Blocking NO synthesis: how,where and why?

Nitric oxide (NO) is a key physiological mediator, and the association of disordered NO generation with many pathological conditions has led to much interest in pharmacologically modulating NO levels. However, the wide range of processes in which NO has been implicated, and the fact that increases or decreases in NO levels might be therapeutically desirable depending on the condition or even at different stages of the same condition, pose considerable challenges for drug development. Here, we focus on the rationale and potential for approaches that reduce NO synthesis, which have led to the development of several compounds that will shortly be entering clinical trials.     

Prediction of warfarin dose: why, when and how?

Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.     

Switching between second-generation antipsychotics: why and how?

The introduction of second-generation antipsychotics represents an important advance in the treatment of schizophrenia. Although these drugs are generally very effective, not all patients respond in the same way. Partial response with persistent positive and negative symptoms and residual symptoms may force physicians to change antipsychotic medication. As more and more second-generation antipsychotics are introduced, the need for practical guidelines on switching these medications becomes increasingly important. In this article we provide a short summary of the second-generation antipsychotics, focusing on efficacy, adverse effect profile and safety. Indications for switching antipsychotic medication are outlined, as well as recommendations when switching is disadvantageous. Three basic switching strategies (abrupt, gradual and overlapping switching) and their potential risks and benefits are described. We review the available evidence concerning techniques, problems and consequences when switching from one second-generation antipsychotic agent to another and discuss potential difficulties.     

Nutritional support in head and neck cancer: how and why?

To devise a meaningful nutritional therapy in cancer, a greater understanding of nutritional dimensions as well as of expectations of patients and disease impact is essential. We have shown that nutritional deterioration in patients with gastrointestinal and head and neck cancer was multifactorial and mainly determined by tumour burden and location. In a larger cohort, stage and location were yet again the major determinants of patients' quality of life (QoL), despite the fact that nutritional deterioration combined with intake deficits was functionally more relevant than the cancer stage. On the basis of this framework, the potential role of integrated oral nutritional support on outcomes was investigated. In a pilot study using individualized nutritional counselling on a heterogeneous patient population, the achieved improvement in nutritional intake was proportional to a better QoL. The role of early nutritional support was further analysed in a prospective randomized controlled trial in patients with head and neck cancer stratified by stage, undergoing radiotherapy. Predefined outcomes were as follows: nutritional status and intake, as well as morbidity and QoL, at the end and 3 months after radiotherapy. Nutritional interventions only given during radiotherapy consisted of three randomization arms: (i) individualized nutritional counselling; (ii) ad-libitum diet plus high-protein supplements; and (iii) ad-libitum diet. Nutritional interventions 1 and 2 positively influenced outcomes during radiotherapy; however, 3 months after its completion, individualized nutritional counselling was the single method capable of sustaining a significant impact on patients' outcomes. The early provision of the appropriate mixture of foods and textures using regular foods may modulate outcomes in patients with cancer.     

Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how?

Absorption, distribution, metabolism, and excretion (ADME) studies are an integral part of the comprehensive safety evaluation of a new molecular entity, and they represent a standard suite of studies included in the registration package for all new small molecule drugs. In vivo studies in preclinical toxicology species and humans using radiolabeled ((3)H or (14)C) compound provide quantitative assessments of overall routes of excretion of drug-related material, pharmacokinetics of total drug-derived radioactivity in circulation, relative to parent compound and quantitation, and characterization of metabolites in excreta and circulation. These data serve as the starting point for metabolite in safety testing (MIST). These studies involve the administration of a radiolabeled drug to laboratory animals and humans followed by a quantitative collection of excreta and blood. Using appropriate plasma-pooling strategies, these studies could allow for modeling the metabolite exposure at the steady state. Information from the radiolabeled human study is used to design clinical drug-drug interaction (DDI) studies and to obtain a waiver for bioequivalence studies. This article describes the various aspects of conducting ADME studies and the use of radiolabeled analogues of drug candidates to investigate their metabolism and how to compare the exposures of metabolites in humans and toxicology species.     

