Dyslipidaemia in the elderly: to treat or not to treat?

Introduction: The elderly population (i.e. aged ≥ 65 years) is increasing worldwide. Ageing is associated with a higher incidence and prevalence of cardiovascular disease (CVD).

Areas covered: The prevalence of CVD risk factors including type 2 diabetes mellitus, hypertension and dyslipidaemia also increases with advancing age, contributing to the higher absolute CVD risk observed in the elderly. The present narrative review comments on the associations of dyslipidaemia with CVD as well as the effects of lifestyle measures and lipid-lowering drugs on lipids and CVD risk with a special focus on the elderly population. Individual treatment goals and therapeutic options according to current guidelines are also reviewed. Finally, we discuss special characteristics of the elderly that may influence the efficacy and safety of drug therapy and should be considered before selection of hypolipidaemic pharmacotherapy.

Expert commentary: There may be a greater CVD benefit in older patients following drug therapy compared with younger ones. Treatment goals and therapeutic options should be individualized according to current guidelines. Specific characteristics that may influence the efficacy and safety of drug therapy in the elderly should be considered in relation to dyslipidaemia treatment.     

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.     

Treating ocular hypertension to reduce glaucoma risk: when to treat?

When to treat the patient who presents with ocular hypertension has been a question that has 'stumped' the ophthalmic community for decades. Population-based studies and intervention trials have provided the basis for understanding why we consider treating such patients. Although the EGPS (European Glaucoma Prevention Study) did not demonstrate that reducing intraocular pressure (IOP) with dorzolamide prevented the onset of glaucoma compared with individuals receiving a placebo, the investigators of the OHTS (Ocular Hypertension Treatment Study) found that the treatment of ocular hypertension can be delayed with topical medication when treated patients were compared with an observation group. There are differences in inclusion criteria, study design and retention rates between the EGPS and the OHTS, which may have led to the discrepancies in outcomes between these two studies. These differences provide a basis for understanding the relevance of the findings of both trials to clinical practice. The clinician should consider key risk factors such as age, thin corneal thickness measurements, large cup-to-disc ratio and mean IOP when determining who should be treated. However, the ultimate decision of when to treat will be determined by other issues such as life expectancy, the general health of the patient and the number of risk factors. Clearly, the treatment of only high-risk patients with ocular hypertension should be considered.     

Nitric oxide-mediated endothelial dysfunction--is there need to treat?

Before it gets to the development of manifest atherosclerotic lesions, all known risk factors primarily induce functional alterations in the vascular wall, namely in endothelial cells. Being termed endothelial dysfunction or endothelial activation, this condition is characterized by an altered availability of nitric oxide (NO). Under physiological conditions, NO is of unequivocal importance for the regulation of vascular homeostasis. Endothelium-derived NO released abluminally increases soluble guanylat cyclase activity in smooth muscle cells, thereby inducing relaxation and consequently vasodilatation. Intraluminally, NO inhibits the expression of adhesion molecules both on endothielial cells and neutrophils, thus preventing the adherence of cellular elements to the vascular wall. Furthermore, NO has antithrombotic effcts by inhibiting platelet aggregation and directly infuencing the synthesis of different factors involved in the coagulation cascade. Finally, in the long term, NO has been shown to exert antiproliferative properties. NO is generated intracellularly from L-arginine via NO-synthase with the help of several cofactors, including tetrahydobiopterin. Interestingly, it has recently become evident that under certain conditions, when there is a lack of tetrahydrobiopterin, NO-synthase produces reactive oxygen species instead of NO. Reactive oxygen species counteract the effects of NO and also scavenge NO resulting in the formation of peroxynitrite (ONOO). Peroxynitrite has been shown to have deleterious effects with respect to vascular function. The aim of the current review is to elucidate recent progress regarding the pathophysiological understanding of endothelial dysfunction. Furthermore, the significance of this condition for the evaluation and prognosis of patients is discussed. Finally, current therapeutical strategies in the treatment and improvement of endothelial dysfunction are highlighted.     

Antioxidant to treat osteoarthritis: dream or reality?

Osteoarthritis is one of the most common chronic diseases that causes pain and physical disability in patient. Although OA is considered as a global disease affecting all joint tissues, cartilage degradation is the end point. The degradation of cartilage results of the combination of mechanical stress and biochemical factors, mainly metalloproteinases and reactive oxygen species (ROS). The activity of reactive oxygen species is balanced by enzymatic and non-enzymatic antioxidants, that act by inhibiting oxidative enzymes, scavenging free radicals or chelating ion metals. Until now, few information is available on the antioxidative status of chondrocytes. Further, the modification of the antioxidative system in osteoarthritis remains unknown. Some antioxidant supplements or drugs with antioxidant properties have been developed to reinforce the cellular antioxidant status. However, until now, there is no consistent evidence that additional antioxidant supply is efficient to relieve OA symptoms or to prevent structural changes in OA cartilage.     

Developing drugs to treat osteoporosis: lessons learned?

Background: Selective estrogen-receptor modulators (SERMs) are drugs that act as estrogen receptor agonists or antagonists depending on the target tissue. Theoretically this class of agents would be an ideal substitute for hormone replacement therapy (HRT), if their effects on the skeleton matched those of estrogen while their actions on other tissues were either neutral or beneficial. Objective: To evaluate a Phase III trial of a new SERM, arzoxefine, for prevention of osteoporosis in younger postmenopausal women. Methods/results: Arzoxifene induced modest but significant increases in bone mineral density versus a control group during 2 years of therapy, with minor adverse events. However, fracture efficacy and other patient-specific outcomes were not evaluated. Conclusion: Despite a positive study of surrogate end points (bone density and biochemical markers of bone turnover), arzoxifene was withdrawn from further FDA evaluation, principally because of long-term side effects and lack of non-vertebral fracture efficacy in the companion Phase III fracture study. Each SERM has a unique profile on bone and other tissues. Regulatory approval of this class of agents may remain problematic for the immediate future.     

How can high-throughput screening deliver drugs to treat atherosclerosis?

Importance of the field: Atherosclerosis is a progressive disease that is characterized by the accumulation of lipid-rich plaques within the artery walls. Despite the past 3 decades witnessing the most significant advances in the pharmacotherapy of atherosclerosis with statins, atherosclerosis is still one of the leading causes of mortality in industrialized and developing nations. The applications of high-throughput screening (HTS) have retrieved hits and lead compounds which may be further developed to new promising therapeutics to achieve more effective reductions in the risk of cardiovascular morbidity and mortality.

Areas covered in this review: The review provides a summary of potential drug targets other than HMG-CoA reductase (primary target of statins) and their application in biochemical or cell-based HTS assays used by pharmaceutical companies and academic laboratories for anti-atherosclerotic drug discovery.

What the reader will gain: The reader will gain an overview of the HTS strategies currently used in the development of anti-atherosclerotic agents. The reader is also provided with some abortive examples in anti-atherosclerotic drug discovery as well as the associated limitations and challenges of the process that HTS delivers new drugs to treat atherosclerosis.

Take home message: HTS can assist in the efficient discovery of new drugs towards the potential targets involved in the progress of atherosclerosis.     

How can high-throughput screening deliver drugs to treat atherosclerosis?

Importance of the field: Atherosclerosis is a progressive disease that is characterized by the accumulation of lipid-rich plaques within the artery walls. Despite the past 3 decades witnessing the most significant advances in the pharmacotherapy of atherosclerosis with statins, atherosclerosis is still one of the leading causes of mortality in industrialized and developing nations. The applications of high-throughput screening (HTS) have retrieved hits and lead compounds which may be further developed to new promising therapeutics to achieve more effective reductions in the risk of cardiovascular morbidity and mortality. Areas covered in this review: The review provides a summary of potential drug targets other than HMG-CoA reductase (primary target of statins) and their application in biochemical or cell-based HTS assays used by pharmaceutical companies and academic laboratories for anti-atherosclerotic drug discovery. What the reader will gain: The reader will gain an overview of the HTS strategies currently used in the development of anti-atherosclerotic agents. The reader is also provided with some abortive examples in anti-atherosclerotic drug discovery as well as the associated limitations and challenges of the process that HTS delivers new drugs to treat atherosclerosis. Take home message: HTS can assist in the efficient discovery of new drugs towards the potential targets involved in the progress of atherosclerosis.     

Use of antibiotics to treat bacteriuria of pregnancy in the Nordic countries. Which antibiotics are appropriate to treat bacteriuria of pregnancy?

Bacteriuria in pregnancy with or without clinical symptoms is frequent and increases the risk of pyelonephritis, preterm labour, and low birth weight infants. Commonly used antibiotics such as ampicillin (pivampicillin), amoxicillin, trimethoprim, and sulphonamide are currently associated with a high degree of resistance of the most common pathogen in the urinary tract, Escherichia coli. During the past few decades a number of new and efficient antibacterial antibiotics have been developed. The presumption that a specific drug is safe for both the pregnant woman and the foetus depends on how widely the drug has been used. A recent survey among general practitioners and obstetricians in Denmark, Finland, Norway, and Sweden confirmed that the beta-lactam antibiotic pivmecillinam and nitrofurantoin are the most commonly used agents in the treatment of bacteriuria in pregnancy in the Nordic countries. However, a surprisingly high number of physicians reported that they prescribe sulphonamides during the first two trimesters in spite of resistance of E. coli and possible adverse effects on the foetus.     

A single pill to treat postmenopausal hypertension? Not yet

Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism(s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk factors, such as dyslipidemias, visceral obesity and endothelial dysfunction. Recently it became apparent that in a large number of hypertensive postmenopausal women, their BP is not well controlled with conventional antihypertensive medications. A clear understanding of the complex pathogenesis of postmenopausal hypertension is needed in order to offer the best therapeutic options for these women.     

FDA approves Cholbam to treat rare bile acid synthesis disorders

On March 17,2015,the U.S.Food and Drug Administration approved Cholbam(cholic acid)capsules,the first FDA approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects,and for patients with peroxisomal disorders(including Zellweger spectrum disorders).Patients with these rare,genetic,metabolic conditions exhibit manifestations of liver disease,steatorrhea(presence of     

Pharmacological studies of traditional Chinese medicine to treat Alzheimer disease

Background： Shen-wu Capsule （SWC） is a new compound containing 6 kinds of traditional Chinese herbs. TSG is a major effective component of SWC. Objective： To investigate the pharmacological effects of SWC and TSG on multiple kinds of AD-like animal models. Methods： The drugs were intragastrically administered to the animal models for 1 or 2 months. Morris water maze test was used to detect learning/memory ability, microarray and RT-PCR to measure gene expression, Western blotting and immuno-histochemistry tO determine related proteins. Results：（1） In APP transgenic mice, SWC and TSG improved learning/memory ability, and decreased Aβ content and β-secretase expression; （2） in Aβ brain injection model, SWC and TSG inhibited microglial activation, and decreased IL-1 and tumor necrosis factor a （TNFα） content; （3） in ibotanic acid-induced basal forebrain colinergic damage rat model, SWC and TSG improved learning/memory ability, increased the ratio of cholinacetyl-transfetase （CHAT） / cholinesterase （AchE）, or enhanced M-receptor density; （4） in naturally aged rats of 24 months old, SWC and TSG improved learning/memory ability, decreased cholinergic cell death, and increased expression of nerve growth factor （NGF） and its receptor trkA in hippocumpus;     

Is the MIC useful in deciding to treat endocarditis surgically?

The infecting pathogen and its susceptibility to antibiotics is used to suggest prognosis in endocarditis. A case study was performed in a tertiary referral cardiology centre to assess the contribution of the measurement of minimum inhibitory concentration (MIC) to the decision to treat endocarditis surgically. The records were examined of 125 patients admitted between 1981 and 1999 in whom the minimum inhibitory concentration for the pathogen had been measured. The measures of outcome were mortality at time of hospital discharge and at 6 months, surgical referral and cure by medical treatment. Endocarditis caused by Staphylococcus aureus with a raised MIC of flucloxacillin (methicillin) was associated with higher mortality even if glycopeptides were used in treatment (< or = 35 mg/l 0/7 versus MIC 1-2 mg/l 4/13, P = 0.01). Elevated MICs of flucloxacillin in S. aureus infection or of gentamicin in streptococcal disease were associated with surgical intervention. There were no significant differences between bacterial pathogens in mortality, surgical referral or cure by medical treatment. The measurement of MIC appears prognostically important in deciding the surgical management of endocarditis.     

Insulin to treat Alzheimer's disease: just follow your nose?

Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes, and lower cerebrospinal insulin levels. Against this background, impaired brain insulin signaling may account for some of the cognitive deficits associated with this disease. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of acute clinical trials involving healthy humans and AD patients have shown that increased CNS insulin action enhances learning and memory processes. This article summarizes and evaluates data from a recently published clinical trial, in which 4 months of intranasal insulin administration (20 IU insulin/day) preserved not only general cognition but also reduced the loss of metabolic integrity of the brain in adults with mild-to-moderate AD.