Experimental and investigational phosphodiesterase inhibitors in development for asthma

Introduction: Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension.

Areas covered: The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed.

Expert opinion: Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.     

Switching between biologics in severe asthma patients. When the first choice is not proven to be the best

During the last decades, new treatments targeting disease mechanisms referred as biologics have been introduced in the therapy of asthma and currently, five monoclonal antibodies have been approved. Although these therapeutic agents have been formulated to target specific asthma endotypes, it is often difficult for the treating physician to identify which patient is the best candidate for each one of these specific treatments especially in the clinical scenario of a patient in whom clinical characteristics overlap between different endotypes, allowing the selection of more than one biologic agent. As no head-to-head comparisons between these biologics have been attempted, there is no evidence on the superiority of one biologic agent over the other. Furthermore, a physician's first therapeutic decision, no matter how carefully has been made, may often result in suboptimal clinical response and drug discontinuation, indicating the need for switching to a different biologic. In this short review, we discuss the available evidence regarding the switching between biologics in patients with severe asthma and we propose a simple algorithm on switching possibilities in case that the physicians’ initial choice is proven not to be the best.     

Electrophysiological markers predicting impeding AV‐block during ablation of atrioventricular nodal reentry tachycardia

1 Background

Radiofrequency (RF) ablation of the slow pathway (SP) in atrioventricular nodal reentry tachycardia (AVNRT) is occasionally complicated with atrioventricular block (AVB) often predicted by junctional beats (JB) with loss of ventriculo‐atrial (VA) conduction.

2 Methods

We analyzed retrospectively 153 patients undergoing ablation of SP for typical AVNRT. Patients were divided into two age groups: 127 ≤ 70 years and 26 > 70 years. We analyzed the interval between the atrial electrogram in the His‐bundle position and the distal ablation catheter [A(H)‐A(RFd)] and between the distal ablation catheter and the proximal coronary sinus catheter [A(RFd)‐A(CS)] before RF applications with and without JB. We evaluated if these intervals can be used as predictors of JB incidence and also of JB with loss of VA conduction. We also assessed if age influences the risk of loss of VA conduction.

3 Results

The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals were significantly shorter in RF applications causing JB than those without JB (33 ± 11 ms vs 39 ± 9 ms, P < 0.001, 14 ± 9 ms vs 20 ± 7 ms, P < 0.001, respectively). The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals were also significantly shorter in RFs causing JB with VA block than those with VA conduction (29 ± 11 ms vs 35 ± 11 ms, P < 0.001, 8 ± 8 ms vs 17 ± 8 ms, P < 0.001, respectively). Patients > 70 years had shorter intervals (36 ± 11 ms vs 29 ± 8 ms, P  =  0.012, 17 ± 8 ms vs 13 ± 7 ms, P  =  0.027, respectively), while VA block was more common in this age group.

4 Conclusions

The A(H)‐A(RFd) and A(RFd)‐A(CS) intervals can be used as markers for predicting JB occurrence as well as impending AVB. JB with loss of VA conduction occur more often in older patients possibly due to a higher position of SP.     

Systemic sclerosis associated with generalized vasculitis and hypopituitarism

Systemic sclerosis (SSc) is a progressively evolving multisystemic disorder of unknown etiology. Beyond skin, several other organs can also be affected with a severity of involvement that is often heterogeneous. We describe a 53-year-old female patient who was admitted urgently to the hospital almost collapsed, because of numerous bleeding deep skin ulcers, located all over the body. Clinical findings and autoantibody screening were typical of SSc. Moreover, both histopathology and immunofluorescence findings were compatible with scleroderma and vasculitis as well. In addition, pituitary hormone investigation revealed severely damaged function of the gland. We assume that severe skin ulceration and serious hypopituitarism were both implications of underlying SSc-associated vasculitis. To the best of our knowledge, these peculiar clinical manifestations have not been described in the international literature to date.     

Poly(ethylene glycol)-block-cationic polylactide nanocomplexes of differing charge density for gene delivery

Representing a new type of biodegradable cationic block copolymer, well-defined poly(ethylene glycol)-block-cationic polylactides (PEG-b-CPLAs) with tertiary amine-based cationic groups were synthesized by thiol-ene functionalization of an allyl-functionalized diblock precursor. Subsequently the application of PEG-b-CPLAs as biodegradable vectors for the delivery of plasmid DNAs (pDNAs) was investigated. Via the formation of PEG-b-CPLA:pDNA nanocomplexes by spontaneous electrostatic interaction, pDNAs encoding luciferase or enhanced green fluorescent protein were successfully delivered to four physiologically distinct cell lines (including macrophage, fibroblast, epithelial, and stem cell). Formulated nanocomplexes demonstrated high levels of transfection with low levels of cytotoxicity and hemolysis when compared to a positive control. Biophysical characterization of charge densities of nanocomplexes at various polymer:pDNA weight ratios revealed a positive correlation between surface charge and gene delivery. Nanocomplexes with high surface charge densities were utilized in an in vitro serum gene delivery inhibition assay, and effective gene delivery was observed despite high levels of serum. Overall, these results help to elucidate the influence of charge, size, and PEGylation of nanocomplexes upon the delivery of nucleic acids in physiologically relevant conditions.     

Factor Structure of Repetitive Behaviors Across Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Journal of Autism and Developmental Disorders - Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in...     

Correction to: “Best Things”: Parents Describe Their Children with Autism Spectrum Disorder Over Time

Journal of Autism and Developmental Disorders -     

Changes in indications for upper gastrointestinal tract endoscopy and endoscopic findings during the last fifteen years in south-western Greece

BACKGROUND: During the past years, major advances in the management of upper gastrointestinal diseases have been achieved. The aim of this study was to determine if changes in indications for upper gastrointestinal endoscopy and endoscopic findings have occurred during the last 15 years in our area. METHODS: Indications for upper gastrointestinal tract endoscopy and endoscopy findings of patients who underwent upper endoscopy in years 1990, 1995, 2000, and 2005 in our department were compared. RESULTS: Over the 15-year period, the number of diagnostic endoscopies performed in our department in years 1990, 1995, 2000, and 2005 increased (953, 1245, 2350, and 2528, respectively). Acute upper gastrointestinal bleeding had become less frequent (40%, 42.8%, 19.7%, 14.3%, P<0.001), but dyspepsia (24.4%, 33.6%, 54.3%, 51.3%, P=0.002) and reflux (1.8%, 1.3%, 5.1%, 10.8%, P=0.005) more frequent indications for upper endoscopy. The endoscopic findings of duodenal ulcer (39.1%, 22.5%, 20.5%, 9.3%, P<0.001), gastric ulcer (15.9%, 8.3%, 5.7%, 4.6%, P=0.036) as well as erosive gastroduodenitis (35.6%, 22.2%, 15.3%, 4.7%, P<0.001) decreased, whereas that of reflux esophagitis (3.1%, 10.1%, 12%, 16%, P=0.034) increased. Moreover, the percentage of patients with negative endoscopy or minimal endoscopic findings (eg, nonerosive gastritis) increased (12.8%, 33.7%, 54.1%, 64.4%, P<0.001). CONCLUSIONS: In south-western Greece, dyspepsia and reflux as an indication for upper endoscopy have been increasing, whereas acute upper gastrointestinal bleeding has been decreasing. The finding of peptic ulcers at the upper gastrointestinal tract endoscopy has become significantly less frequent, while the percentage of patients with negative results of endoscopy seems to have been increasing rapidly.