose, hemoglobin A1c (HbA1c), and C-peptide] were evaluated for a 2-year follow-up period. Data are presented for a total of 19 patients who remained in the study for its duration. Two years after diagnosis, mean +/- SD HbA1c was 6.3 +/- 0.5% and 6.2 +/- 0.3% for the CSII and ISIT groups, respectively (p=not significant). Compared with baseline values, an increase of baseline C-peptide of 38% for the CSII group and 27% for the ISIT group was observed; however, the difference between the groups was not significant. The insulin requirement for the entire duration of the study, but not at entry and 3 months, was significantly higher in CSII compared with ISIT patients (0.62 +/- 0.4 IU/kg/day vs. 0.3 +/- 0.4 IU/kg/day, respectively; p<0.01). After trial completion patients on CSII continued with this mode of therapy. Implementation of CSII as well as ISIT at diagnosis of Type 1 diabetes and continuation for 2 years thereafter achieved similar and optimal metabolic control, but more insulin was required with the CSII group. Both types of intensive insulin therapy combined with NA are able to preserve C-peptide secretion or even increase baseline levels for up to 2 years after diagnosis.     

Aging,respiratory efforts during sleep,and pulsus paradoxus

Forty patients with either obstructive sleep apnea syndrome or a clinical complaint of daytime sleepiness with measured nocturnal increase in upper airway resistance and snoring were investigated during sleep for the presence of pulsus paradoxus, which is defined as a decrease in systolic blood pressure (SBP) of at least 10 mmHg during inspiration. Two thirds of the subjects presented pulsus paradoxus. Age, lowest oxygen saturation (SaO₂), and negative inspiratory esophageal pressure nadir (an index of inspiratory effort) were the only studied variables which could statistically dissociate patients presenting pulsus paradoxus. We then divided the patient population into three different subgroups of equal number based upon the degree of decrease in SBP (i.e., >20 mmHg, <20 but >10 mmHg, and <10 mmHg). In this second analysis, age was the only significant variable that separated the three groups. Lowest SaO₂ could not be used to statistically separate subjects with mild to moderate pulsus paradoxus from those without it; and negative inspiratory esophageal pressure measurements could only significantly identify subjects with severe pulsus paradoxus (i.e., >20 mmHg) from those without any pulsus paradoxus. The variable which correlated best with age was negative inspiratory esophageal pressure nadir (R = 0.83). Our interpretation is that as age increased, negative inspiratory esophagel pressure became less negative, due to the known impact of aging on muscles, and pulsus paradoxus was no longer observed. Offprint requests to: C. Guilleminault     

Risk Estimation Modeling and Feasibility Testing for a Mobile eHealth Intervention for Binge Drinking Among Young People: The D-ARIANNA (Digital-Alcohol RIsk Alertness Notifying Network for Adolescents and young adults) Project

Background: Binge drinking is common among young people but often relevant risk factors are not recognized. eHealth apps, attractive for young people, may be useful to enhance awareness of this problem. We aimed at developing a current risk estimation model for binge drinking, incorporated into an eHealth app—D-ARIANNA (Digital-Alcohol RIsk Alertness Notifying Network for Adolescents and young adults)—for young people. Methods: A longitudinal approach with phase 1 (risk estimation), phase 2 (design), and phase 3 (feasibility) was followed. Risk/protective factors identified from the literature were used to develop a current risk estimation model for binge drinking. Relevant odds ratios were subsequently pooled through meta-analytic techniques with a random-effects model, deriving weighted estimates to be introduced in a final model. A set of questions, matching identified risk factors, were nested in a questionnaire and assessed for wording, content, and acceptability in focus groups involving 110 adolescents and young adults. Results: Ten risk factors (5 modifiable) and 2 protective factors showed significant associations with binge drinking and were included in the model. Their weighted coefficients ranged between ?0.71 (school proficiency) and 1.90 (cannabis use). The model, nested in an eHealth app questionnaire, provides in percent an overall current risk score, accompanied by appropriate images. Factors that mostly contribute are shown in summary messages. Minor changes have been realized after focus groups review. Most of the subjects (74%) regarded the eHealth app as helpful to assess binge drinking risk. Conclusions: We could produce an evidence-based eHealth app for young people, evaluating current risk for binge drinking. Its effectiveness will be tested in a large trial.     

Subclinical leaflet thrombosis after transcatheter aortic valve replacement and anticoagulant treatment: lights and shadows

Journal of Thrombosis and Thrombolysis -     

Efficacy of interleukin-1 blockade in Schnitzler’s syndrome without detectable monoclonal gammopathy: a case-based review

Clinical Rheumatology - Schnitzler’s syndrome (SchS) is a rare autoinflammatory disorder characterized by urticarial rash and monoclonal gammopathy which is currently regarded as IL-1...