Tetraspanins: gateways for infection

The tetraspanins constitute a conserved superfamily of four-span membrane proteins that are widely distributed in multi-cellular organisms. A characteristic property of tetraspanins is their ability to form lateral associations with one another and with other membrane proteins, giving rise to tetraspanin enriched microdomains (TEM) that are involved in the molecular organisation of many membrane-associated functions such as adhesion, fusion and trafficking. Increasing evidence suggests that intracellular pathogens, especially viruses, have "hijacked" tetraspanins as a means of entering, traversing and exiting cells during the course of infection. This article reviews current evidence for the role of tetraspanins in the uptake, trafficking and spread of viruses as well as intracellular bacteria, fungi and parasites. Finally, the prospects of targeting tetraspanins for therapeutic intervention in infections caused by such pathogens are discussed.     

Section Review: Cardiovascular & Renal: Genetic therapies for vascular diseases and lipid disorders

In the early 1990s, gene therapy was considered to have applications solely in essential genetic deficiencies, such as monogenic lethal diseases. However, recognition of the tremendous potential of this technology has ensured that gene therapy is no longer perceived as a last chance therapy but, rather, as a promise for cure for a variety of complex and/or acquired lethal conditions, such as cancer, neurodegenerative and cardiovascular diseases, for which medical need is largely unsatisfied and current therapies are often purely palliative. Increasing evidence now supports the principle that these diseases have a very strong genetic background. Although their clinical manifestations are often observed in the elderly population, genetic predisposition strongly influences the lifetime impact of other environmental factors. Proof of principle that complex diseases such as atherosclerosis could be altered by a single change in some dominant genetic factors was first obtained in transgenic animals. For example, Rubin et al. were the first to demonstrate that the expression of apoA-I in transgenic mice could revert their susceptibility to high fat diet-induced atherogenesis [1], a finding which was later confirmed in a variety of genetically engineered strains of mice with different abnormalities, such as apoE deficiency [2,3] or apo(a) overexpression [4] - both of which result in enhanced susceptibility to atherosclerosis. The gene transfer technology itself is currently improving and the demonstration by Nabel and colleagues [5] that genetic information could successfully be transduced into the intact vasculature of live animals provided the opportunity to design novel therapeutic strategies for a variety of vascular disorders. However, the potential benefits of such strategies are unknown as there are no gene therapy products currently on the market. According to the National Health Examination Survey, about 5 million Americans have ischaemic heart disease, the most costly and common of the untimely complications of atherosclerosis [6]. Atherosclerosis remains the leading cause of death in males > 35 years and in all persons > 45 years. As atherosclerosis can be considered as a disorder of both the vessel wall (intravascular cellular dysfunctions) and lipid metabolism, we propose to follow this artificial distinction throughout this review.     

Electroencephalogram-based pharmacodynamic measures: a review

Pharmacokinetics and pharmacodynamics can provide a useful modeling framework for predicting drug activity and can serve as a basis for dose optimization. Determining a suitable biomarker or surrogate measure of drug effect for pharmacodynamic models can be challenging. The electroencephalograph is a widely-available and non-invasive tool for recording brainwave activity simultaneously from multiple brain regions. Certain drug classes (such as drugs that act on the central nervous system) also generate a reproducible electroencephalogram (EEG) effect. Characterization of such a drug-induced EEG effect can produce pharmacokinetic/pharmacodynamic models useful for titrating drug levels and expediting development of chemically-similar drug analogs. This paper reviews the relevant concepts involved in pharmacokinetic/pharmacodynamic modeling using EEG-based pharmacodynamic measures. In addition, examples of such models for various drugs are organized by drug activity as well as chemical structure and presented.     

5-Hydroxytryptamine (Serotonin): Biphasic Dose Responses

This article briefly summarizes the occurrence of biphasic dose-response relationships associated with 5-hydroxytryptamine (5-HT) receptor systems, as well as 5-HT agonists and antagonists. Such biphasic responses have been reliably reported in multiple experimental settings that explored a broad range of responses, including aggressive behavior, cardiovascular functioning, muscle relaxation, and interactions with other receptor systems such as adrenergic interaction as well as with neurotransmitters such as NMDA.     

