Nicotine-replacement therapy in pregnancy-the end of the road?

ABSTRACT:: Smoking in pregnancy is associated with serious perinatal risks, leading to attempts to prevent smoking with the use of nicotine-replacement therapy (NRT). After more than a decade of studies failing to show the effectiveness of NRT for smoking cessation in pregnancy, a recent large, randomized trial has clearly shown that the failure may be caused by >90% dropout rate. Several secondary analyses of randomized trials have shown that NRT is efficacious in decreasing smoking in pregnancy and in optimizing fetal growth among women who take the product. But to be effective in smoking cessation, any drug has to be taken by the patients. Can we overcome the dismal rates of pregnant women's adherence to NRT, so we can save unborn babies from the serious risks associated with their mothers' smoking?     

Embracing the polypill as a cardiovascular therapeutic: is this the best strategy?

ABSTRACT

Introduction: Cardiovascular disease (CVD) is an important cause of mortality and morbidity worldwide. CVD morbidity and mortality are associated with significant financial costs related to hospitalization, medication, and lost productivity. The concept of the ‘polypill’ for the reduction of cardiovascular risk was proposed in 2000. A polypill is a fixed combination of drugs in a single tablet or capsule. The initial polypill consisted of three different classes of antihypertensive drugs (each at half dose), in addition to aspirin, a statin, and folic acid. The challenge today is to produce polypills containing drugs with established efficacy and complementary actions.

Areas covered: The authors provide their expert perspectives on the polypill and consider the randomized clinical trials that have evaluated the safety, efficacy, adherence, and cost-effectiveness of polypills.

Expert opinion: The polypill makes prescribing easier by reducing the need for complex treatment algorithms and dose titration. It also appears to be cost-effective. However, there are several issues that need to be addressed before the polypill can be used routinely. A single polypill formulation may not be suitable for all patients. It may be necessary to develop several types of polypill to meet the needs of different patient groups.     

Advanced pharmacist practice: where is the United Kingdom in pursuit of this ‘Brave New World’?

International Journal of Clinical Pharmacy - Pharmacy has developed many novel patient-facing roles across the globe, typically delivered through the lens of pharmaceutical care. The macro-level...     

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.     

“You’re all going to hate the word ‘recovery’ by the end of this”: Service users’ views of measuring addiction recovery

Abstract

Aims: To explore how service users’ views of measuring addiction recovery differ from those of service providers. Methods: Five focus groups conducted in two English cities with (i) people currently using Class A drugs (n?=?6); (ii) people currently using alcohol (n?=?12); (iii) individuals in residential detoxification (n?=?12); (iv) individuals in residential rehabilitation (n?=?7); and (v) people who defined themselves as ex drug or alcohol users (n?=?7). Each focus group reviewed 76 measures of recovery previously identified by senior service providers. Findings: Service users identified multiple problems with the 76 measures. Difficulties could be categorized as expecting the impossible of service users; the dangers of progress; the hidden benefits of negative outcomes; outcomes that negate the agency in recovery; contradictory measures; failure to recognise individual differences; entrenched vulnerabilities; the misattribution of feelings and behaviours; and inappropriate language. Conclusions: Service users experience recovery as a process and personal journey that is often more about ‘coping’ than ‘cure’. Involving service users in designing measures of recovery can lessen the likelihood that researchers develop assessment tools that use inappropriate, contradictory or objectionable outcomes, and ambiguous and unclear language. People who have experienced drug or alcohol problems can highlight important weaknesses in dominant recovery discourses.     

Identification of a nicotinic acid receptor: is this the molecular target for the oldest lipid-lowering drug?

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia, producing a desirable normalization of a range of cardiovascular risk factors. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a Gi-type G protein-coupled receptor, resulting in the inhibition of adipocyte lipolysis, may contribute. This review describes the identification of this elusive receptor, and outlines the evidence suggesting that this may be the molecular target for the clinical effects of nicotinic acid.     

Neuropathic pain: is the end of suffering starting in the gene therapy?

