Tumor necrosis factor inhibitors in the management of juvenile idiopathic arthritis: an evidence-based review

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder of unknown origin that is often treated with a variety of disease-modifying agents. Tumor necrosis factor (TNF) inhibitors are a group of genetically engineered biologic agents that target the proinflammatory cytokine TNF. This review focuses on the use of TNF inhibitors in JIA. Etanercept was the first TNF inhibitor approved for use in children with moderate to severe polyarticular-course JIA following encouraging results from a randomized, double-blind, placebo-controlled, multicenter trial in children. Open-label extension studies of the original trial involving 8 years of follow-up demonstrated the long-term safety and efficacy of etanercept in children. Other studies from established registries also corroborate the safety of etanercept in JIA. The second TNF inhibitor to be approved for use in JIA is adalimumab following recent favorable results from another randomized, placebo-controlled, multicenter study in polyarticular-course JIA. While infliximab is not approved by the US FDA for use in JIA, it is frequently used in clinical practice for this indication. However, because the chimeric structure of infliximab incorporates murine components, it has the potential for allergic and infusion reactions. Patient responses to individual TNF inhibitors may vary depending on concomitant medications such as methotrexate, and also on the category of JIA.     

Drug-induced gynecomastia: an evidence-based review

Introduction: Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. Areas covered: Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. Expert opinion: Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.     

Hypertension in the elderly: an evidence-based review

The progressive ageing of world population, and the increasing prevalence hypertension in elderly people are leading to the consideration that hypertension in the elderly is one of the main topic in hypertension treatment. Multiple mechanisms, including stiffening of large arteries, endothelial dysfunction, cardiac remodeling, autonomic dysregulation, renal aspects, contribute to the great prevalence of hypertension in the elderly and to increased cardiovascular morbidity and mortality. Treatment of hypertension can hardly put back older patients in a low risk category, especially if target organ damage is present. Nevertheless, blood pressure control can successfully prevent stroke, cognitive decline, coronary heart disease and heart failure, and reduce mortality in the elderly, and even in patients > 80 years, as recently demonstrated. Blood pressure should be lowered below 140/90 mmHg also in older patients. However the HYVET study suggests that a goal of 150/90 mmHg can be reasonable in patients aged 80 years or more. Drug treatment should be titrated with particular caution to adverse responses and excessive blood pressure lowering.     

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV₁%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden.

Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications.

Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.     

Role of antiarrhythmic therapy in patients at risk for sudden cardiac death: an evidence-based review

Sudden cardiac death (SCD) accounts for more than half of all cardiac deaths occurring each year in the United States. Although it has several causes, patients at greatest risk are those with coronary artery disease and impaired left ventricular function, heart failure secondary to ischemia or idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, documented sustained ventricular tachycardia or ventricular fibrillation, and survivors of cardiac arrest. The presence of asymptomatic ventricular arrhythmias, positive signal-averaged electrocardiogram (ECG), low heart rate variability index, or inducible ventricular tachycardia or ventricular fibrillation increases the risk. In primary prevention trials in patients with ischemic heart disease, beta-blockers reduced both total mortality and SCD, whereas class I antiarrhythmic drugs, especially class IC, increased mortality. Among class III agents, d,l-sotalol and dofetilide have a neutral effect on mortality, whereas d-sotalol increases mortality. Amiodarone has a neutral effect on total and cardiac mortality but does reduce the risk of arrhythmic death and cardiac arrest. Three primary prevention trials in patients with ischemic heart disease were conducted with implantable cardioverter-defibrillators (ICDs). Patients with low ejection fractions (EFs), asymptomatic ventricular arrhythmias, and inducible ventricular tachycardia or ventricular fibrillation had significant reductions in total, cardiac, and arrhythmic death with ICDs compared with either no drug therapy or conventional antiarrhythmic agents. The ICDs did not reduce mortality in patients with low EFs and a positive signal-averaged ECG undergoing coronary bypass graft. In those with heart failure, beta-blockers reduced total and SCD mortality, but dofetilide and amiodarone had a neutral effect on mortality. In the secondary prevention of SCD, antiarrhythmic drugs alone generally are not thought to improve survival. In three trials in patients with documented sustained ventricular tachycardia or ventricular fibrillation, or survivors of SCD, ICDs reduced cardiac and arrhythmic mortality. Total mortality, however, was significantly reduced in only one of these trials. The role of antiarrhythmic drugs in secondary prevention of SCD is limited to patients in whom ICD is inappropriate or in combination with ICD. Antiarrhythmics can be given selectively with ICDs to decrease episodes of ventricular tachycardia or fibrillation to reduce ICD discharges, to suppress episodes of nonsustained ventricular tachycardia that trigger ICD discharges, to slow the rate of ventricular tachycardia to increase hemodynamic stability, to allow effective antitachycardia pacing, or to suppress supraventricular arrhythmias.     

Insulin aspart : an evidence-based medicine review

This paper provides a review and evaluation of the published evidence relating to the efficacy, safety and ease of administration of the rapid-acting insulin analogue insulin aspart in comparison with human insulin (HI) in diabetes mellitus in the following categories: (a) in adults, (b) in children, and (c) in continuous subcutaneous insulin infusion (CSII). A search for publications on insulin aspart was conducted for the following databases: Cochrane, BIOSIS, EMBASE-DP and MEDLINE. Publications were examined for relevance by two independent assessors and were graded using a system developed by the Oxford Centre for Evidence-Based Medicine. Overall, the evidence comparing insulin aspart with HI was of high quality, with all three categories graded as grade A evidence. Studies showed strong evidence for better glycaemic control, without an increased risk of hypoglycaemia, together with evidence supporting improved convenience and flexibility in administration of insulin aspart compared with regular HI in adult diabetic patients. Evidence from three trials in adults with type 1 diabetes showed a lower incidence of major nocturnal hypoglycaemia with insulin aspart versus regular HI. Published evidence also confirmed the more rapid action of insulin aspart versus HI, and a comparable efficacy and safety profile for both insulin types in type 1 paediatric patients. There was also strong evidence that insulin aspart is well tolerated and efficacious for CSII/pump use. Insulin aspart better mimics the physiological response to meals than regular HI, and may offer advantages in terms of glycaemic control and reduction of hypoglycaemia combined with flexibility and convenience of administration. Overall, there is a good body of evidence to support the efficacy, tolerability and ease of administration of insulin aspart in patients with type 1 and type 2 diabetes.     

Drug removal by plasmapheresis: an evidence-based review

Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publications-mostly case reports of overdoses-have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.     

Pharmacological management of Huntington's disease: an evidence-based review

INTRODUCTION: Despite the increasing body of published reports on pharmacological interventions in Huntington's disease (HD), an evidence based review (EBR) of treatment studies has not yet been published. METHOD: Systematic literature searches were done using Medline (1965-August 2005), the central database in the Cochrane Library (1969-August 2005), and reference lists published in review articles and other clinical reports. Randomized controlled trials (RCTs) were classified as level-I-studies in this paper. Level-II evidence was assigned to non-randomized, controlled clinical studies. Level-III-studies comprised open label trials excluding case reports. Measures of efficacy as well as safety and tolerability were considered for each compound. RESULTS: We identified 218 publications on pharmacological interventions in HD since 1965. Among them were 20 level-I, 55 level-II, 54 level-III trials, and 89 case reports. All these papers are listed and analyzed. Chorea was the primary end point in all level-I and level-II symptomatic intervention trials. There is some evidence for treating chorea with haloperidol or fluphenazine, and less evidence for olanzapine. These three drugs have been considered "possibly useful" for the treatment of chorea in this analysis. Other substances (e.g. amantadine, riluzole, and tetrabenazine) are considered "investigational" for chorea. There is very low evidence for the treatment of other problems: "possibly useful" drugs are L-dopa and pramipexole for rigidity; amitryptiline and mirtazapine for depression; risperidone for psychosis; and olanzapine, haloperidol, and buspirone for behavioral symptoms in HD. Three substances are considered "investigational" for possible neuroprotection: coenzyme Q10, minocycline, and unsaturated fatty acids. CONCLUSION: There is poor evidence in management of HD today. The analysis of the twenty level-I studies fails to result in any treatment recommendation of clinical relevance. High-quality RCT are highly warranted to advance HD treatment in clinical practice.     

