COPD: is there light at the end of the tunnel?

No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified and new treatments are in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-alpha. Several broad-spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. There is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.     

More light at the end of the tunnel – apixaban in atrial fibrillation

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation.

Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups.

Expert opinion: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.     

Is there a role for immunoconjugates in the treatment of AIDS?

The use of antibodies to deliver therapeutic agents to specific cells is a well-established concept in the treatment of malignancy. Therapeutic effects have been shown in both animal models and human clinical trials. By analogy, antibodies and other ligands may be used to treat AIDS by targeting cells that are actively producing HIV and spreading the infection. Immunoconjugates with specificity for HIV antigens or structures on the surface of HIV-infected cells have been made. These agents have undergone extensive in vitro testing. In tissue culture they can eliminate infected cells and halt the production of HIV. A number of agents have been shown to enhance the efficacy of anti-HIV immunoconjugates. Because animal models of HIV-infection are problematic, there has been little preclinical testing. Nevertheless, several clinical trials have begun.     

Is there a distinct subtype of major depression in the elderly?

Evidence for and against the notion of a specific subtype of depressive illness in the elderly is reviewed. There is little to support a distinction based on clinical features, neurobiological markers, treatment response or prognosis, but subtle organic cerebral change may predispose to late-onset depression in a significant minority of cases.     

Is there a need for a new generation of vaccines against pertussis?

Current vaccines against pertussis have proved their safety and efficacy in large-scale clinical trials. Despite high vaccination coverage, pertussis is still prevalent and increasing, probably as a result of waning immunity. Addition of new antigens, such as adenylate cyclase, to current vaccines might improve some aspects of the immune response to vaccination, but are unlikely to significantly increase the duration of protection. Intranasal, oral and DNA pertussis vaccines are some way from clinical development, although one live attenuated, intranasal pertussis vaccine may soon enter Phase I trials. In the meantime, the potential of currently available safe and efficacious pertussis vaccines should be maximised. Rationalisation of pertussis boosters in childhood and introduction of widespread repeat booster vaccination in adolescents and adults would already lessen disease prevalence and morbidity among susceptible infants.     

Is RGS-2 a new drug development target in cardiovascular disease?

Hypertension is the most common cardiovascular disease. The regulator of G-protein signalling (RGS) proteins modify the activity of G proteins, and mice deficient in RGS-2 are hypertensive. On vascular smooth muscle, RGS-2 is involved in cross-talk between the nitric oxide (NO)-relaxation pathway and thrombin-contraction pathway. RGS-2 binds to the cGMP-dependent protein kinase I-alpha from the NO relaxation pathway to terminate protease-activated receptor-1 signalling. It has been suggested that RGS-2 is a new drug development target for hypertension. Mice deficient in RGS-2 also have impaired antiviral immunity. It is difficult to envisage how RGS-2 could be targeted to have effects on the cardiovascular system without affecting immunity. Also, it is not clear whether or not targeting RGS-2 will have advantages over targeting receptors. Only an increased understanding of the physiological and pathological role of RGS-2 will help us resolve these issues.     

Is there a role for therapeutic drug monitoring of new anticonvulsants?

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants. The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.     

Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.     

Is there a role for vitamin D in the treatment of chronic pain?

A brief survey of recent literature was conducted with regard to vitamin D and pain. There is evidence for and against a role for vitamin D in the treatment of chronic pain. The contradictory findings may have to do with study design or perhaps the type and intensity of pain. To answer the question whether there is a role for vitamin D in the treatment of chronic pain, larger and longer duration studies need to be conducted. The design should also be such to assess whether vitamin D might act to increase the effectiveness of existing analgesics and/or reduce the dose and duration of their use, thereby increasing safety.     

Is there a case for MDMA-assisted psychotherapy in the UK?

