Is there a growing role for endocrine therapy in the treatment of breast cancer?

Novel biochemical findings on the molecular mechanisms of estrogen actions may help us to understand some of the unexplained observations seen in breast cancer treatment and suggest new therapeutic opportunities. Thus, apart from the challenge of improving the clinical treatment of patients with advanced disease, results from trials in this setting may reveal new therapeutic principles that may be evaluated in the adjuvant setting. The role of endocrine therapy in metastatic as well as early breast cancer is increasing, and the possibility of improving cure rates for breast cancer by implementing therapy with novel aromatase inhibitors in the adjuvant setting is exciting. While the results from prevention trials are most interesting, suggesting the possibility of reducing breast cancer incidence in high-risk groups, more data are needed before we can decide whether such interventions are warranted in women at high risk of developing breast cancer.     

An evaluation of fevipiprant for the treatment of asthma: a promising new therapy?

ABSTRACT

Introduction

Asthma is a heterogeneous disease characterized by chronic airway inflammation that affects more than 230 million people worldwide. Current guidelines recommend an escalating stepwise decision model for the management of asthma. However, disease control continues to be a challenge, particularly in patients with severe asthma. Biologics have proven to be an effective add-on treatment especially in eosinophilic or type 2 airway disease. Comparatively, pre-biologics may represent a successful novel therapy. Fevipiprant (QAW039) is a selective, reversible, antagonist of the prostaglandin D₂ receptor (DP₂).     

The case for a role for adenosine in asthma: almost convincing?

Mice rendered adenosine deaminase-deficient manifest an 'asthma' phenotype in the lungs that includes mast cell degranulation, eosinophilia, mucus hypersecretion and bronchial hyperresponsiveness. These changes can be reversed by enzyme therapy with adenosine deaminase, and attenuated by theophylline. Theophylline also blocks the pro-inflammatory effects of adenosine in allergen-challenged mice. Adenosine A(2A) receptors are an essential part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses. In recent clinical studies, increases in plasma adenosine have been shown to accompany exercise-induced asthma, and adenosine concentrations in exhaled breath condensate are increased in asthmatics. These new data provide support for a key role for adenosine in asthma, which has become increasingly persuasive in recent years. The evidence is now convincing, and the time has come for the asthma community to give its full support to the design and evaluation of molecules that mimic or block the biological effects of adenosine as potential novel therapeutics for this condition.     

Does antiviral therapy have a role in the control of Japanese encephalitis?

Approximately 2 billion people live in countries where Japanese encephalitis (JE) presents a significant risk to humans and animals, particularly in China and India, with at least 700 million potentially susceptible children. The combined effects of climate change, altered bird migratory patterns, increasing movement of humans, animals and goods, increasing deforestation and development of irrigation projects will inevitably lead to further geographic dispersal of the virus and an enhanced threat. Although most human infections are mild or asymptomatic, some 50% of patients who develop encephalitis suffer permanent neurologic defects, and 25% die. Vaccines have reduced the incidence of JE in some countries. No specific antiviral therapy is currently available. Interferon alpha-2a was tested in a double-blind placebo-controlled trial on children with Japanese encephalitis, but with negative results. There is thus a real need for antivirals that can reduce the toll of death and neurological sequelae resulting from infection with JE virus. Here we briefly review the epidemiological problems presented by this virus, the present state of drug development and the contributory role that antiviral therapy might play in developing future control strategies for JE.     

What role for prucalopride in constipation?

?Prucalopride (Resolor - Shire Pharmaceuticals Ltd) is licensed, only in women, for symptomatic treatment of chronic constipation when laxatives fail to provide adequate relief. It is promoted as being "effective in helping to restore normal bowel movements and alleviating a broad range of constipation symptoms in women." Here we review the evidence for prucalopride and consider the drug's place as a treatment for chronic constipation.     

What role for tigecycline in infections?

Tigecycline (pronounced tie-ge-sigh-cleen; Tygacil--Wyeth) is a broad-spectrum antibacterial and the first glycylcycline to be marketed in the UK. It is active against certain resistant bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and bacteria that produce extended-spectrum beta-lactamase (ESBL). Tigecycline is licensed for intravenous treatment of adults with complicated skin and soft tissue infections, and complicated intra-abdominal infections. We review tigecycline and assess its place for these infections.     

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.     

What is the role of NSAIDs in pre-emptive analgesia?

NSAIDs inhibit the cyclo-oxygenase enzymes, and decrease peripheral and central prostaglandin production. In addition to reducing the inflammation that accompanies tissue injury, decreasing prostaglandin production attenuates the response of the peripheral and central components of the nervous system to noxious stimuli. Such a reduction in the response to pain can reduce the peripheral and central sensitisation induced by noxious stimuli, and reduce the pain experienced in response to subsequent noxious stimuli. These properties would seem to make NSAIDs ideal drugs to use in a pre-emptive fashion, where analgesics are administered prior to a noxious stimulus, such as surgery, with the expectation that reduction in peripheral and central sensitisation will lead to a decrease of pain.However, the available perioperative trials of pre-emptive NSAID use have yielded modest or equivocal results, and these may be due, in part, to controversy associated with the definition of pre-emptive analgesia and how to conduct the corresponding clinical trials. Although NSAIDs may have a limited ability by themselves to induce a pre-emptive analgesic effect, the available trials suggest how the perioperative use of these drugs may be made more effective. It is expected that NSAIDs will play an increasing role in multimodal analgesia and pain relief in general.     

Anti-oxidant therapy: does it have a role in the treatment of human disease?

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural anti-oxidant defences have also been found to be defective in many of the same diseases. Many researchers have concluded that, if the imbalance between the oxidative stresses and anti-oxidant defence can be corrected by supplementing natural anti-oxidant defences, it may be possible to prevent or retard disease progression. Potential anti-oxidant therapies include natural anti-oxidant enzymes and vitamins or synthetic agents with anti-oxidant activity. Diseases where anti-oxidant therapy may be beneficial can be divided into those involving acute intervention, such as reperfusion injury or inflammation, and those involving chronic preventative therapy, such as atherosclerosis, carcinogenesis and diabetic vascular disease. The pharmaceutical considerations are different in each case. The principles guiding the development, use and assessment of anti-oxidant therapies are discussed in this review.     

Long-acting beta2-adrenoceptor agonists: a smart choice for asthma?

An endogenous defect in beta(2)-adrenoceptors that results in impaired relaxation of airway smooth muscle was originally proposed as a putative underlying cause of the asthmatic condition. Short-acting beta(2)-adrenoceptor agonists such as salbutamol are still recommended for relieving acute episodes of bronchial smooth muscle spasm. Twice-daily long-acting beta(2)-adrenoceptor agonists (LABAs) such as salmeterol are advocated for use as add-on bronchodilator therapies to inhaled corticosteroids such as beclomethasone, which are used as first-line anti-inflammatory therapy. There is recent evidence of increased asthma exacerbations and associated deaths in subjects taking salmeterol compared with those taking placebo. My opinion is that, in certain situations, the use of LABAs could have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. In this article, I examine the possible pharmacological mechanisms and use of LABAs in certain situations, which are relevant to the benefits and risks of these drugs in asthma.     

Is there a role for inhaled corticosteroids and macrolide therapy in bronchiectasis?

Bronchiectasis is characterised by permanent dilatation of the bronchi that arises from chronic inflammation predominantly caused by bacterial infection. This condition remains a major cause of excess respiratory morbidity and treatment is generally only partly successful. There is an urgent need for improved anti-inflammatory medication to treat bronchiectasis. Two potentially useful therapies are inhaled corticosteroids (ICS) and macrolides. The clinical trials that have been performed in bronchiectasis with these two medications can be considered to be preliminary data. This article reviews the anti-inflammatory properties, clinical efficacy and adverse effects of ICS and macrolides.ICS have a large number of potent anti-inflammatory properties. ICS remain the first-line treatment in asthma, reduce exacerbations in chronic obstructive pulmonary disease, and may improve lung function and symptoms in cystic fibrosis (CF). Four small clinical trials have assessed the effect of high-dose ICS on bronchiectasis. The main reported effect of these trials was a reduction in sputum volume and this may be a marker of decreased airway inflammation. Other possible benefits included decreased cough and sputum inflammatory cells/biomarkers. ICS have a relatively high prevalence of local adverse effects, and may be associated with ocular complications and osteoporosis. These adverse effects can be minimised by prescribing low doses of the medication.Macrolides have both antibacterial and immunomodulatory properties. Macrolides have less marked immunosuppressive properties than corticosteroids, and effects include decreasing mucous production, inhibiting virulence factors and biofilm formation of Pseudomonas aeruginosa, decreasing leukocyte numbers and altering inflammatory mediator release. Macrolides have been shown to be extremely effective in the treatment of diffuse panbronchiolitis, improve lung function and symptoms in asthma and CF, and reduce nasal polyps and secretions in sinusitis. Five small clinical trials have assessed the effect of macrolides on bronchiectasis. Reported benefits include reduced sputum volume, improved lung function and better symptom control. Macrolides are generally well tolerated, although they do have a number of drug interactions. There are concerns about the development of resistance, especially to non-tuberculous mycobacteria, with prolonged macrolide use.The evidence available suggests that both medications have a role in the management of bronchiectasis. More definitive trials of ICS and macrolides in bronchiectasis will clarify the likely benefit of these therapies.