Management of essential hypertension

Hypertension, in spite of a very high prevalence, remains undertreated. This is not due to a lack of effective therapeutic modalities. Non-pharmacological treatments can be effective in many patients. If those treatments fail to reduce blood pressure sufficiently, the physician can choose between numerous classes of antihypertensive agents. However, interpatient variability in response to these agents is high, and use of multiple agents is frequently necessary. Thus, no single class has proven to be superior for the majority of patients. This article will review the different non-pharmacological and pharmacological methods available to treat hypertension, as well as the guidelines that are available to aid in proper selection of a treatment regimen.     

Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature.

Atypical antipsychotic agents seem to be effective treatments for bipolar disorder, especially as adjunctive treatments. They may be a safer and more effective alternative to the common practice of maintenance adjunctive treatment with traditional antipsychotic agents in patients with bipolar disorder. However, currently available research studies are limited methodologically mainly to open-label, uncontrolled designs. Further research is required before the definitive efficacy of these agents in bipolar disorder is established. If randomized or double-blind data support the open-label data reviewed here, atypical antipsychotic agents may possess an important role in the adjunctive treatment of bipolar disorder.     

Outcomes associated with the use of biologic agents in moderate to severe psoriasis

An estimated 2.1% of Americans have psoriasis and approximately 30% of them have moderate to severe psoriasis. Although the disease is not associated with mortality, it has a significant impact on health-related quality of life among patients. Several therapies are available for psoriasis including topical agents, phototherapy, and systemic medications. Recently, effective yet expensive biologic agents have been added as treatments for moderate to severe psoriasis. Biologics are recommended in patients for whom all other available treatment options have failed. This extensive review provides important information on the clinical and patient-related outcomes associated with the biologic agents used in psoriasis.     

How to use calcium antagonists in hypertension: putting the JNC-VI guidelines into practice. Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure.

The prevention and treatment of hypertension remain as major challenges for clinicians all over the world. The recently published Sixth Report of the Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VI) uses evidence-based medicine in providing guidelines to aid clinicians in the prevention, detection and treatment of high blood pressure, including pharmacological approaches. Calcium antagonists are used widely for the treatment of hypertension, and JNC-VI focuses on specific situations where calcium antagonists could be considered as preferred treatments. There are a large number of calcium antagonists available, with a variety of pharmacodynamic and pharmacokinetic actions. Several sustained-release formulations of these drugs are also available. In terms of blood pressure control, calcium antagonists are more effective as antihypertensive treatments than beta-blockers, ACE inhibitors and angiotensin II receptor blockers in Black patients. The dihydropyridine calcium antagonists have been shown to reduce morbidity and mortality in elderly patients with isolated systolic hypertension. The rate-lowering calcium antagonists can be used as alternatives to beta-blockers in patients with coronary artery disease and hypertension. Calcium antagonists can be used as alternatives to ACE inhibitors in patients with hypertension and concomitant diabetes mellitus and/or renal disease. Some dihydropyridine calcium antagonists may be useful as alternatives to ACE inhibitors in patients with hypertension and systolic heart failure. Calcium antagonists appear to be extremely useful in patients with cyclosporin-induced hypertension, and in patients with hypertension and concomitant Raynaud's phenomenon and/or migraine. The rate-lowering agents can be used in patients with atrial tachyarrhythmias and hypertension. Clinicians should be aware of drug-drug interactions involving calcium antagonists, especially after the recent problems with mibefradil. Although retrospective studies have caused controversy regarding the safety of calcium antagonists in patients with hypertension, recent prospective studies have revealed no major safety concerns with these drugs.     

Long-term prophylaxis in bipolar disorder

Bipolar disorder is a major cause of disability, and the prevention of relapse is a key management goal. Pharmacological interventions, effectively delivered through enhanced clinical care, are central to long-term management.This article summarises the available evidence for a range of pharmacological options, and provides guidance on common issues in clinical management in line with current practice guidelines. The use of medications for long-term prophylaxis should be considered in all patients meeting criteria for bipolar I disorder. Increasing high-quality evidence from randomised trials informs management decisions relating to both novel agents, such as lamotrigine and olanzapine, and longer-established therapies, such as lithium and valproate, in monotherapy. Medications taken long-term in bipolar disorder differ in the extent to which they protect against manic and depressive relapse. Consequently, the emerging challenge is to understand how combination treatments can enhance efficacy and effectiveness based on data from controlled trials rather than random polypharmacy.Clinical care can be enhanced with effective education about the illness, and the use of strategies to improve treatment adherence and the recognition and management of stressors or prodromal symptoms. Where available, a range of specific psychological interventions can be effective as an adjunct to medication.When discontinuation of prophylaxis is necessary, gradual tapering of dose over weeks or months is recommended.     