Much has been written in scientific and popular literature in recent years about the dangers surrounding the recreational use of the drug MDMA/ecstasy.What is little known and understood however is the history of the apparently safe and effective use of MDMA as a therapeutic tool for psychotherapy. In this paper the author explores this history and describes the recent re-emergence of scientific interest in MDMA and other psychedelic drugs. There are currently several new double-blind randomised controlled trials underway re-visiting the subject. By acknowledging the limitations of this new research and emphasising the importance of exercising appropriate but realistic caution, the author asks that the medical profession consider a dispassionate and open-minded debate to examine whether MDMA might have a legitimate place as an adjunct to psychotherapy in modern psychiatric practice.     

Evolution of interventional vancomycin trials in light of new antibiotic development in the USA, 1999–2012

Use of vancomycin has increased following the emergence of resistant Gram-positive bacterial infections. Investigation into recent vancomycin clinical studies provides insight into the optimal use of vancomycin and the development of novel antibiotics for the treatment of resistant infections. Interventional vancomycin trials registered in ClinicalTrials.gov from January 1999 to December 2012 were identified. Trial trends and characteristics were evaluated in the context of vancomycin use and new antibiotic development. Overall, 122 interventional vancomycin trials were identified, with a significant increase in the number of registered trials per year (P < 0.001). The top three indications studied were skin and soft-tissue infections (28.7%), Clostridium difficile infections (13.1%) and surgical prophylaxis (12.3%). Trials testing vancomycin as an experimental agent differed from trials using vancomycin as an active comparator. Experimental agent trials commonly investigated new formulations, dosing regimen optimisation and combination therapy, which were less likely to be in phase 2 or 3 (25% vs. 70%; P < 0.001), adopt a randomisation procedure (70% vs. 98%; P < 0.001), report results (15% vs. 35%; P = 0.02) or be funded by industry (8% vs. 76%; P < 0.001). Active comparator trials mainly focused on monotherapy, which led to six FDA-approved drug products and ten investigational new drugs in late-phase development. This study demonstrated a significant increase in interventional vancomycin trials and its recent success, which resulted in several novel agents against resistant Gram-positive bacteria. Further studies are warranted to determine how these agents can best be incorporated within clinical practice.     

Is there a role for a mucosal influenza vaccine in the elderly?

Influenza infection is an acute respiratory disease with a high morbidity and significant mortality, particularly among the elderly and individuals with chronic diseases. The majority of countries now recommend annual influenza vaccination for all people aged 65 years or older, and for those with high risk conditions. Most commercially available influenza vaccines are administered systemically and while these are effective in children and young adults, efficacy levels in elderly individuals have been reported to be much lower. Mucosal vaccines may offer an improved vaccine strategy for protection of the elderly. As the influenza virus causes a respiratory infection, it is potentially more beneficial to administer a vaccine that will boost protection in the mucosal surfaces of the upper and lower respiratory tract. Mucosal influenza vaccines are aimed at stimulating protective immunity in the respiratory tract via oral or intranasal immunisation. This review examines our present knowledge of mucosal immunity and current strategies for mucosal vaccination. It also stresses that the use of serum antibody levels as a 'surrogate marker' for protection against influenza is potentially misleading; serum antibody, for example, may be a quite inappropriate marker to assess a mucosal vaccine. This marker does not reflect other immune responses to vaccination that are crucial for protection.     

Drug development in the light of translational science: shine or shade?

Approximately a decade ago, translational medicine was invented both as a catchword and as a novel approach to improve success in drug development and ameliorate the low-output syndrome from collapsing pipelines. However, no major breakthroughs regarding rates of expensive late attrition or market approvals have been detected, and drug industry condensation continues to accelerate. Here, I discuss what went wrong: namely the fact that the concept does not exist apart from general claims and attributes, and no robust structures, such as toolboxes, algorithms, reproducible standards and procedures, and assessment tools have been developed and/or implemented. Translational medicine might be a clue to the survival of biomedical research, but it needs to be filled with scientific and operational substance.