5-Hydroxytryptamine (serotonin): biphasic dose responses

This article briefly summarizes the occurrence of biphasic dose-response relationships associated with 5-hydroxytryptamine (5-HT) receptor systems, as well as 5-HT agonists and antagonists. Such biphasic responses have been reliably reported in multiple experimental settings that explored a broad range of responses, including aggressive behavior, cardiovascular functioning, muscle relaxation, and interactions with other receptor systems such as adrenergic interaction as well as with neurotransmitters such as NMDA.     

Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development

While narcotic analgesics such as morphine, which act preferentially through mu opioid receptors, remain the gold standard in the treatment of severe pain, their use is limited by detrimental liabilities such as respiratory depression and drug dependence. Thus, there has been considerable interest in developing ligands for kappa opioid receptors (KOR) as potential analgesics and for the treatment of a variety of other disorders. These include effects mediated both by central receptors, such as antidepressant activity and a reduction in cocaine-seeking behavior, and activity resulting from the activation of peripheral receptors, such as analgesic and anti-inflammatory effects. While the vast majority of opioid receptor ligands that have progressed in preclinical development have been small molecules, significant advances have been made in recent years in identifying opioid peptide analogs that exhibit promising in vivo activity. This review will focus on possible therapeutic applications of ligands for KOR and specifically on the potential development of peptide ligands for these receptors.     

Angiogenesis: Future of pharmacological modulation

Angiogenesis is a fundamental biological process that is regulated by a fine balance between pro- and antiangiogenic molecules, and is deranged in various diseases. Historically, angiogenesis was only implicated in few diseases, such as, cancer, arthritis, and psoriasis. However, in recent years, it has been increasingly evident that excessive, insufficient or abnormal angiogenesis contributes to the pathogenesis of many more disorders. Research in angiogenesis offers a potential to cure a variety of diseases such as Alzheimer''s and AIDS. Modulation of angiogenesis may have an impact on diseases in the twenty-first century similar to that which the discovery of antibiotics had in the twentieth century.     

Measurement and expression of risk: Optimizing decision strategies

A significant proportion of the >6 million articles published annually present data in terms of risk and risk reduction. While the measurement of risk and risk reduction is often straightforward, there are a variety of ways that risk may be expressed. Risk is defined as the rate of an occurrence of a particular disease or adverse event and is determined by the number of events divided by the person-years or number of individuals in the at-risk population. The portrayal of risk can be achieved using different techniques but is typically provided in demographic maps, time-trend charts, or incidence bar graphs. Risk can be expressed in relative terms such as relative risk or absolute measures such as attributable risk or number needed to treat. Understanding risk determination as well as the differences in risk depiction and expression is necessary to ascertain the relevance of the data to one's clinical practice as well as to make optimal clinical and pharmacoeconomic treatment decisions. A review of terms, together with examples, is presented, such that clinicians evaluating the medical literature will be able to identify differences in the way that risk-related results are expressed and optimize the application of such evidence to their practice.     

Hypotensive natural products: current status

Hypertension is a common and progressive disorder that possesses a major risk for cardiovascular and renal disease. Recent data have revealed that the global burden of hypertension is an important and increasing public health problem worldwide and that the level of awareness, treatment and control of hypertension varies considerably among countries. Hypertension is often called a 'silent killer' because persons with this pathological condition can be asymptomatic for years and then have a fatal heart attack or stroke. The field of naturally occurring antihypertensive agent is a research area rapidly expanding due to the high potential of such molecules as new antihypertensive drugs. Recently, a great number of plant-derived substances have been evaluated as possible antihypertensive agents through different mechanisms of action such as alkaloids, flavonoids and terpenoids. In this mini-review we will discuss the medicinal chemistry of these compounds.     

Adiponectin: a key fat-derived molecule regulating inflammation

Adiponectin is the abundant adipocyte-derived protein with well-established anti-atherogenic and insulin-sensitising properties. Besides these well characterised biological functions, recent evidence supports a strong anti-inflammatory function. Whereas initial studies demonstrated that adiponectin suppresses the production of the potent pro-inflammatory cytokine TNF-alpha, current studies showed that this adipokine also induces various anti-inflammatory cytokines, such as IL-10 or -1 receptor antagonists. These effects are paralleled by various other immune-regulatory properties, such as specific effects on endothelial cell functions. These in vitro effects are directly translated into various animal models of inflammation, demonstrating a potent anti-inflammatory effect for adiponectin. Thiazolidinediones selectively upregulate peroxisome-proliferator-activated receptor-gamma, leading to increased tissue and serum concentrations of adiponectin. Adiponectin has emerged as a key mediator regulating and affecting the balance between fat and inflammation. Therefore, either adiponectin itself or its inducing agents, such as thiazolidinediones, might be of key therapeutic interest in the near future far beyond diseases being associated with insulin resistance.     