Medical management of urinary stone disease

Kidney stones occur in approximately 10% of patients in their lifetimes, and > 10 crystal types have been reported in the literature. After treatment, a subset of these patients will have recurrent calculi, leading to significant morbidity and potential for serious chronic renal disease. Detailed metabolic evaluation is indicated in patients at high risk for stone recurrence, as a reversible metabolic abnormality can be identified in > 90% of them. Once the patient's underlying physicochemical and physiologic derangements are defined, targeted medical therapy can be initiated in order to prevent growth of pre-existing stones and new stone formation. In this report, the author provides a comprehensive review of the presently available selective and nonselective pharmacologic treatments for stones. Several exciting investigational pharmaceutical agents for kidney stone prevention are also discussed. Although many of these agents are effective, there remain clinical scenarios in which existing medicines are insufficient.     

Recent advances in antiviral agents: antiviral drug discovery for hepatitis viruses

Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated liver diseases are now one of the important health problems in the world because of the high numbers of patients and the serious consequences. Recently, however, relatively effective treatments with antiviral agents have become available. Interferon (IFN), lamivudine and adefovir are now approved for treatment of HBV-associated liver diseases and they have been shown to be fairly effective. The goal of treatments for HBV-associated liver disease is to achieve a clinical cure in as short a period as possible without producing resistance mutation of the virus. Several nucleotide analogues with more potent antiviral activities are now in clinical trials. In the case of HCV-associated liver diseases, Pegylated IFN (Peg IFN) + ribavirin combination therapy is the standard and most effective treatment with a sustained response of 60-70%. The goal of the treatments for these liver diseases is to induce the complete eradication of the infected virus and at present new anti HCV drugs targeting the molecular segments of the virus are under development. It is expected that the complete eradication of infected virus will be possible in most cases in the near future.     

Amyotrophic lateral sclerosis: progress and prospects for treatment

Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.     

Safety considerations with combination therapies for psoriasis

ABSTRACT

Introduction: Psoriasis is a chronic inflammatory skin disease that waxes and wanes, and long-term remission can be difficult to achieve regardless of disease severity. Currently, numerous treatment options are available for psoriasis including steroid and non-steroid topical agents, phototherapy, oral systemic agents, and biologics, with many more therapeutic agents under development.

Areas covered: This article will review various combination therapy strategies such as rotational therapy and sequential therapy and describe a variety of safe and effective combination therapies for the treatment of psoriasis. Two or more agents with different mechanisms of action and safety profiles can be used to achieve and/or maintain adequate disease control while minimizing the toxicity of treatments. Combination therapy can also be used when a single agent is not enough for treating recalcitrant disease. Choosing a combination regimen that maximizes safety and efficacy while considering patient usability and compliance can be a challenge.

Expert opinion: Given the various treatment options currently available for psoriasis and more agents under development, combination therapy will continue to be a valuable treatment strategy for any patient with psoriasis. It is crucial for clinicians to carefully consider the fine balance between safety and efficacy when combining various therapeutic agents.     

Pharmacologic therapy for cough

Cough is the commonest symptom for which patients seek medical care and yet effective, well-tolerated cough medicines remain a significant unmet clinical need. The development of anti-tussive agents has probably been restricted by a number of factors; our understanding of the specific mechanisms evoking cough in different diseases and how this differs from the role of cough as a protective reflex is limited. Also well-validated tools for the assessment of cough have been lacking. These issues have not encouraged investment by the pharmaceutical industry and there have been no new licensed treatments for cough in more than 50 years. This article will use a mechanism-based approach to discuss the clinical evidence for the anti-tussive activity of currently available agents.     