Montelukast in the treatment of allergic rhinitis: an evidence-based review

Cysteinyl-leukotrienes (CysLTs) are endogenous mediators of inflammation and play an important role in allergic airway disease by stimulating bronchoconstriction, mucus production, mucosal oedema and inflammation, airway infiltration by eosinophils, and dendritic cell maturation that prepares for future allergic response. Montelukast inhibits these actions by blocking type 1 CysLT receptors found on immunocytes, smooth muscle and endothelium in the respiratory mucosa. Initially developed as a treatment for asthma, montelukast has more recently found use in the treatment of allergic rhinitis (AR). We conducted a systematic review of studies that have evaluated montelukast in the treatment of seasonal AR (SAR) and perennial AR (PAR), with and without concomitant asthma. Primary consideration was given to large, randomised, placebo-controlled, double-blind clinical trials in which AR endpoints were assessed and the use of concurrent treatments for AR was excluded. Eight such studies were found in the literature. The primary endpoint in these was daytime nasal symptom severity represented by a composite score derived from individual self-ratings of nasal congestion, rhinorrhoea, nasal pruritus and sneezing. Secondary endpoints have included these individual nasal symptom scores, additional scores for eye, ear and throat symptoms, the impact of rhinitis on quality of sleep, global evaluations of outcome by patients and physicians, and measures of the severity of concomitant asthma. A general outcome was that patients treated with montelukast had significantly greater improvements in their symptoms of SAR and PAR than did patients who were given a placebo. As monotherapy, montelukast exhibited efficacy similar to that of loratadine, but less than that of the intranasally administered corticosteroid fluticasone propionate. The use of montelukast in combination with antihistamines such as loratadine or cetirizine has generally resulted in greater efficacy than when these agents were used alone, and in some studies has produced results comparable with intranasally applied corticosteroids. In patients with AR comorbid with asthma, montelukast treatment has resulted in significant improvements in both, compared with placebo. Montelukast is well tolerated and has a favourable safety profile; adverse events have occurred at similar frequencies in patients taking either montelukast or placebo. Montelukast provides an effective and well tolerated oral treatment for allergic airway inflammation in patients with SAR or PAR without asthma, and in patients in whom AR is comorbid with asthma.     

Role of interleukin-1 in bacterial atherogenesis

The high incidence of cardiovascular diseases resulting from atherosclerosis, especially in individuals lacking classic risk factors, has spawned interest in the possibility of unrecognized risk factors, such as chronic bacterial infection. Longstanding low-grade infections, such as periodontal disease, have the potential to affect distant sites in the body by inducing host cells to release inflammatory mediators into the bloodstream. Inflammatory mediators are released by macrophages upon interaction with activated T-helper cells or upon direct recognition of bacterial antigens, and by nonimmune cells upon recognition of antigen through Toll-like receptors. One key mediator, interleukin-1 (IL-1) is released in response to bacterial infection and is known to have specific proatherogenic properties. Increased levels of IL-1 enhance vascular adhesion, vascular permeability, macrophage activation, endothelial and smooth muscle cell proliferation, and protease-induced plaque rupture - all key steps in the progression of atherogenesis. In a recent study, we demonstrated a profound reduction in the progression of atherosclerosis in IL-1 knockout mice. IL-1 holds potential as a target for future antiatherosclerotic therapies, although given its ubiquity in the body, this would not come without unwanted side effects, such as immunosuppression.     

Approved and investigational uses of modafinil : an evidence-based review

Modafinil is a wake-promoting agent that is pharmacologically different from other stimulants. It has been investigated in healthy volunteers, and in individuals with clinical disorders associated with excessive sleepiness, fatigue, impaired cognition and other symptoms. This review examines the use of modafinil in clinical practice based on the results of randomized, double-blind, placebo-controlled clinical trials available in the English language in the MEDLINE database. In sleep-deprived individuals, modafinil improves mood, fatigue, sleepiness and cognition to a similar extent as caffeine but has a longer duration of action. Evidence for improved cognition in non-sleep-deprived healthy volunteers is controversial.Modafinil improves excessive sleepiness and illness severity in all three disorders for which it has been approved by the US FDA, i.e. narcolepsy, shift-work sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure (CPAP). However, its effects on safety on the job and on morbidities associated with these disorders have not been ascertained. Continued use of CPAP in obstructive sleep apnoea is essential. Modafinil does not benefit cataplexy.In very small, short-term trials, modafinil improved excessive sleepiness in patients with myotonic dystrophy. It was efficacious in fairly large studies of attention deficit hyperactivity disorder (ADHD) in children and adolescents, and was as efficacious as methylphenidate in a small trial, but has not been approved by the FDA, in part because of its serious dermatological toxicity. In a trial of 21 non-concurrent subjects, with 2-week treatment periods, modafinil was as effective as dexamfetamine in adult ADHD. Modafinil was helpful for depressive symptoms in bipolar disorder in a trial that excluded patients with stimulant-induced mania. A single dose of modafinil may hasten recovery from general anaesthesia after day surgery. A single dose of modafinil improved the ability of emergency room physicians to attend didactic lectures after a night shift, but did not improve their ability to drive home and caused sleep disturbances subsequently.Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo.Trials of modafinil for excessive sleepiness in Parkinson's disease, cocaine addiction and cognition in chronic fatigue syndrome provided inconsistent results; all studies had extremely small sample sizes. Modafinil cannot be recommended for these conditions until definitive data become available.Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes. The modafinil dose should be reduced in the elderly and in patients with hepatic disease. Caution is needed in patients with severe renal insufficiency because of substantial increases in levels of modafinil acid. Common adverse events with modafinil include insomnia, headache, nausea, nervousness and hypertension. Decreased appetite, weight loss and serious dermatological have been reported with greater frequency in children and adolescents, probably due to the higher doses (based on bodyweight) used. Modafinil may have some abuse/addictive potential although no cases have been reported to date.     

Anidulafungin: an evidence-based review of its use in invasive fungal infections

Introduction:

Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases.

Aims:

This review assesses the pharmacology and evidence for the use of anidulafungin in the treatment of serious fungal infections.

Evidence review:

There is substantial evidence that anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of anidulafungin on economic outcomes will be beneficial.

Place in therapy:

Current evidence supports the use of anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.     

Subcutaneous apomorphine : an evidence-based review of its use in Parkinson's disease

Apomorphine, a short-acting dopamine D1 and D2 receptor agonist, was the first dopamine receptor agonist used to treat Parkinson's disease. Subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory levodopa-induced 'off' states in fluctuating Parkinson's disease either as intermittent rescue injections or continuous infusions. Other indications include the challenge test for determining the dopaminergic responsiveness and finding the appropriate dose of the drug in intermittent subcutaneous administration. Except for a rapid on- and offset of the antiparkinsonian response with subcutaneous apomorphine, the magnitude and pattern of the motor response to single dose of subcutaneously administered apomorphine is qualitatively comparable to that of oral levodopa. Seventy-five percent of patients achieve a clinically significant improvement with a dose of apomorphine 4mg. The efficacy of intermittent subcutaneous apomorphine injections as an add-on to levodopa therapy in advanced Parkinson's disease was explored in one short-term, randomised, double-blind, placebo-controlled trial, one short-term and six long-term, open-label, uncontrolled studies, including a total of 195 patients. These studies provide evidence that this mode of administration was successful in aborting 'off' periods and improving Parkinson's disease motor scores, but tended to increase dyskinesias. No levodopa-sparing effect was observed. Eleven long-term, open-label, uncontrolled studies, including a total of 233 patients evaluated the efficacy of continuous subcutaneous apomorphine infusions in monotherapy or as an add-on to levodopa therapy in advanced Parkinson's disease. These studies proved that subcutaneous apomorphine infusions are successful in aborting 'off' periods, reducing dyskinesias and improving Parkinson's disease motor scores with the added benefit of a substantial levodopa-sparing effect. The apomorphine challenge test has at least 80% overall predictive ability to clinically diagnose Parkinson's disease across the different stages of the disease and parkinsonian syndromes. Similarly, those data also indicate that the apomorphine challenge test has a >80% ability to predict dopaminergic responsiveness across all stages of Parkinson's disease. Adverse events are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric adverse effects. The incidence of adverse effects is higher in patients receiving continuous infusion than in those receiving intermittent pulsatile administration. Based on the results of these studies it is recommended that subcutaneous apomorphine either as intermittent injections or continuous infusions should be offered to any suitable Parkinson's disease patient who has difficulties in his/her management with conventional therapy. Low-dose levodopa therapy in combination with waking-day hours subcutaneous apomorphine infusion would probably be the most efficient treatment. Continuous subcutaneous apomorphine infusions should be evaluated before more invasive measures or neurosurgical interventions are contemplated.     

Anidulafungin: an evidence-based review of its use in invasive fungal infections

INTRODUCTION: Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases. AIMS: This review assesses the pharmacology and evidence for the use of anidulafungin in the treatment of serious fungal infections. EVIDENCE REVIEW: There is substantial evidence that anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of anidulafungin on economic outcomes will be beneficial. PLACE IN THERAPY: Current evidence supports the use of anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.     

Adalimumab in ankylosing spondylitis: an evidence-based review of its place in therapy

INTRODUCTION: Ankylosing spondylitis (AS) is an idiopathic chronic inflammatory disease that has prominent effects on the spine and peripheral joints. In addition, extraarticular manifestations such as enthesitis and acute anterior uveitis may be clinically important. In recent years, the therapy of AS has changed, largely due to the introduction of inhibitors of the proinflammatory cytokine tumor necrosis factor (TNF). Adalimumab, a human monoclonal antibody specifically for TNF, is the most recent of the TNF blocking agents that have been approved for the treatment of active, nonsteroidal antiinflammatory drug (NSAID)-refractory patients with AS. AIMS: To evaluate the evidence for the therapeutic value of adalimumab in ankylosing spondylitis. EVIDENCE REVIEW: There is clear evidence that adalimumab, administered 40 mg subcutaneously every 2 weeks, substantially improves the signs and symptoms of NSAID-refractory, active AS when compared with placebo treatment. There is ample evidence that adalimumab causes significant improvements in physical health status and overall AS-specific, health-related quality of life and physical functioning, which consequently leads to better work productivity. There is substantial evidence that adalimumab improves spinal and sacroiliac joint inflammation in AS patients. Initial results from clinical trials suggest that there is no increased risk of serious infections or malignancies in adalimumab-treated patients with AS. The most common adverse events were injection-site reactions. Limited economic evidence suggests that adalimumab 40 mg may be cost effective when used according to current valid treatment guidelines. PLACE IN THERAPY: Adalimumab is an effective treatment for patients with active AS.     

Mcl-1 inhibitors: a patent review

Introduction: The myeloid cell leukemia?1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need.

Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein.

Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.     

Adalimumab in ankylosing spondylitis: an evidence-based review of its place in therapy

Introduction:

Ankylosing spondylitis (AS) is an idiopathic chronic inflammatory disease that has prominent effects on the spine and peripheral joints. In addition, extraarticular manifestations such as enthesitis and acute anterior uveitis may be clinically important. In recent years, the therapy of AS has changed, largely due to the introduction of inhibitors of the proinflammatory cytokine tumor necrosis factor (TNF). Adalimumab, a human monoclonal antibody specifically for TNF, is the most recent of the TNF blocking agents that have been approved for the treatment of active, nonsteroidal antiinflammatory drug (NSAID)-refractory patients with AS.

Aims:

To evaluate the evidence for the therapeutic value of adalimumab in ankylosing spondylitis.

Evidence review:

There is clear evidence that adalimumab, administered 40 mg subcutaneously every 2 weeks, substantially improves the signs and symptoms of NSAID-refractory, active AS when compared with placebo treatment. There is ample evidence that adalimumab causes significant improvements in physical health status and overall AS-specific, health-related quality of life and physical functioning, which consequently leads to better work productivity. There is substantial evidence that adalimumab improves spinal and sacroiliac joint inflammation in AS patients. Initial results from clinical trials suggest that there is no increased risk of serious infections or malignancies in adalimumab-treated patients with AS. The most common adverse events were injection-site reactions. Limited economic evidence suggests that adalimumab 40 mg may be cost effective when used according to current valid treatment guidelines.

Place in therapy:

Adalimumab is an effective treatment for patients with active AS.     

Complementary and alternative medicines in the treatment of dementia: an evidence-based review

Alternative medicines may have potential beneficial results in treating certain forms of dementia and related symptoms, as well as slowing disease progression. Alternative medicines may ameliorate disturbances in cognition, mood, sleep and activities of daily living. Primary mechanisms of action include modifications in neurotransmitter synthesis, inhibition of neurotransmitter reuptake and enzyme-induced neurotransmitter breakdown, antioxidant and anti-platelet activity, enhanced blood flow and glucose metabolism. Adverse events can include cardiovascular, gastrointestinal, mood, autonomic and dermatologic effects. However, adverse events, when reported represent, a small percentage of treated groups and direct links between adverse events and alternative therapies are tenuous. Many studies of alternative medicines in dementia are inconclusive and characterised by methodological deficiencies such as small sample sizes and inadequate controls. If alternative medicines can be shown to be efficacious using more rigorous experimental designs, both consumers and clinicians could avail themselves of a wider range of pharmacological substances that may offer the advantage of being better tolerated and exhibiting safer therapeutic margins than some allopathic medicines. While a number of complementary interventions have shown both strengths and weaknesses, huperzine A, levacecarnine and EGB 761, based on the overall quality of the studies, identified mechanisms of activity and safety profiles merit further examination in controlled clinical outcome studies.     

COX-2 inhibition versus gastroprotection with dual COX inhibitors: an evidence-based approach

Highly selective inhibitors of cyclooxygenase-2 (COX-2i) were introduced to minimize peptic ulcers and their complications caused by dual COX inhibitors (COXi). Co-prescribing a (generally cheap) dual COXi with a gastroprotectant is an alternative strategy, proven to reduce the incidence of NSAID-associated endoscopic ulcers. This review compares the efficacies of these two strategies and makes some estimates of their relative cost-effectiveness. In standard risk patients, endoscopic ulcers are reduced to about the same extent (around 70-80%) by either co-prescribing omeprazole or lansoprazole with a dual COXi or preferring a COX-2i alone. COX-2i reduced ulcer complications by a weighted mean of around 60% in comparative studies with dual COXi. There is little information about the influence of PPI on this endpoint, although one study using H. pylori treatment as a possible surrogate for placebo intervention found 77% protection against recurrent upper gastrointestinal bleeding by co-administered omeprazole. One direct comparison of the two strategies in high-risk patients (recent ulcer bleed) found quite high rates of re-presentation with bleeding ulcer using either strategy, and the differences between them were not significant. Drug costs in four Western countries were compared for each strategy. In one, the costs were similar, but in the others the combination of a cheap dual COXi with omeprazole was usually more expensive than using a COX-2i. The safest strategy in highest risk patients may be to co-prescribe a gastroprotectant with a COX-2i, with resulting higher drug costs but possibly offset by savings in other health costs. The efficacy and cost-benefit of this alternative approach warrants investigation.