Phytochemistry and pharmacological activities of Ficus carica latex: a systematic review

Ficus carica tree produces a white sap that is traditionally used for the treatment of skin conditions, such as warts. Ficus carica latex is considered a rich source of proteins and metabolites that have various pharmacological activities. Most of the latex pharmacological activities are attributed to its phenolic content, such as anticancer, antiviral, antioxidant, anti-angiogenic, hepatoprotective, and wound-healing activities. Moreover, Ficus carica latex contains proteases that are involved in the treatments of skin conditions, such as warts, and display antiparasitic activity. Additionally, chitinase enzymes and coumarins are isolated from Ficus carica latex and involved in the antimicrobial activities of latex.     

Clinical economics review: irritable bowel syndrome

The ubiquitous nature of irritable bowel syndrome (IBS), coupled with a lack of good treatment options, has created the impression that the condition must represent a large drain on health-care resources. The literature certainly appears to support this view but is largely based on patients seen in referral centres (10–15%) and it may not be appropriate to extrapolate these data to the IBS population as a whole (85–90%).
In addition to reviewing such literature that exists on the economics of IBS, this paper contains some new data, which suggest that the direct costs of the condition, certainly in the UK, may not be quite as high as has previously been assumed. This may be partly due to factors such as the low cost of the drugs used to treat the condition and the tendency for many patients to stop consulting because of disenchantment with the inadequacies of current therapy. Conversely, the indirect and intangible costs of the disorder appear to be much greater, but these burdens obviously do not have such an impact on those responsible for purchasing and providing health care for IBS sufferers.
Paradoxically, if a new, effective therapy for IBS were forthcoming, the situation could change dramatically, especially if it involved a new drug. Any such agent would inevitably be more expensive than anything available today, leading to a potentially dramatic escalation in the direct costs of this disorder.     

Hemoglobin and myoglobin associated oxidative stress: from molecular mechanisms to disease States

The heme based respiratory proteins myoglobin and hemoglobin can, under certain conditions, exhibit a peroxidase-like enzymic activity, in which a catalytic cycle, driven by peroxides, leads to oxidation of bio molecules. These heme proteins are implicated in what is termed "oxidative stress" as this catalytic cycle, when it occurs in vivo, generates cytotoxic product that are implicated in the pathology of a number of disease states. Here we review the evidence that such reactions occur in vivo, in particular in animal models and human patients and examine the underlying chemical mechanism. This mechanism involves the production of ferryl heme (Fe(IV)=O(2-)) and it is this and associated radicals that initiate processes such as lipid peroxidation and the generation of bioactive molecules such as isoprostanes. The reactivity of the high oxidation state of the heme also allows us to identify unambiguous biomarkers for its presence in vivo in such conditions as rhabdomyolysis and brain hemorrhage. Ways to inhibit the peroxidatic cycle are discussed and the role of iron chelators such as desferrioxamine is discussed in terms of their often neglected properties as reducing agents. Suppression of the peroxidatic activity of hemoglobin is discussed in the context of the development of blood substitutes.     

Developmental origins of health and disease: new insights

Epidemiological and animal studies show that small changes in the developmental environment can induce phenotypic changes affecting an individual's responses to their later environment. These may alter the risk of chronic disease such as metabolic syndrome or cardiovascular disease. Recent research shows that animals exposed to such a mismatch between prenatal and postnatal environment develop obesity, reduced activity, leptin and insulin resistance, elevated blood pressure and vascular endothelial dysfunction. Epigenetic processes are involved in such effects, targeted to promoter regions of specific genes in specific tissues. Such fine control of gene expression suggests that the mechanisms have been retained through evolution through their adaptive advantage, rather than representing extreme effects of developmental disruption akin to teratogenesis. There may be adaptive advantage in a developmental cue inducing a phenotypic change in generations beyond the immediate pregnancy, and a range of data that support this concept. In animals, epigenetic effects such as DNA methylation can be passed to successive generations. Environmental toxins, including endocrine disruptors, may induce greater risk of chronic disease, even at low exposure levels, if they affect such normal developmental epigenetic processes. Appropriate interventions may have long-term multigenerational effects to reduce the risk of chronic disease.     