Paediatric uses of atypical antipsychotics

Antipsychotics are commonly prescribed to children and adolescents. With the relatively recent availability of the atypical antipsychotics, physicians have begun prescribing these agents to young people in the hope of finding safe, effective alternatives to the typical antipsychotics. This report reviews what is currently known about the use of the atypical antipsychotics in young people. Most of the currently available data are based on case reports and case series. The results of only a handful of prospective trials pertaining to the use of the atypical antipsychotics in youths have been reported. Based on the available information, it appears that clozapine has a role in juvenile treatment resistant schizophrenia. When considered as a group, the 'first-line' atypical antipsychotics risperidone, olanzapine and quetiapine appear to have promise as treatments for several neuropsychiatric disorders in young people. These conditions include psychotic, mood, disruptive, movement and pervasive developmental disorders. Unfortunately, as has historically been the case, the demand to address the clinical needs of young patients with neuropsychiatric disorders has outpaced empirically based information. This is particularly important because significant side effects can occur when children or adolescents are treated with atypical antipsychotics. Since there is a paucity of short-term and almost no long-term safety data pertaining to these agents in young people, careful consideration must be made prior to initiating atypical antipsychotic treatment for a child or teenager. Based upon what is known about these agents, a rational approach to the use of these drugs in juveniles is offered.     

Paediatric uses of atypical antipsychotics

Antipsychotics are commonly prescribed to children and adolescents. With the relatively recent availability of the atypical antipsychotics, physicians have begun prescribing these agents to young people in the hope of finding safe, effective alternatives to the typical antipsychotics. This report reviews what is currently known about the use of the atypical antipsychotics in young people. Most of the currently available data are based on case reports and case series. The results of only a handful of prospective trials pertaining to the use of the atypical antipsychotics in youths have been reported. Based on the available information, it appears that clozapine has a role in juvenile treatment resistant schizophrenia. When considered as a group, the ‘first-line’ atypical antipsychotics risperidone, olanzapine and quetiapine appear to have promise as treatments for several neuropsychiatric disorders in young people. These conditions include psychotic, mood, disruptive, movement and pervasive developmental disorders. Unfortunately, as has historically been the case, the demand to address the clinical needs of young patients with neuropsychiatric disorders has outpaced empirically based information. This is particularly important because significant side effects can occur when children or adolescents are treated with atypical antipsychotics. Since there is a paucity of short-term and almost no long-term safety data pertaining to these agents in young people, careful consideration must be made prior to initiating atypical antipsychotic treatment for a child or teenager. Based upon what is known about these agents, a rational approach to the use of these drugs in juveniles is offered.     

Current therapy of pemphigus vulgaris

Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease of the skin and mucous membranes, characterized by flaccid bullae that rupture and leave erosions. Its treatment is challenging. Although the use of systemic corticosteroids remains the cornerstone of effective therapeutic regimens for PV, their prolonged administration may lead to serious side effects. It is therefore necessary, for many patients, to add immunosuppressive agents or use immunomodulatory procedures to achieve remission. This paper will summarize the treatments available for PV, while focusing on the most recently available therapeutic options.     

Current and potential pharmacological treatments for obsessive-compulsive disorder

In the past 20 years, several effective treatments have been developed for obsessive-compulsive disorder. Despite this, it is a disorder that is often inadequately treated by available therapies. Recent advances in neuroimaging and neurophysiology have provided some clues to possible treatments that may be more effective in treating this disorder. Serotonin agents remain the cornerstone of pharmacological treatment for obsessive-compulsive disorder. The development of agents that target specific serotonin receptor subtypes may improve the effectiveness of drug treatment. Other possible future treatment approaches are also discussed.     

Antibody treatments of inflammatory arthritis

Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis are extremely common in the community, with a prevalence of up to 5%, and they cause substantial morbidity. The development of anti-TNF agents for use initially in rheumatoid arthritis, and subsequently more broadly in inflammatory arthritis, represents the biggest advance in management of these conditions since the introduction of corticosteroid agents, and is a major vindication of public funded arthritis research. However, there are limitations of even these highly effective agents. A significant minority of patients with inflammatory arthritis do not respond to these anti-TNF agents, they are associated with substantial risk of toxicity, require parenteral administration, and are extremely expensive. New antibody treatments in development can be divided into anti-cytokine agents, cell-targeted therapies, co-stimulation inhibitors, and treatments aimed at preventing joint erosion consequent on inflammation. This review discusses the state of the art in the development of these agents for management of this common group of diseases.     