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. It is a devastating and difficult to manage consequence of peripheral nerve injury and has a variety of clinical symptoms. Neuropathic pain is a major health problem. It has been estimated that 70% of patients with advanced cancer and inflammatory pathologies are afflicted by chronic pain. About 95% of patients with spinal cord injuries have neuropathic pain problems. Chronic pain is debilitating and cause of depression and decreasing quality of life. Pharmacological treatment for the symptoms of painful neuropathy is difficult, because there has been limited understanding of the underlying causes and systemic levels that an effective dose can have on multiple side effects. The use of molecular methods, such as gene therapy, stem cell therapy and viral vector for delivery of biologic antinociceptive molecules, has led to a better understanding of the underlying mechanisms of the induction of intractable neuropathic pain.     

Proton pump inhibitors: the beginning of the end or the end of the beginning?

Despite the dramatic success of pharmacological acid suppression in healing peptic ulcers (PUs) and managing patients with gastro-esophageal reflux disease (GERD) a number of challenges remain in the management of acid-related disorders. Several new drugs are currently being investigated to provide a significant advance over current treatments. These include new drug formulations, novel proton pump inhibitors (PPIs) as well as potassium-competitive acid blockers (P-CABs), which have already reached clinical testing. Some others (like NO-releasing antisecretory compounds) are still in preclinical development and require proof of concept in humans. While H(2)-receptor antagonists (especially soluble or OTC formulations) will become the 'antacids of the third millennium' and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. Since an increasing proportion of patients fail to respond to the best PPI treatment, more potent and long-acting drugs and more effective regimens are needed.     

Exclusion of ‘nonRCT evidence’ in guidelines for chronic diseases – is it always appropriate? The Look AHEAD study

Evidence-based medicine (EBM) is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The introduction of EBM was a conceptual and practical milestone in the history of medicine, with far-reaching impact yet to be fully realized. EBM has limitations, including inapplicability to populations dissimilar to those in studies, and may not reflect duration of exposure to risk factors, details of lifestyle, incubation period, latency, or environmental changes during chronic diseases. Routine exclusion of evidence other than randomized controlled trials (RCTs) or meta-analyses from consideration in treatment may not always be wise. This review is not a result of a search, but rather a conceptual unification of (a) the increasing restrictions in guideline-writing favoring more RCTs, and rejecting observational studies when chronic diseases with a long incubation period may sometimes be best probed by the latter; (b) the possibility RCTs may be inconclusive, nonapplicable, or result in ‘negative’ results which may misdirect future therapy by physicians and undermine adherence by patients; (c) the potential improvement in patient care from having all available information evaluated (especially epidemiological studies of chronic diseases) and synthesized in guidelines. The example of the Look AHEAD study is chosen – a ‘negative’ RCT with significant information overlooked by reviewers, who initially declared that weight loss and physical activity were ineffective in treating diabetes, or in preventing cardiovascular complications. In this review, placing this study in perspective, among others, suggests the opposite – exercise and weight loss are effective if done early and sufficiently.

Synthesizing worthy data from many sources, including prospective and pathophysiological studies, particularly when RCTs are unavailable, has the potential to add depth and expand the understanding of disease. In addition, integrated data may generate useful, rich material for use during shared decision making discussions with patients, and clarify future hypotheses.     

Abuse of medicines for performance enhancement in sport: why is this a problem for the pharmaceutical industry?

The misuse of medicines for performance enhancement in sport (doping) is not approved by regulatory agencies, and is illegal in many countries. In addition to the 'traditional' doping agents such as steroids, β-blockers and blood transfusions, the list of agents and techniques used in doping is increasing and now includes newer medicines such as erythropoiesis-stimulating agents and growth hormones. Innovative new medicines are of particular interest as would-be dopers may believe them to be undetectable by current methods. Close collaboration between the biopharmaceutical industry and anti-doping agencies such as the World Anti-Doping Agency is critical to a successful anti-doping strategy. Industry is ideally placed to identify the doping potential of new medicines at early stages and to support early development of detection assays. A strong, united front between the biopharmaceutical industry and anti-doping agencies is essential to counter the misuse of medicines for performance enhancement, as well as to promote fair play and clean sport.     

