β(2) -adrenoceptor agonists: current and future direction

Despite the passionate debate over the use of β(2) -adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of β(2) -adrenoceptor agonists with long half-lives, also called ultra long-acting β(2) -adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a β(2) -adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development.     

Assessing the viability of long-acting β2-agonists in paediatric asthma patients: a pharmacokinetic/pharmacodynamic perspective

Introduction: Long-acting β₂-agonists (LABAs) combined with inhaled corticosteroids (ICSs) are still commonly prescribed to asthmatic children. Unfortunately, pediatric LABA use is based primarily on data from adults, despite the fact that children are not simply small adults and the magnitude of changes in dose exposure and/or exposure response may not be solely reflected by differences in body weight.

Areas covered: The differences in pharmacokinetics (PK) and pharmacodynamics (PD) of LABAs are described and discussed with reference children and adults.

Expert opinion: Data on the PK behavior of LABAs is very limited and there is almost no data on once-daily LABAs available in the pediatric population. We do not believe that this is due to a fundamental lack of information because therapeutic response and adverse effects are more useful for the optimization of β₂-agonist treatment than measurement of plasma drug concentrations per se. Nevertheless, population PK-PD studies in children are needed according to the European rules in order to define rational, patient-tailored dosing schemes. Population PK-PD modeling and simulation using non-linear mixed effect modeling should be considered as the preferred tool to develop effective and safe dosing regimens for children because they present an opportunity to analyze sparse and unbalanced datasets, thereby minimizing the burden for each child.     

Pharmacological characterization of adenosine receptors on isolated human bronchi

Adenosine induces airways obstruction in subjects with asthma, but the receptor subtype responsible remains unknown. The objectives of this study were to determine the pharmacological profile of adenosine receptor subtypes mediating contraction and to investigate the mechanism in normal and passively sensitized human airway tissues. Contraction of bronchial rings isolated from resected lung tissue of patients with lung carcinoma was measured in response to nonselective adenosine receptor agonists, 5-AMP and 5'-(N-Ethylcarboxamido)adenosine, and A(1) receptor agonist, N(6)-cyclopentyladenosine, in the absence and presence of selective adenosine receptor antagonists. Pharmacological antagonists, chemical ablation of airway sensory nerves using capsaicin, and passive sensitization of tissue with serum from subjects with atopy and asthma was used to investigate the mechanism of contraction. Human bronchial tissue contracted in a concentration-dependent manner to adenosine agonists that showed a rank order of activity of A(1) > A(2B) > A2(A) = A3. The maximum contractile response to N(6)-cyclopentyladenosine (231.0 ± 23.8 mg) was significantly reduced in tissues chemically treated with capsaicin to desensitize sensory nerves (desensitized: 101.6 ± 15.2 mg; P < 0.05). Passive sensitization significantly augmented the contraction induced by adenosine A(1) receptor activation (sensitized: 389.7 ± 52.8 mg versus nonsensitized; P < 0.05), which was linked to the release of leukotrienes, and not histamine (MK571: 25.5 ± 1.7 mg; epinastine 260.0 ± 22.2 mg versus control; P < 0.05). This study provides evidence for a role for adenosine A(1) receptors in eliciting human airway smooth muscle constriction, which, in part, is mediated by the action of capsaicin sensitive sensory nerves.     

Hepatitis B Virus-Related Cryoglobulinemic Vasculitis: Review of the Literature and Long-Term Follow-Up Analysis of 18 Patients Treated with Nucleos(t)ide Analogues from the Italian Study Group of Cryoglobulinemia (GISC)

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90–100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.     

Specific alloantigen self-control by regulatory T cells in organ transplantation: a review

Multidrug immunosuppressive protocols have increased short-term patient and graft survival rates from 50% to 90% in the past two decades. Unfortunately, chronic graft rejection still remains the main cause of long-term failure and patients must undergo lifelong immunosuppression. The severe side effects such as life-threatening infections, secondary malignancies, and cardiovascular dysfunction all together include roughly 50% of deaths among kidney transplant patients with functioning grafts. Therefore, it should be of crucial importance to reduce immunosuppression and seek induction of specific tolerance to donor alloantigens. Several investigations have suggested that the acquisition of tolerance to self and/or foreign antigens is dependent on the number and function of naturally occurring and acquired regulatory T cells, which can control all aggressive T cells. The regulatory T cells together with their receptors, costimulatory molecules, cytokines, chemokines, and growth factors all contribute to maintain an equilibrium between aggressive and suppressive effector immune responses. As a consequence of increased knowledge, new immunosuppressive approaches based on either alloantigen-specific regulatory T-cell expansion in vivo or in vitro have been proposed to achieve donor-specific transplantation tolerance in kidney allograft recipients. This contribution attempted to summarize knowledge about regulatory T cells and developing methods to induce specific tolerance in kidney transplantation.