Current Pharmaceutical Design - Volume 21, Issue 13, 2015

Advanced age is a relevant risk factor for the heart failure (HF). The development of new pharmacological and non-pharmacological approaches has determined an improvement in survival of patients with HF, leading to the selection of an older and frailer population with HF. The clinical approach to such a complex population should require clear indications to assist physicians during their daily practice, but there is a huge lack of evidence regarding the treatment of HF in the oldest among the elderly patient population. In addition, the co-occurrence of specific conditions that are extremely prevalent in older individuals with HF, such as cognitive impairment, comorbidities, and polypharmacy, can further complicate the clinical man agement of this condition. Thus, a multidisciplinary approach with the goal of recognizing and treating conditions associated with HF may be necessary to improve the quality of care and to reduce expenditures. Several studies have assessed the effect of a comprehensive geriatric assessment and management on quality of care in HF patients, demonstrating a substantial improvement in patient outcomes and administration of the appropriate drug treatment.

There is a rapidly growing number of persons reaching extreme age limits. Indeed, the fastest growth is found in those over the age of 80 years or octogenarians. Along with this continuous rise, there is a significant increase in type 2 diabetes in this population. Unfortunately, individuals living past 80 years of age are often accompanied by numerous comorbidities and geriatric conditions, all which render anti-diabetic treatment options challenging. Indeed the principles of managing type 2 diabetes are similar to younger patients. Special considerations in this delicate group are essential due to the increased prevalence of comorbidities and relative inability to tolerate adverse effects of medication and severe hypoglycemia. It is important to recall that octogenarians have shown to have a greater prevalence for cognitive impairment, physical disability, ren al and hepatic dysfunction, and syndromes, such as frailty compared to younger elders. The frailty syndrome is considered one of the most important limitations when treating octogenarians with type 2 diabetes in polypharmacy. Due to the lack of evidence for specific targets of glucose and glycated hemoglobin (A1C) levels in the elderly, available treatment guidelines are based on data extrapolation from younger adults and expert opinion citing reliable evidence. Overall, the most important conclusion emerging from these groups is to accomplish a moderate glycemic control (A1C levels between 7 -8%) in complex elderly patients. However, the risk of hypoglycemia from some treatments may present the greatest significant barrier to optimal glycemic control for the very old. The present review discusses the highlights from the latest guidelines for treating older persons and underlines the need for specific considerations when treating the very old in order to maintain a balance between treating comorbidities and maintaining quality of life.

The treatment of older and oldest old patients with COPD poses several problems and should be tailored to specific outcomes, such as physical functioning. Indeed, impaired homeostatic mechanisms, deteriorated physiological systems, and limited functional reserve mainly contribute to this complex scenario. Therefore, we reviewed the main difficulties in managing therapy for these patients and possible remedies. Inhaled long acting betaagonists (LABA) and anticholinergics (LAMA) are the mainstay of therapy in stable COPD, but it should be considered that pharmacological response and safety profile may vary significantly in older patients with multimorbidity. Their association with inhaled corticosteroids is recommended only for patients with severe or very severe airflow limitation or with frequent exacerbations despite bronchodilator treatment. In hypoxemic patients, long-term oxygen therapy (LTOT) may improve not only general comfort and exercise tolerance, but also cognitive functions and sleep. Nonpharmacological interventions, including education, physical exercise, nutritional support, pulmonary rehabilitation and telemonitoring can importantly contribute to improve outcomes. Older patients with COPD should be systematically evaluated for the presence of risk factors for non-adherence, and the inhaler device should be chosen very carefully. Comorbidities, such as cardiovascular diseases, chronic kidney disease, osteoporosis, obesity, cognitive, visual and auditory impairment, may significantly affect treatment choices and should be scrutinized. Palliative care is of paramount importance in end-stage COPD. Finally, treatment of COPD exacerbations has been also reviewed. Therapeutic decisions should be founded on a careful assessment of cognitive and functional status, comorbidity, polypharmacy, and agerelated changes in pharmacokinetics and pharmacodynamics in order to minimize adverse drug events, drug-drug or drug-disease interactions, and non-adherence to treatment.