Gamma-secretase as a pharmacological target in Alzheimer disease research: when, why and how?

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (Abeta peptides) in the form of senile plaques as well as neurofibrillary tangles (NFTs) in the brain. In the amyloidogenic pathway, the amyloid-beta precursor protein (APP) is cleaved by beta-secretase first, followed by gamma-secretase cleavage producing therefore Abeta. This review summarizes the recent findings in the AD field and focuses on the different gamma-secretase inhibitors that have been developed as a therapeutic approach toward AD.     

Biological therapy in the management of recent-onset Crohn's disease: why, when and how?

Crohn's disease is a chronic inflammatory bowel disease that may involve any part of the gastrointestinal tract. Conventional therapy consists of corticosteroids, azathioprine or methotrexate, but the clinical management of Crohn's disease is significantly hampered by adverse effects. With the introduction of biological agents (such as infliximab), the goals of therapy have advanced, including induction of remission with bowel healing as well as reduction in the rate of complications, surgeries and mortality. Current therapy for moderate to severe Crohn's disease is based on 'step-up' algorithms, which initiate treatment with corticosteroids followed by immunomodulatory agents, and defer therapy with biological agents until patients become refractory to conventional therapeutics. Recently, it has been shown that induction therapy with infliximab and azathioprine in recent-onset Crohn's disease (i.e. 'top-down' approach) is superior to current step-up algorithms to induce clinical remission. The underlying molecular mechanisms responsible for these differences in clinical outcome remain to be defined. Experimental studies have demonstrated that corticosteroids are able to induce impaired apoptosis of immune cells, including T cells and dendritic cells, resulting in loss of tolerance and subsequent autoimmunity. Further research will have to determine whether corticosteroid therapy augments the mechanism of loss of tolerance in Crohn's disease, which could complicate future clinical management.     

Methylene blue and vasoplegia: who, when, and how?

Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role. In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.     

Impact of microdosing clinical study -- why necessary and how useful?

The microdose (MD) clinical study enables to select a “better” compound for new drug candidate that shows desirable PK profiles in human. This new methodology is highly expected to streamline the drug development and to increase the success probability in the clinical trial. Since only a small amount of the test compound (less than 100 μg) is administered, the risk of harmful events to a human subject is regarded as minimal in the MD clinical study. However, the low dose also incurs the arguments about the usefulness of this method, since it may result in different PK profiles of drugs from that at the therapeutic dose. In addition, information on the efficacy/safety of the test compound cannot be obtained from the MD clinical study. On the other hand, PBPK model analysis based on the data of both the MD clinical study and in vitro study on metabolism, transport and binding enables the accurate prediction of PK profiles in humans at the therapeutic dose. PET molecular imaging technology further enhances the usability and applicability of the MD clinical study by offering the information on efficacy/safety. These methodologies, if coordinated effectively, are expected to innovate the new drug discovery and development.     

Occasional smoking in college: Who,what, when and why?

Introduction

The majority of college students who smoke do so on an occasional basis and generally do not define themselves as smokers. This represents a considerable challenge for public health efforts to prevent escalation of use and to promote cessation. Strengthening such efforts will require further examination of the motivations behind occasional smoking within this vulnerable group.

Methods

Based within a priori identified content areas, we conducted eight focus groups of occasional smokers (N = 53) at two demographically diverse colleges in the southeastern U.S.

Results

Few participants self-identified as a smoker and few had immediate desire to quit. Most identified extrinsic motivations for future quitting, including college graduation and parenthood. Although participants acknowledged smoking-related health risks, they minimized them as being personally irrelevant. Participants highlighted social (i.e., alcohol and other smokers) and stress-related smoking triggers. They also described how they carefully managed the situations in which they would, and would not smoke in order to preserve their identity.

Conclusions

College students who smoke occasionally appear to engage in impression management, taking effort to shape their personal image to not appear as a smoker. They use smoking mainly as a social engagement tool, but also to alleviate negative emotions. They express minimal desire to quit and believe they are immune to the health risks of smoking. Public health messages should address this common pattern of smoking among young adults differently than regular smoking patterns by highlighting the social, emotional, and health consequences of occasional smoking before nicotine dependence has fully developed.     