Review article: lactose--a potential prebiotic

Lactose maldigestion, which affects a large majority of the world's population, has been mostly linked with uncomfortable symptoms. In addition, dairy consumption is variably blamed or recommended for a number of ill effects. There is, however, emerging evidence that certain lactic acid-producing bacteria, which selectively consume prebiotics, may be beneficial against some lower intestinal diseases. Lactose maldigestion and lactose should perhaps be re-evaluated as a potential provider of such a prebiotic. This historical and observational review discusses lactose and argues the opinion that it has prebiotic potential. Moreover, in maldigesters, natural ingestion or lack thereof may be relevant in the pathogenesis of diseases such as colorectal cancer and inflammatory bowel diseases.     

Non-selective cation channel blockers: potential use in nervous system basic research and therapeutics

Non-selective cationic channels (NSCC) are a heterogeneous family of channels, widely expressed in non-excitable and excitable cells, that share several functional characteristics but have diverse molecular origin. NSCC can be formed by transient receptor potential (TRP) channels, calcium activated non-selective channels, hyperpolarization activated cation currents, acid-sensitive cationic channels (ASIC), etc. As a result of its wide expression, as well as to the fact that the activation of such currents produce a persistent membrane depolarization, NSCC have been involved in a variety of neuronal processes such as signal transduction, firing pattern (including plateau potentials and bursting mechanisms) as well as synaptic transmission. Due to the relevance of such channels, alterations in their normal function have been associated with the pathophysiology of several nervous system diseases. Over the last years several blockers of such channels have been discovered. Here we review the pharmacology of NSCC blockers including trivalent cations, verapamil derivates, flufenamic acid, the "typical" TRP blockers 2-APB, ACA and SKF 96365 as well as ASIC blockers. This review focuses on the pharmacological properties of such drugs and their potential use for the understanding of the nervous system as well as for the treatment of neurological diseases.     

Social modeling as a determinant of drinking behavior: Implications for prevention and treatment

The consumption of alcohol has often been described as a socially mediated activity (MacAndrew & Edgerton, 1969). Social-learning approaches of alcohol use endorse this view and conceptualize drinking habits as being on a continuum from abstinence to problem drinking. On such a continuum the “social drinker” represents a moderate level of alcohol use. Moderate drinking habits are said to develop via the laws of learning, including the influence of social processes such as modeling. Since we learn adaptive styles and levels of alcohol use via such social influence processes it seems likely that the use of techniques such as modeling should be a highly effective strategy for preventing and treating the development of maladaptive drinking habits.     

Drug-Cytokine Interactions: Focus on Cyclosporine

The immune system is a complex network that regulates and maintains the host's defense system. Changes and alterations in the immune system precipitate a series of reactions to prevent further damage as well as initiate repair. The systems cellular component relies on cytokines (interleukins, tumor necrosis factor, interferons, etc.) to facilitate communication in response to a foreign antigen. Cytokine concentrations are therefore elevated during times of inflammation, such as rejection of a transplanted organ. Recent research suggests that interleukin-6 may have an inhibitory effect on cytochrome P-450 3A and thus affect drug metabolism. Cyclosporine, which is administered to prevent rejection of transplanted organs, is metabolized primarily by the P-450 3A system. Thus, the inhibitory effect of interleukin-6 may alter cyclosporine concentrations, which in turn may increase its adverse effects, such as nephrotoxicity.     

The treatment of Tourette's syndrome: current opinions

Correct education of the patient is one of the most important aspects in the treatment of Tourette's syndrome. Pharmacotherapy is often unsatisfactory and therefore should be limited to those patients who are significantly impaired. Therapy must be individualised and the most troublesome symptom should be targeted first. In the treatment of tics, dopamine receptor blocking agents are currently the most effective drugs. It is currently unknown whether classic neuroleptics, such as pimozide, selective dopamine receptor antagonists, such as sulpiride, or newer atypical antipsychotics, such as risperidone, have the best adverse effect profile. Tiapride can be used as an alternative, particularly in children. Selective serotonin-re-uptake inhibitors are recommended for the treatment of obsessive-compulsive behaviour. In children suffering from attention deficit hyperactivity disorder, psychostimulants, such as methylphenidate, are the treatment of choice. Recent studies have provided increasing evidence that stimulants do not cause a significant increase in tics in the majority of patients.