Pharmacotherapy for Alzheimer's disease: what's new on the horizon?

INTRODUCTION: Alzheimer's disease (AD) is a debilitating disease, with no cure. Recently, a monoclonal antibody (aducanumab) directed toward amyloid aggregates was approved as a disease-modifying treatment (DMT) for the disease. Other compounds (symptomatic or DMTs) are at different stages of clinical trial development. AREAS COVERED: The authors conducted a search on PUBMED, MEDLINE, and clinicaltrials.gov for compounds in phase III clinical trials for cognitive impairment due to AD. Mechanisms of action and clinical trial data related to these compounds are discussed in this paper. EXPERT OPINION: There is an unmet need for both treatment approaches (symptomatic and DMTs) to improve outcomes in individuals at different stages of the AD continuum. Future trials with symptomatic therapies should rely on biomarkers to improve enrollment of participants with pure AD. More sensitive, innovative, and composite assessment tools should be used. Given the complexity and heterogeneity of AD, combining several DMTs with synergistic mechanisms of action is a promising approach to achieve a significant impact on reversing cognitive decline. We recommend testing DMTs early on in the disease continuum, even in asymptomatic individuals at risk for AD. Longer duration of follow-up in clinical trials with DMTs is recommended.

Comparison of the Impact of the Mediterranean Diet, Anti-Inflammatory Diet, Seventh-Day Adventist Diet, and Ketogenic Diet Relative to Cognition and Cognitive Decline.

PURPOSE OF REVIEW: Increasing evidence points toward the importance of diet and its impact on cognitive decline. This review seeks to clarify the impact of four diets on cognition: the Mediterranean diet, the anti-inflammatory diet, the Seventh Day Adventist diet, and the Ketogenic diet. RECENT FINDINGS: Of the diets reviewed, the Mediterranean diet provides the strongest evidence for efficacy. Studies regarding the anti-inflammatory diet and Seventh Day Adventist diet are sparse, heterogeneous in quality and outcome measurements, providing limited reliable data. There is also minimal research confirming the cognitive benefits of the Ketogenic diet. Increasing evidence supports the use of the Mediterranean diet to reduce cognitive decline. The MIND-diet, a combination of the Mediterranean and DASH diets, seems especially promising, likely due to its anti-inflammatory properties. The Ketogenic diet may also have potential efficacy; however, adherence in older populations may be difficult given frequent adverse effects. Future research should focus on long-term, well-controlled studies confirming the impact of various diets, as well as the combination of diets and lifestyle modification.

The association between neck adiposity and long-term outcome.

Anthropometric indices of obesity (e.g. body mass index, waist circumference and neck circumference) are associated with poor long-term cardiovascular outcome. Prior studies have associated neck circumference and central body adiposity. We explored the association between neck fat volume (NFV) and long-term cardiovascular outcome. The study provides a retrospective analysis of all patients undergoing computerized tomography angiography for suspected cerebrovascular accident between January and December 2013. NFV was assessed by three dimensional reconstructions and was adjusted to height to account for differences in body sizes, thus yielding the NFV/height ratio (NHR). Univariate and multivariate analysis were utilized to explore the association between various indices including NHR and all-cause mortality. The analysis included 302 patients. The average age was 61.9±14.3 years, 60.6% of male gender. Diabetes mellitus, hypertension and cardiovascular disease were frequent in 31.5%, 69.9%, and 72.2% of patients, respectively. The median NHR was 492.53cm2 [IQR 393.93-607.82]. Median follow up time was 41.2 months, during which 40 patients (13.2%) died. Multivariate analysis adjusting for age, sex, and diabetes mellitus indicated an independent association between the upper quartile of NHR and all-cause mortality (hazard ratio = 2.279; 95% CI = 1.209-4.299; p = .011). NHR is a readily available anthropometric index which significantly correlated with poor long-term outcome. Following validation in larger scale studies, this index may serve a risk stratifying tool for cardiovascular disease and future outcome.

The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.

INTRODUCTION: Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. AREAS COVERED: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. EXPERT OPINION: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

Lungs in White Induced by Docetaxel.

