Progressive stent technologies: new approaches for the treatment of cardiovascular diseases

The CYPHER^® (Cordis, Johnson & Johnson) sirolimus-eluting stent and the TAXUS^® (Boston Scientific) paclitaxel-eluting stent have been extensively evaluated and have been proven to be significant novel tools for the treatment of coronary artery disease. Several sirolimus derivatives have already emerged, receiving CE Mark approval. However, in the future, it is likely that drugs presently under investigation will address additional mechanisms associated with neointimal formation, either as single agents or in combination with antiproliferative compounds. Concurrently, alterations on stent platform design (helicoidal, open-closed cell), coatings (biodegradable, bioabsorbable, nanoporous) and polymers are being explored.     

Progressive stent technologies: new approaches for the treatment of cardiovascular diseases

The CYPHER (Cordis, Johnson & Johnson) sirolimus-eluting stent and the TAXU (Boston Scientific) paclitaxel-eluting stent have been extensively evaluated and have been proven to be significant novel tools for the treatment of coronary artery disease. Several sirolimus derivatives have already emerged, receiving CE Mark approval. However, in the future, it is likely that drugs presently under investigation will address additional mechanisms associated with neointimal formation, either as single agents or in combination with antiproliferative compounds. Concurrently, alterations on stent platform design (helicoidal, open-closed cell), coatings (biodegradable, bioabsorbable, nanoporous) and polymers are being explored.     

Pharmacological approaches for the treatment of obesity

The high incidence of obesity, its multifactorial nature, the complexity and lack of knowledge of the bodyweight control system, and the scarcity of adequate therapeutics have fuelled anti-obesity drug development during a considerable number of years. Irrespective of the efforts invested by researchers and companies, few products have reached a minimum level of effectiveness, and even fewer are available in medical practice. As a consequence of anti-obesity research, our knowledge of the bodyweight control system increased but, despite this, the pharmacological approaches to the treatment of obesity have not resulted yet in effective drugs. This review provides a panoramic of the multiple different approaches developed to obtain workable drugs. These approaches, however, rely in only four main lines of action: control of energy intake, mainly through modification of appetite;control of energy expenditure, essentially through the increase of thermogenesis;control of the availability of substrates to cells and tissues through hormonal and other metabolic factors controlling the fate of the available energy substrates; andcontrol of fat reserves through modulation of lipogenesis and lipolysis in white adipose tissue. A large proportion of current research is centred on neuropeptidic control of appetite, followed by the development of drugs controlling thermogenic mechanisms and analysis of the factors controlling adipocyte growth and fat storage. The adipocyte is also a fundamental source of metabolic signals, signals that can be intercepted, modulated and used to force the brain to adjust the mass of fat with the physiological means available. The large variety of different approaches used in the search for effective anti-obesity drugs show both the deep involvement of researchers on this field and the large amount of resources devoted to this problem by pharmaceutical companies. Future trends in anti-obesity drug research follow closely the approaches outlined; however, the increasing mass of information on the molecular basis of bodyweight control and obesity will in the end prevail in our search for effective and harmless anti-obesity drugs.     

Pharmacological prevention of cardiovascular diseases

At present, cardiology makes use of a wide range of drugs belonging to various pharmacological classes for both preventing and treating cardiovascular diseases. Results of recent large clinical trials show the importance of carrying out preventive actions, but data of evidence based medicine suggest that only some of the methods of pharmacological prophylaxis have unequivocally demonstrated their ability to improve the forecast of life for patients with cardiovascular pathology. We have summarized data on the efficacy of some groups of drugs used in cardiology and assessed this information from the positions of proved validity of the prophylactic effect in particular groups of patients.     

Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β₂ inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications.     

Therapeutic strategies for hypertension treatment in patients with selected cardiovascular diseases

Patients with hypertension and concomitant cardiovascular (CVD) conditions are at high risk for developing deleterious CVD-related clinical sequelae. The selection of therapeutic strategies for hypertension management in patients with cardiovascular diseases is an important first step in normalizing blood pressure (BP) levels (<140/90 mmHg). The ultimate goal of BP normalization for this high-risk group of hypertensive patients is target-organ protection. This review will discuss the management of hypertension in patients with selected CVD conditions (congestive heart failure, coronary artery disease, renal insufficiency/end-stage renal disease) and will incorporate both nondrug and drug therapies. Nondrug therapy, including weight reduction, physical activity, restriction of dietary sodium and alcohol intake are effective strategies for lowering BP. If these measures are not adequate, then the addition of drug therapy is needed in order to provide gradual BP normalization. Drug regimens may include a single antihypertensive agent with up-titration of the dose, or a combination of antihypertensive agents at a lower dose of each agent. The availability of different classes of antihypertensive agents enables therapeutics strategies to be implemented in the management of hypertension that provide maximum target-organ protection for each entity of CVD. Thus, aggressive hypertension management is crucial for delaying/preventing target organ damage and subsequent CVD clinical events.     