Will personalized drugs for cardiovascular disease become an option? – Defining ‘Evidence-based personalized medicine’ for its implementation and future use

It is generally accepted that the implementation of pharmacogenomics and, more broadly, personalized medicine will have to be ‘evidence-based’. However, there is a lack of consensus on the level of evidence required to justify the use of pharmacogenomic testing in clinical practice. In the cardiovascular field, this lack of agreement has led to somewhat contradicting recommendations by different organizations regarding the clinical utility and use of pharmacogenomic tests or information. Here, we argue that randomized, controlled trials are paramount in order to enable and accelerate the widespread implementation of pharmacogenomics, not only to demonstrate the clinical efficacy and cost-effectiveness of such tests, but because such level of evidence is required to support the considerable changes associated with the implantation of pharmacogenomics in clinical practice.     

Trospium chloride in patients with neurogenic detrusor overactivity: is dose titration of benefit to the patients?

OBJECTIVE: To determine whether dose titration based on therapeutic response is superior to standard dosing of oral trospium chloride in patients with neurogenic detrusor overactivity and, moreover, to investigate the possible underlying causes of differences in efficacy at equal doses in some patients. PATIENTS AND METHODS: Using a double-blind approach, two groups (standard dose and adjustable dose) with a total of 80 patients were treated with trospium chloride coated tablets for a period of 3 - 5 weeks. Treatment duration and daily doses varied depending on change ofurodynamic parameters defined as therapeutic response. In Week 1, both groups started on 45 mg/day (3 x 15 mg). In the adjustable dose group, it was permissible to increase the daily dose to 90 or 135 mg/day depending on the urodynamic treatment response. In contrast, doses remained unchanged in the standard dose group although a need for dose adjustment had been recognized under the double-blind conditions. Therapeutic response was defined as improvement of at least two of the following three urodynamic parameters: bladder compliance 2 20 ml/cmH20, maximum cystometric capacity > 250 ml and maximum detrusor pressure < 40 cmH20. Changes in individual urodynamic parameters were defined as secondary efficacy variables. Primary and secondary parameters were assessed by comparing baseline values with those at the end of treatment. Therapeutic response was analyzed by using the Fisher-Yates test, and the Mann-Whitney U-test was used for secondary parameters. Trospium plasma concentration was measured to assess patient's compliance and as a tool to elucidate possible factors influencing treatment efficacy. Safety and tolerability were evaluated based on withdrawal rates and adverse events. RESULTS: Both dose groups had comparable baseline characteristics. Therapeutic response was achieved in 58% of patients in the adjustable dose group (ADG) and in 72% of those in the standard dose group (SDG, p -0.23). Clinically relevant increases in maximum cystometric capacity and bladder compliance were observed, and there was a clear decrease in detrusor pressure. After Day 7, the daily dose was increased in 52.8% of all patients in the adjustable dose group and (seemingly) in 32.5% of those of the standard dose group. Further dose escalation after Day 14 was assessed as necessary in 15% of the standard dose group and 22% of the adjustable dose group. The main changes in urodynamic parameters occurred during the first 7 days of treatment, but in some patients it takes a longer time. No statistically significant differences between plasma trospium chloride levels in the two dose groups were observed at any time, but increase of plasma concentration with higher doses became obvious when patients were differentiated to individual dose stages. In both groups, the most common treatment-related adverse event was dry mouth (ADG 35%, SDG 37%), which never led to discontinuation of treatment. Rates of other adverse events such as dry skin, dysopia, increased heart rate and gastrointestinal disorders were much lower. CONCLUSION: Generally, in patients with neurogenic detrusor overactivity daily doses of 45 mg trospium chloride can be considered as being the standard dose, and dose adjustment, e.g. due to increased body weight, might usually not be necessary. However, increased daily doses of up to 135 mg appear to be safe when prescribed in individual patients less responsive to the drug.     

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or ‘developed’ countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia–reperfusion (I–R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I–R injury. The δ- and κ-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses.