What is the future of PEGylated therapies?

The tremendous potential of biologic drugs is hampered by short half-lives in vivo, resulting in significantly lower potency than activity seen in vitro. These short-acting therapeutic agents require frequent dosing profiles that can reduce applicability to the clinic, particularly for chronic conditions. Therefore, half-life extension technologies are entering the clinic to enable improved or new biologic therapies. PEGylation is the first successful technology to improve pharmacokinetic (PK) profiles of therapeutic agents and has been applied in the clinic for over 25 years. Over 10 PEGylated therapeutics have entered the clinic since the early 1990s, and new PEGylated agents continue to expand clinical pipelines and drug patent life. PEGylation is the most established half-life extension technology in the clinic with proven safety in humans for over two decades. Still, it is one of the most evolving and emerging technologies that will be applied for the next two decades.     

Do HPMA copolymer conjugates have a future as clinically useful nanomedicines? A critical overview of current status and future opportunities

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing doxorubicin designed in the late 1970s/early 1980s as anticancer polymer therapeutics were the first synthetic polymer-based anticancer conjugates to enter clinical trial beginning in 1994. Early clinical results were promising, confirming activity in chemotherapy refractory patients and the safety of HPMA copolymers as a new polymer platform in this setting. Subsequent Phase I/II trials have investigated conjugates containing paclitaxel (PNU 166945), camptothecin (PNU 166148) (both failed in clinical trials underlining the importance of rational design), and most recently HPMA-copolymer platinates (AP5280 and then AP5346-ProLindac^TM) entered Phase II clinical development. There are a growing array of second generation HPMA copolymer-based systems involving combination therapy, incorporating putative targeting ligands, having an ever more complex architecture, and both drug and protein conjugates are being proposed as novel treatments for diseases other than cancer. Despite their promise, and the success of polymeric drugs and polymer-protein conjugates, no polymer-drug conjugate (HPMA copolymer-based or otherwise) has yet entered routine clinical use. It is timely to reflect on the progress made over the last 30 years, the relative merits of HPMA copolymers as a platform compared to other polymeric carriers, and comment on their future potential as polymer-based nanomedicines into the 21st century in comparison with the many alternative strategies now emerging for creation of nanopharmaceuticals.     

Long-acting β-agonists in asthma management: what is the current status?

Large surveillance studies or phase IV clinical studies of long-acting β-agonists (LABA) compared with placebo in asthma patients using variable (from nil to regular) doses of inhaled corticosteroids (ICS) have raised the issue of mortality risk in patients with asthma taking regular LABA. There have been a number of meta-analyses and systematic reviews that have examined the risk of LABA in asthma patients, and the general conclusion is that LABA added to ICS reduces asthma-related hospitalizations compared with ICS alone and there is no statistical increase in mortality. However, LABA without ICS do increase mortality risk in asthma. All reviews and analyses show a greater number of LABA deaths, but not all are statistically significant. A recent meta-analysis found LABA with concomitant ICS had a higher mortality rate in asthma than ICS alone. The flaw in the study is the higher doses of ICS in the control arms, but the implicit message remains: the essential need for enough ICS to control airway inflammation. We suggest that the pragmatic solution is to have LABA only available in the same device as ICS for asthma treatment. We do not think that a study comparing the safety of LABA plus ICS versus ICS alone in asthma is necessary. If such a study is conducted, the measurement of morbidity from increased doses of ICS is an essential design consideration. Furthermore, the critical focus in asthma management should not be forgotten - education of health professionals and the community of the critical role of ICS, and the need for good communication between health professionals and the asthma patient to facilitate good asthma control. The same arguments apply to the asthma-with-chronic obstructive pulmonary disease overlap syndrome in older patients. There is an urgent need to provide medical practitioners with the capability to diagnose the overlap syndrome.     

Antitumorigenic targets of cannabinoids – current status and implications

Introduction: Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment.

Areas covered: The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids.

Expert opinion: The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds. In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions. Thus, drugs aiming at the endocannabinoid system may represent potential ‘antimetastatics’ for an upgrade of a future armamentarium against cancer diseases.     

Drug agglomeration and dissolution - What is the influence of powder mixing?

This study determined the influence of mixing speed and time on the dissolution and deagglomeration of a micronised, poorly water-soluble drug, indomethacin, in lactose interactive mixtures. Mixing occurred in a Turbula mixer; dissolution studies were performed using the USP paddle method, and the extent of deagglomeration was determined using modelling strategies and laser diffraction particle sizing of the powder mixtures. During low energy mixing at low rates and short mixing times, dissolution profiles showed an unusual flat asymptote indicating incomplete extents of dissolution caused by agglomerates that did not readily disperse in the dissolution medium. The study showed that increasing both speed and time of mixing increased the extent of dissolution and deagglomeration of the indomethacin powder. Nonlinear least squares modelling of the dissolution data using a sigmoidal equation provided estimates of the extent and rate of dissolution. Mixing speed and time had a much greater influence on the extent of dissolution which was controlled by deagglomeration than on the initial dissolution rate which was related to dispersed indomethacin. While some deagglomeration did occur at higher mixing energies, the deagglomeration of the indomethacin was not complete with only about 58-80% of indomethacin particles overlapping with the primary indomethacin particle size distribution. The significant outcome of this study was that mixing conditions have a major influence on the mixing quality, especially in areas where agglomerate characteristics influence performance.     

What is the pathophysiology of the septic host upon admission?

The enormous case-fatality rate of severe sepsis and septic shock has resulted in considerable efforts being made towards understanding their complex mechanisms of pathogenesis. This has been done with the hope that agents that interfere with the pathways of pathogenesis and modulate the immune response of the host may be candidates for therapy. Disappointing results from most trials of immunomodulators in sepsis have led to understanding that the progression of patients to multiple organ dysfunction syndrome involves blunting of the pro-inflammatory cytokine storm. Instead, the compensatory anti-inflammatory response syndrome (CARS) develops, which is characterised by immunoparalysis. Components of this syndrome are impaired phagocytosis by neutrophils, decreased expression of HLA-DR on monocytes, impairment of ex vivo cytokine stimulation of monocytes, CD4 lymphopenia due to apoptosis of lymphocytes and predominance of anti-inflammatory T(h)2 and regulatory T-cell responses over pro-inflammatory T(h)1 and T(17) responses. CARS is not the sole explanation for the failure of trials of immunomodulators in sepsis. Recent data from the Hellenic Sepsis Study Group demonstrate that components of CARS upon transition from sepsis to severe sepsis/shock differ in relation to the underlying type of infection. These data underscore that the pathogenesis of sepsis presents considerable heterogeneity from one patient to another. That heterogeneity should be taken into consideration when deciding to administer an immunomodulator.     

On the mechanism of the persistent action of salmeterol: what is the current position?

The mechanism of the long duration of action of salmeterol at β₂-adrenoceptors has long been a matter of debate, and is still unresolved. Szczuka and colleagues have both summarized the position to date and suggested a new mechanistic contender, receptor rebinding. Despite this, they still do not come to any clear conclusion. Much of the literature data that they have drawn upon appears contradictory, and mathematical models are inevitably flawed by the questionable validity of key values applied to them. Although the issue will undoubtedly eventually be resolved, it will probably require investigators to apply carefully designed studies on simple experimental systems such as isolated membranes or cultured cells. Only then should studies be extended to more complex systems such as isolated preparations of airways smooth muscle, where tissue bulk inevitably presents a complicating factor, particularly where relatively lipophilic compounds are concerned.