Pharmacological approaches to the treatment of obstructive sleep apnoea

Background: Currently the treatment of choice for symptomatic obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Some patients with OSA do not tolerate CPAP or have insufficiently severe symptoms to justify its use; for these patients, drug therapy would be a desirable potential therapeutic alternative. Objective: To summarize the current evidence on the effectiveness of drug therapy in patients with OSA. Methods: A systematic review of randomized controlled trials was performed to investigate the effects of drug therapy on OSA. Results/conclusions: Searches of bibliographical databases revealed 33 trials investigating the effects of 27 different drugs on OSA severity and/or symptoms. The mechanisms by which these drugs are supposed to improve OSA include, amongst others, an increase in tone of the upper airways, an increase in ventilatory drive, a reduction in airway resistance, and alterations in surface tension forces in the upper airway. In most of these studies there was no significant effect on OSA observed. However, there is evidence from a few small trials that some drugs, especially those thought to increase upper airway muscle tone, have the potential to reduce OSA severity; but further data from larger studies of adequate duration are needed.     

Pharmacological approaches to the treatment of morphine-type dependence.

Of the two pharmacologically different possibilities of interfering with the processes of either tolerance or dependence of the morphine type, the so-called maintenance method commonly using methadone is predominantly a matter of tolerance, whereas the blockade with specific opiate antagonists such as cyclazocine intervenes in processes underlying dependence and withdrawal. The experimental evidence for these mechanisms is described.     

Pharmacological approaches to the treatment of intermittent claudication.

Intermittent claudication is a common condition of the elderly, occurring in 3 to 20% of individuals over the age of 65 years. Although local disease is usually benign, life expectancy in patients with intermittent claudication is reduced by approximately 10 years due to associated cardiovascular mortality. Several classes of drugs have been used in intermittent claudication, but clinical studies evaluating their efficacy leave much to be desired. Pentoxifylline (oxpentifylline), a rheological agent, and naftidrofuryl, an enhancer of aerobic metabolism, are the 2 most widely investigated and utilised drugs. The combined results of 10 placebo-controlled studies with pentoxifylline and 4 with naftidrofuryl estimate increases in claudication distances of 51 and 42%, respectively. However, due to publication bias, these figures are probably overestimates of the true benefit from treatment with these drugs. It is likely that any benefit from pentoxifylline or naftidrofuryl is small and of little clinical importance. The suggestion that naftidrofuryl has greater efficacy in older patients remains unproven. Other classes of drugs including vasodilators, antiplatelet drugs, anticoagulants and prostaglandins have not been shown to be effective. Only 2 approaches to the management of intermittent claudication have been shown convincingly to be of benefit: stopping smoking and exercising regularly.     

法舒地尔对心脑血管疾病的药理作用及临床应用

摘 要：法舒地尔（Fasudil）是一种 Rho 激酶抑制剂,通过阻断血管收缩过程肌球蛋白轻链磷酸化来扩张血管,抑制血管痉挛,临床上主要用于治疗蛛网膜下腔出血。近年来,关于法舒地尔对心脑血管疾病的机制研究不断深入。对法舒地尔治疗短暂性脑缺血发作、脑梗死、椎基底动脉供血不足、蛛网膜下腔出血等脑血管疾病及冠状动脉性心脏病、心肌肥厚、心肌梗死、充血性心力衰竭等心血管疾病的药理作用及临床应用进行综述。     

Therapeutic approaches to the treatment of neuroinflammatory diseases

Microglia cells are present in the central nervous system and respond quickly to pathogenic stimuli in order to protect the brain. When these immunological responses activate inappropriately or are prolonged, they can contribute to the neuronal damage observed in many neurodegenerative diseases. A variety of immune system modulators including complement proteins, inflammatory cytokines such IL-1 alpha, IL-1 beta, IL-3, IL-6, TNF-alpha, and S100 beta, colony-stimulating factor-1, coagulation proteins and matrix metalloproteases are made by both microglia and astrocytes. Additionally astrocytes, the predominant glial component of the brain, express cell-adhesion molecules, cytokine receptors and induce nitric oxide synthease. The pathophysiology of Alzheimer's disease, stroke, traumatic brain injury, and multiple sclerosis suggest that a large portion of the irreversible damage observed can be attributed to a neuroinflammatory mechanism. The immunomodulators of these diseases are reviewed and new agents within specific molecular mechanisms are presented and discussed.     