Depression is very common in older people and it is associated with negative consequences such as functional decline, increased morbidity and mortality and higher healthcare costs. Despite this, it is still underdiagnosed and undertreated and the issue is particularly relevant for people older than 80 years. The main reasons for underdiagnosis are: atypical presentation, concomitant cognitive decline, inadequate diagnostic tools, and prejudice that depression is a normal part of ageing. On the other hand, the main reasons for undertreatment are: multimorbidity, concerns about adverse events and drug interactions, lack of confidence in the efficacy and safety of pharmacological and non-pharmacological treatments in the oldest old depressed patients, who are underrepresented in clinical studies. The new antidepressants are the drugs most frequently used, due to their perceived more favorable safety profile than older antidepressants. Psychotherapy is equally effective but less frequently used and should request some adaptive strategies for the peculiarities of octogenarians. Electroconvulsive therapy is limited to severe psychotic late-life depression resistant to other treatments. In light of the heterogeneity of people aged 80 years and over, with multiple and different medical, functional, socioeconomic problems, a multidimensional approach is probably the most suitable both for diagnosis and treatment, in order to develop an individualized care plan. These considerations should guide the formulation of future research studies, specifically tailored for the oldest depressed patients.

The so-called “silver tsunami” is a metaphor that the individuals 65 and older represent the most rapidly growing segment of the Western world population. Aging is an ongoing process that leads to the loss of functional reserve of multiple organ systems, increased susceptibility to stress, it is associated with increased prevalence of chronic disease, and functional dependence. Determined by a combination of genetic and environmental factors, this process is highly individualized and poorly reflected in chronologic age. The heterogeneity and the complexity of the older old population represent the main challenge to the treatment of cancer in those patients. We should discern "fit" elderly in whom standard cancer treatment appears to be comparable to a younger population and “unfit” or "frail" elderly, in which the risks of the treatment may overwhelm potential benefits. There are many aspects that have to be assessed before treating an elderly patient, or before to choose the treatment itself. In our review we will try to explain and describe the meaning and the most important aspects related to the oldest old complex patients, and how to manage those patients.

Pain is one of the most frequent reasons for consultations in general practice, presenting either alone or associated with some comorbidity. In all care settings for older and oldest old patients, a gap exists between best-practice recommendations and current clinical practice. Clinical manifestations of persistent pain are often complex and multifactorial in the frail population, so the approach to pain management in older persons differs from that for younger people. The purpose of this review is to describe the best approach to assess and manage persistent cancer and no-cancer pain in the elderly, to explain the principles of pain treatment in this so often frail and complex population and compare the different drugs that should be used or avoided in older and oldest old patients considering the agerelated physiologic changes. Considerable emphasis is placed on conditions more common in the elderly such as neuropathic pain or typical subsets of the aging population such as the assessment of pain in people with dementia.

The presence of sarcopenia is not only rapidly rising in geriatric clinical practice and research, but is also becoming a significant concept in numerous medical specialties. This rapidly rising concept has encouraged the need to identify methods for treating sarcopenia. Physical activity measures using resistance training exercise, combined with nutritional interventions (protein and amino acid supplementation) have shown to significantly improve muscle mass and strength in older persons. Moreover, resistance training may improve muscle strength and mass by improving protein synthesis in skeletal muscle cells. Aerobic exercise has also shown to hold beneficial impacts on sarcopenia by improving insulin sensitivity. At the moment, the literature indicates that most significant improvement in sarcopenia is based on exercise programs. Thus, this type of intervention should be implemented in a persistent manner over time in elders, with or at risk of muscle loss. At the same time, physical training exercise should include correcting nutritional deficits with supplementation methods. For example, in older sarcopenic patients with adequate renal function, daily protein intake should be increased to >1. 0 grams of protein per kilogram of body weight. In particular, leucine, β- hydroxy β-methylbutyrate (HMB), creatine and some milk-based proteins have been shown to improve skeletal muscle protein balance. In addition, it is also recommended for adjustment of for vitamin D deficiency, if present, considering the crucial role of vitamin D in the skeletal muscle. In this review, we provide evidence regarding the effects of different physical exercise protocols, specific nutritional intervention, and some new metabolic agents (HMB, citrulline malate, ornithine, and others) on clinical outcomes related to sarcopenia in older adults.

The serotonergic system is involved in pathomechanisms of both epilepsy and neuropathic pain. So far, participation in the epileptogenesis and maintenance of epilepsy was proved for 5-HT1A, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 receptors as well as 5-HTT serotonin transporter. Depending on the receptor type or its localization, its stimulation may increase or decrease neuronal excitability. According to the available data, neuropathic pain mechanisms involve 5-HT1A/1B/1D, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6 5-HT7 receptors and 5-HTT serotonin transporter. Changes in their expression modulate pain mainly by affecting the transmission through serotonergic descending pathways. Several compounds, whose mechanisms of action base on influence on the serotonergic system, are already in use. These are 5-HT3 agonists (triptans) in case of migraine, tricyclic antidepressants or monoamine reuptake inhibitors in neuropathic pain treatment. In addition, selective and non-selective ligands are tested for their anticonvulsant or analgesic properties. Some ED50 values have been already obtained in such animal models as maximal electroshock (MES)-induced seizures (epilepsy), spinal nerve ligation (SNL), chronic constriction injury (CCI) or formalin (neuropathic pain). This review shows that in case of drug discovery within the serotonergic system one must take into account special significance of factors such as: the species, the type of model, the route of administration, and the dose range.

Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional activity and lowered calcemic side effect. Recent in vivo experiments clearly demonstrated the potential use of these analogs in new therapeutic areas such as autoimmune and hyper-proliferative diseases, including cancer and the systemic treatment of psoriasis. Although some of these analogs are already approaching clinical trials, the molecular mechanism of action and their improved efficiency still remain to be fully understood. In this review the key steps of the convergent synthetic strategies that combine the modified A-ring and the CD-ring fragment carrying the altered side-chain are presented. The advantages of using the natural alicyclic and acyclic precursors are demonstrated as well as all the modern synthetic methodologies used for combining structural fragments. The results of molecular mechanics modeling are critically examined as well as the advantages and limitations of the use of the models of vitamin D proteins for the docking experiments and the design of new analogs. The potential use of advanced structural approaches, including high resolution X-ray crystallography, is discussed as to the prospect of providing a better understanding of the observed activity of modified analogs. Biological profiles in vitro and in vivo for groups of analogs are presented in a new tabular form to illustrate structure activity relationships.

The renin-angiotensin system has been established as an attractive target for pharmacological intervention since the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarily used in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism of action involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensin II and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinin degradation. Currently there are thirteen family members approved for use in humans. They differ in structure, chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic and toxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy. Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistent dry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximum safety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be an absolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially- used ACE-Is.

Atherosclerosis is a systemic inflammatory disease leading to lipid-laden inflammatory lesions in the arterial walls that may destabilize and rupture. It is becoming clear that addressing the “classical” risk factors for atherosclerosis does not entirely reduce the risk of cardiovascular events. Novel biomarkers to be used in highthroughput assays are necessary for diagnosis, for determination of the residual risk and for monitoring the effects of the therapy. Since inflammation is a hallmark of atherosclerosis, tests for pro-inflammatory biomarkers have been introduced such as for hsCRP, fibrinogen and IL-6, with many more at different stages of development. There has been a dearth of novel approaches for the diagnosis and management of atherosclerosis, reflected in a continuous reliance on LDL cholesterol as a proven target of investigations. To bring another perspective, here we briefly overview the accumulated epidemiological and sero-epidemiological evidence suggesting systemic infections as a component of atherosclerotic inflammations. We have shown that different individuals’ plaques are colonized with different bacterial species (atherosclerosis microbiota). Most of the time the pathogens are likely in an intracellular state, shielded from the host immune responses. There are controlled clinical trials and metaanalyses that corroborate the infections, specifically periodontal disease as a contributing risk factor of atherosclerosis. Infection-related markers, including transcriptome signatures, may identify latent infection patients with sub-clinical disease. Thus, the emerging infection- associated markers of inflammation could complement the existing ones and their use as companion diagnostics for atherosclerosis should stimulate the growing field of personalized medicine within cardiovascular diseases.