BACKGROUND: Taxanes are often used in the treatment of many types of cancers. Side effects of docetaxel are not as well documented as paclitaxel, but both can cause pulmonary injury. We present a dramatic case of a patient being treated for prostatic adenocarcinoma with docetaxel who presented with interstitial pneumonitis and responded dramatically to the early treatment with corticosteroids. This case is important as it reveals the side effects of docetaxel administration without administration of other chemotherapeutic agents, and it illustrates the importance of early diagnosis and treatment of docetaxel-induced interstitial pneumonitis. Further research into the mechanism of the side effects of docetaxel is warranted.

The association between systemic lupus erythematosus and valvular heart disease: an extensive data analysis.

BACKGROUND: Association between antiphospholipid syndrome in systemic lupus erythematosus (SLE) and valvular heart disease (VHD) is well reported, but relatively few studies have been carried out to establish the linkage between VHD and SLE itself. We aimed to investigate link between VHD and SLE and to evaluate the association of diverse factors with VHD among these patients in a large-scale population-based study. MATERIALS AND METHODS: We used the databases of the largest state-mandated health service organization in Israel. All SLE patients were included (n = 5018) as well as their age and sex-matched controls (n = 25 090), creating a cross-sectional population-based study. Medical records of all subjects were analysed for documented VHD and the presence of antiphospholipid antibodies (aPLs). A logistic regression model was carried out to evaluate the diverse factors including SLE and aPLs as independent risk factors for VHD. RESULTS: Valvular heart disease were found to be more frequent among SLE group when compared to controls (aortic stenosis, 1·08% vs. 0·35% respectively, P < 0·001; aortic insufficiency, 1·32% vs. 0·29% respectively, P < 0·001; mitral stenosis, 0·74% vs. 0·21% respectively, P < 0·001; mitral insufficiency, 1·91% vs. 0·39% respectively, P < 0·001). Male sex, hypertension, aPLs and SLE were found to be significant independent risk factors for VHD. CONCLUSION: All VHD are more prevalent among SLE patients when compared to controls. SLE and aPLs are independent risk factor for VHD (OR of 2·46 and 1·7, respectively). Physicians must be aware of such significant association, and routine echocardiography should be considered in SLE patients regardless of their aPL status.

Sponsorship, antidepressant dose, and outcome in major depressive disorder: meta-analysis of randomized controlled trials.

OBJECTIVE: Differences in dosing may influence results of pharmaceutical industry-sponsored medication trials. This study aims to determine the relationship between sponsorship and antidepressant dosing and efficacy in randomized controlled trials for major depressive disorder. DATA SOURCES: Trials were identified through English-language searches of MEDLINE and PsycINFO (January 1996-June 2010) using specific drug names and classes and depressive disorder or major depression and double blind or double-blind method. Other limitations included human subjects and treatment study designs using the clinical queries option. Other sources were also searched following a strict set of inclusion and exclusion criteria. STUDY SELECTION: Randomized controlled trials were included if they examined antidepressant treatment for major depressive disorder, reported mean final medication dosages, acknowledged an association with industry, and included study arms of medications produced by the associated manufacturer and a competitor ("sponsor" and "nonsponsor" arms) (58 trials involving 15,026 patients from 101 citations identified). DATA EXTRACTION: Data on dosing, efficacy, baseline severity, and adverse events were extracted by 2 of the authors. RESULTS: Meta-analyses were used to examine dosing and efficacy data. Using consensus guidelines for medication dosing, we determined that sponsor medication was dosed relatively higher than nonsponsor medication, in 37% (22/60) of comparisons as opposed to 5% (3/60) in which the nonsponsor medication was dosed higher (χ²2 = 25.9, P < .001). Trials in which sponsor drugs were dosed higher than nonsponsor drugs demonstrated higher remission rates for the sponsor drug (OR = 1.28, 95% CI = 1.11-1.47, P < .001). These results were confirmed using regulatory dosing guidelines. There was no significant correlation between dosing or outcome with baseline severity or adverse events. CONCLUSIONS: Sponsor drugs are dosed higher than nonsponsor drugs in antidepressant randomized controlled trials, and higher dosing is associated with better sponsor drug outcomes in some cases.