Pharmacological approaches in the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with substantial cardiovascular morbidity and mortality. The arrhythmia can be initiated and/or maintained by rapidly firing foci, single- and multiple-circuit reentry. Once initiated, AF alters atrial electrical and structural properties (atrial remodeling) in a way that promotes its own maintenance and recurrence and may alter the response to antiarrhythmic drugs. Thus, initial episodes of paroxysmal (self-terminating) AF lengthens to the point where the arrhythmia becomes persistent (requires cardioversion to restore sinus rhythm) and permanent. AF usually requires a trigger for initiation and a favorable electrophysiological and/or anatomical substrate for maintenance. The substrate includes both cardiovascular (coronary artery disease, valvular heart disease, heart failure, hypertension, dilated cardiomyopathy) and non cardiovascular diseases (thyrotoxicosis, pulmonary diseases). Accordingly, the initial step in patients with AF requires a careful assessment of symptoms and identification of underlying reversible triggers and potentially modifiable underlying structural substrate and treat them aggressively. In contrast to other cardiac arrhythmias, antiarrhythmic drugs (ADs) are the mainstay of therapy. Long-term treatment of AF is directed to restore and maintain the sinus rhythm with class I and III ADs (rhythm-control) or to allow AF to persist and ensure that the ventricular rate is controlled (rate-control) with atrioventricular nodal blocking drugs (digoxin, beta-blockers, verapamil, diltiazem) and prevent thromboembolic complications with anticoagulants. However, the long-term efficacy of ADs for preventing AF recurrence is far from ideal, because of limited efficacy (AF recurs in at least one-half of the patients) and potential side effects, particularly proarrhythmia. Thus, the choice of the appropriate AD will depend on the temporal pattern of the arrhythmia, the presence of associated diseases, easy of administration and adverse effects profile, particularly the risk of proarrhythmia. The recent finding that angiotensin converting enzyme inhibitors and beta-blockers reduce the incidence of AF in patients post myocardial infarction with left ventricular dysfunction confirmed the importance of targeting the underlying arrhythmogenic substrate. This review focuses on the mechanisms underlying AF and the mechanism of action and the efficacy and safety profile of the ADs used in the treatment of atrial fibrillation. The advantages and disadvantages of rhythm and rate control, the role pill in a pocket concept and the role of the new ADs are dicussed.     

Novel antithrombotic strategies in cardiovascular diseases

Ischemic cardiovascular diseases represent the most common cause of mortality and morbidity in the western world, and atherothrombosis occupies a central role in their pathophysiology. Venous thrombi, which form under low shear conditions, are predominantly composed of fibrin and red cells, while arterial thrombi form under high shear conditions and are composed primarily of platelet aggregates held together by fibrin strands. Several successful strategies targeting specific steps in coagulation and platelet function or interaction have been developed to prevent or treat atherothrombotic disorders. Intense research is currently underway in an effort to develop more safe and effective compounds, such that novel antithrombotics are emerging to target specific steps in the coagulation cascade, as well as in pathways of platelet adhesion, activation and aggregation. This review will focus on the recent advances in research in this fast-evolving field.     

Immunomodulatory treatment strategies for allergic diseases

Over the last decades the prevalence of allergic disorders, such as hayfever and asthma has increased worldwide, mostly in westernised countries where up to 20 % of the population are affected. The "hygiene hypothesis" suggests that modernised lifestyles such as improved housing conditions, altered dietary habits and smaller family sizes may be responsible for the decrease in infectious and the increase in allergic diseases. Childhood atopic diseases, like eczema, food allergies and recurrent wheezy bronchitis represent a considerable health problem and a major socioeconomic burden due to the chronicity of these disorders. In recent years, a better understanding of the immunopathogenesis of allergic diseases has evolved, which has contributed to the development of novel more targeted forms of therapy. Allergen injection immunotherapy is the only treatment in current use with the potential for modifying the course of allergic disease. In order to better target mucosal allergies, new approaches of administering allergen, via the sublingual or intranasal route, are being developed. The use of modified allergens, allergen peptides, DNA immunization and the use of novel adjuvants represent alternatives to conventional immunotherapy with potential for improved efficacy with less side effects. For atopic asthma, novel treatment strategies aim at locally targeting inflamed airways. Nebulized monoclonal blocking antibodies and soluble interleukin receptors against "Th(2)-type" cytokines have been designed. An alternative approach has been the administration of "Th(1) -type" cytokines. Although, immunomodulatory strategies provide a promising outlook for the treatment of allergic patients, more studies are needed in the future to address issues of efficacy, safety and long-term effects of altered immune responses.     

Pharmacological approaches in the treatment of binge eating disorder

Binge eating disorder (BED) is a newly defined diagnostic category characterized by recurrent episodes of binge eating not followed by the inappropriate compensatory weight loss behaviors characteristic of bulimia nervosa. BED is usually associated with overweight or obesity and psychopathology. Pharmacotherapy may be a useful component of a multidimensional treatment approach. Although pharmacotherapy research in BED is still in its preliminary stages. some drugs have been shown to be promising agents. This paper reviews available pharmacological treatment studies of BED and related conditions. Currently, three main classes of drugs have been studied in double-blind, placebo controlled trials in BED: antidepressants, anti-obesity agents, and anticonvulsants. Serotonin selective reuptake inhibitors (SSRIs) are the best studied medications. Thus, fluoxetine, fluvoxamine, sertraline and citalopram have been shown to modestly but significantly reduce binge eating frequency and body weight in BED over the short term. More recently, the anti-obesity agent sibutramine and the anticonvulsant topiramate have been shown to significantly reduce binge eating behavior and body weight in BED associated with obesity. Special issues concerning current pharmacological trials and future research directions in this area are also discussed.