Current and potential pharmacological treatments for obsessive-compulsive disorder

In the past 20 years, several effective treatments have been developed for obsessive-compulsive disorder. Despite this, it is a disorder that is often inadequately treated by available therapies. Recent advances in neuroimaging and neurophysiology have provided some clues to possible treatments that may be more effective in treating this disorder. Serotonin agents remain the cornerstone of pharmacological treatment for obsessive-compulsive disorder. The development of agents that target specific serotonin receptor subtypes may improve the effectiveness of drug treatment. Other possible future treatment approaches are also discussed.     

Reducing the average number of patients needed in a phase II trial through novel design

Abstract

Phase II represents a very important part of the drug development process. It is important that genuinely effective treatments have a high chance of succeeding whilst treatments that will fail at phase III are screened out. Because of the high number of treatments available for testing and limited resources and patients available, it is increasingly of interest to apply novel designs to improve the efficiency of phase II trials. This paper shall argue that phase II presents the most promising area for applying novel designs and will review some recent developments in three classes of novel design: group-sequential designs, multi-arm designs, and enrichment designs. All three types of design considerably improve the efficiency of phase II trials on average and also ensure that patients are more likely to be treated with the best available treatment for them. Although the designs have drawbacks, the considerable advantages mean that these designs will become increasingly important in phase II.     

An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy

Neuropathic pain is a persistent pain condition that develops secondary to nerve injury. The two most common types of peripheral neuropathic pain are post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). Amitriptyline, nortriptyline, desipramine and imipramine are TCAs that have been shown to be effective for the symptomatic relief of PHN and PDN. Serotonin noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine have been shown to be very promising for the treatment of PDN with fewer adverse effects than TCAs. Selective serotonin reuptake inhibitors (SSRIs) were shown in a number of studies to have some efficacy in relieving PDN-related pain, yet other studies of the SSRIs have demonstrated conflicting outcomes. Most of the older antiepileptic studies were performed in patients with PDN; consequently, little is known about the efficacy of these drugs in patients with PHN. Carbamazepine, phenytoin and valproic acid were shown to be effective in ameliorating PDN-related pain. Other antiepileptic agents, including lamotrigine, oxcarbazepine and topiramate, have demonstrated some beneficial effects for the treatment of PDN, although they were also found to be ineffective in some PDN studies. alpha2delta Ligands such as gabapentin and pregabalin have been proven to be effective for the treatment of PHN and PDN in a number of large placebo-controlled trials. These drugs are useful not only in relieving pain but also in improving quality of life. Although the use of opioids for the treatment of neuropathic pain is controversial, a number of studies support the efficacy and safety of opioids in the treatment of neuropathic pain. Of these, oxycodone and tramadol have been shown to be superior to placebo for the treatment of PHN and PDN. A number of small studies have shown that dextromethorphan was effective in patients with PDN but not in patients with PHN. Topical agents such as lidocaine 5% patches and topical capsaicin are useful in ameliorating pain in patients with PHN but these agents are unsatisfactory for use as a sole agent. Although a number of drug treatments are available for the symptomatic relief of neuropathic pain symptoms, these agents do not provide satisfactory relief in all patients. For these patients, other treatment alternatives such as combination drug therapy that produces pain relief via distinctly different mechanisms may be successful. The purpose of this review is to compare the efficacy and limitations of currently available pharmacological treatments for the symptomatic relief of PHN and PDN, and to discuss the potential of combination therapy in PHN and PDN.     

The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide

INTRODUCTION: Linaclotide is a novel intestinal secretagogue that is in the advanced stages of development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. These functional gastrointestinal disorders are highly prevalent in adults and children and often do not respond satisfactorily to available treatments. Linaclotide appears to be a promising new agent for patients who are not satisfied with currently available agents. AREAS COVERED: This article is formed from a literature review of all the studies published about linaclotide up to January 2011. It covers the pharmacodynamics and pharmacokinetics of this novel agent. It also provides a summary of the published clinical trials concerning efficacy and safety in patients with chronic constipation and IBS-C. The authors provide the reader with a better understanding of how the molecular pathophysiology of certain enteropathic diarrheal bacteria lead to the development of this novel prosecretory drug. The reader will also learn about the development of molecularly-based treatment options for chronic constipation and other constipation-associated disorders such as IBS-C. EXPERT OPINION: Linaclotide appears to be a well-tolerated and effective agent for many patients with chronic constipation and IBS-C. Two Phase III studies in chronic constipation and two in IBS-C have provided promising data on the efficacy and safety of this agent for these two disorders. The positioning of linaclotide among the various available agents for these two disorders remains to be established after approval from the FDA is granted.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.