Dyspepsia: how to manage and how to treat?

Recent guidelines for dyspepsia, defined as pain or discomfort centred in the upper abdomen, emphasize that in younger patients with no alarm features and not taking nonsteroidal anti-inflammatory drugs, testing for Helicobacter pylori and treatment of the infection if present is a standard of care. If H. pylori is not present, empirical management (e.g. acid suppression) is often prescribed. It is further recommended that if patients relapse or fail to respond to treatment then upper endoscopy be undertaken. However, these guidelines have become controversial for a number of reasons. Firstly, the prevalence of H. pylori infection is falling as is the incidence of peptic ulcer disease due to the infection. Idiopathic peptic ulcer disease is also being increasingly recognized. Furthermore, the cost-effectiveness of endoscoping treatment failures has been questioned, as the yield is low and patient management is usually not altered. Finally, it remains controversial whether the treatment of H. pylori infection in functional dyspepsia is of value, and two recent high quality meta-analyses have reached diametrically opposite conclusions. Alternative strategies, such as initially treating with acid suppression and then considering H. pylori infection in those who fail have been suggested, as has in low H. pylori prevalent regions the abandonment of a test-and-treat strategy. However, appropriate management trials of these alternative strategies in primary care are lacking. The management of patients with functional dyspepsia who fail initial antisecretory therapy is now difficult; prokinetics have fallen into some disrepute. Tricyclic antidepressants (at a low dose) may be useful in a subset, but adequate trials are lacking.     

Evidence-based treatment: Why,what, where,when, and how?

Research and clinical perspectives are blended in this commentary on the rapidly emerging requirement for evidence-based treatment (EBT) in substance abuse programs. Although, historically, it has not been a standard of care in behavioral health, there are sound scientific, ethical, and compassionate reasons to learn and deliver an EBT as it becomes available. This article explores a series of issues, including the following: (1) Why should EBTs be used in substance abuse treatment? (2) What kinds of treatment are EBTs, and how are they determined? (3) Where can EBTs be implemented—at what levels of service delivery? (4) When should EBTs be used? and (5) How do clinicians learn EBTs? Potential pitfalls in implementing EBTs are also considered.     

Over‐the‐counter ibuprofen: how and why is it used?

Objectives — To pilot an over‐the‐counter (OTC) medicine pharmacovigilance project, using ibuprofen as a model. Method — All users of any tablet or capsule form of ibuprofen (excluding compound products) purchased from 61 participating community pharmacies, aged ≥18 years and able to give informed consent, were eligible to join the study. A postal questionnaire one week after the index purchase monitored the follow‐up rate, drug usage, past medical history, concurrent medication, symptoms and health service utilisation. Setting — Primary care: community pharmacies in Grampian, Scotland. Key findings — A total of 443/544 (81 per cent) questionnaires were completed. The recommended daily dose of OTC ibuprofen (1,200mg) was exceeded by 35 customers (8 per cent) on at least one day and the recommended maximum daily dose that can be prescribed by a physician (2,400mg) was exceeded on five occasions. During the seven days after the index purchase, ibuprofen was used by 15 customers (4 per cent) with an active or past history of peptic ulcer, and 30 (7 per cent) with an active or past history of asthma. Thirty‐eight per cent had purchased ibuprofen for a chronic condition and 32 per cent were still taking it at the end of the initial seven‐day period. Twenty‐eight of 412 customers (7 per cent) sought advice during the seven‐day period about at least one symptom: 13 consulted their general practitioner, 12 consulted a pharmacist, two consulted both their GP and a pharmacist, and one consulted a hospital doctor. Some of these consultations (23/28, 82 per cent) might have related to an adverse reaction to ibuprofen: 11 customers (3 per cent) consulted about lower abdominal symptoms, nine about gastric symptoms and three about wheeziness. Conclusions — This pilot study identifies instances of contraindicated and excessive use of OTC ibuprofen, indicating a need for pharmacovigilance studies of OTC medicines; it also demonstrates the feasibility of a major study.