Leptin: from animals to humans

Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese/diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.     

Lipid-based amphotericin B formulations: from animals to man

Amphotericin B has been the mainstay of systemic antifungal therapy for over 30 years, despite its serious side-effects, and, although numerous alternative antifungal agents have been developed, none to date has matched the efficacy of amphotericin B. However, modern drug delivery technology has improved the safety of amphotericin B by incorporating it into lipid-based delivery systems, including liposomes. Three such formulations, based on the natural affinity of amphotericin B for lipids, are currently marketed. All increase the therapeutic index of amphotericin B, thereby allowing more aggressive treatment than is possible with the conventional product. However, they differ in structure, side-effect profiles and evidence of proven efficacy as discussed in this review.     

Levosimendan: from basic science to clinical trials

Levosimendan is one of the documented pharmacological agents used in the management and treatment of acute and chronic heart failure; it is a novel inodilator agent which enhanced myocardial performance without changes in oxygen consumption. The combination of positive inotropic and vasodilator effects of levosimendan relates to its Ca(2+) - sensitizing and K(+) channels opening effects. Levosimendan has been proposed, in the recent past, to be non-inferior and may have some advantages to standard inotropes; further possible indications for levosimendan have been described, in some observational studies, such as a perioperative use, cardioprotection, cardiogenic shock, sepsis and right ventricular dysfunction. The ability of levosimendan to improve myocardial function without substantially increasing oxygen consumption may appear paradoxical but is possible via improved efficacy not only with regard to the effects on the contractile apparatus of the cardiomyocytes. The aim of this review is to describe the pharmacological characteristics of levosimendan and its clinical applications. The patent review data regarding the use of levosimendan are also discussed in this review article.     

Translating cognition from animals to humans

Many clinical disorders, whether neurological (e.g. Alzheimer's disease) or neuropsychiatric (e.g. schizophrenia and depression), exhibit cognitive symptoms that require pharmacological treatment. Cognition is multi-faceted and includes processes of perception, attention, working memory, long-term memory, executive function, language and social cognition. This article reviews how it is feasible to model many aspects of human cognition with the use of appropriate animal models and associated techniques, including the use of computer controlled tests (e.g. touch-screens), for optimising translation of experimental research to the clinic. When investigating clinical disorders, test batteries should aim to profile cognitive function in order to determine which aspects are impaired and which are preserved. In this review we have paid particular attention to the validation of translational methods; this may be done through the application of common theoretical principles, by comparing the effects of psychological manipulations and, wherever feasible, with the demonstration of homologous neural circuitry or equivalent pharmacological actions in the animal and human paradigms. Of particular importance is the use of ‘back-translation’ to ensure that the animal model has validity, for example, in predicting the effects of therapeutic drugs already found in human studies. It is made clear that the choice of appropriate behavioral tests is an important element of animal models of neuropsychiatric or neurological disorder; however, of course it is also important to select appropriate manipulations, whether genetic, neurodevelopmental, neurotoxic, or pharmacological, for simulating the neural substrates relevant to the disorders that lead to predictable behavioral and cognitive impairments, for optimising the testing of candidate compounds.     

Gastrointestinal cytoprotection: from basic science to clinical perspectives

An essential point of cytoprotection is that the prostaglandins are able to prevent chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a property specific to prostaglandins. Since then gastrointestinal cytoprotection has been shown with various agents (anticholinergic agents, H₂RA, growth factors) and retinoids the latter differing from the actions of vitamin A. In examining the various components of gastrointestinal cytoprotection we have performed studies in isolated cells, stable cell lines, animal experiments, healthy human subjects, and in patients with gastrointestinal diseases. Our attention has focused on the effects of cytoprotective agents on cellular viability, mitochondrial and DNA damage, oxygen free radicals, natural antioxidant systems, mucosal biochemistry, vascular events, gastrointestinal mucosal protection as well as in their prevention of different human diseases. This paper gives a short overview on the different approaches for the exploring gastrointestinal cytoprotection. Received 28 August 2006; revised version 27 October 2006; accepted 27 October 2006     

Substance abuse prevention: moving from science to policy

Substance abuse exacts tremendous social and economic costs in the United States, making a response to this problem a priority for policy makers at all levels of government. Although little argument exists about whether government should play a role in substance abuse control, considerable debate has been generated about exactly what that role should be. Currently, the United States spends about twice as much on supply reduction as demand reduction strategies. Supply reduction strategies, such as law enforcement and interdiction, are often harsh and based on little or no scientific evidence that demonstrates efficacy. As a demand reduction strategy, drug treatment has been demonstrated to be cost-effective. Substance abuse prevention, however, has failed to establish a critical body of research with which to make its case. This paper suggests several direct ways in which prevention science can influence public policy and thus move prevention science to more effective substance abuse prevention policy.     

Calorific restriction: can we extrapolate from animals to humans?

Dietary restriction in animals results in a dramatic reduction of cancer incidence. Several attempts have been made to extrapolate this observation to the human situation. Recent developments in our knowledge of gene-dietary interactions, particularly in relation to vitamins, have been taken into account in a new examination of the likely effects of dietary restriction in humans, but this is a relatively new area of research. Epidemiological studies in relation to diet have also been considered, but probably need to be refined further because of the subtle effects of dietary interactions. Until more detailed information is available the extrapolation can still only be made with the utmost caution.     

Extrapolation from animals to man: predictions, pitfalls and perspectives

Comparative drug disposition studies can be useful in extrapolating from animals to man provided that the criteria indicating interspecies similarity in disposition reflect similar exposure to the foreign compound. Interspecies variability, on the other hand, can often be related to physiological or biochemical differences, thereby providing a rationale for the unsuitability or limitations of a species as a model for human metabolism. Retrospective evaluation of the following examples illustrates the relevance of the indicated disposition characteristics to risk and efficacy assessment: (a) oxaprozin (route of excretion, enterohepatic circulation and exposure; plasma concentrations and efficacy prediction); (b) ciramadol (species differences in presystemic elimination and major metabolic pathway); (c) acebutolol (pharmacologically active human metabolite absent in one of the toxicology species); (d) esmolol (duration of pharmacologic effect controlled by species dependent nature of blood esterases). Stereochemical preferences in the disposition of racemic drugs often differ among species. Extrapolations from one species to another cannot be made in this situation. Pharmacokinetic parameters based on measurements of the sum of the isomers are meaningless and potentially misleading. Future improvements can come from: computer assisted predictions of metabolic pathways; increased use of human tissues; and use of animal species physiologically similar to humans, e.g. the miniature swine.     

Alcoholism in Australia, the 1880s to the 1980s: from medical science to political science

The disease concept of alcoholism has been central to the response to alcohol-related problems in Australia. The history of alcoholism from colonial times to the present is discussed with reference to alcohol consumption, legislative action, inquiries by medical and other bodies, and services especially treatment services provided by government and non-government organisations. In the 1980s the position of the disease concept perspective has been declining while a wider politico-economic perspective has become established.     

NAVAGATE: a rubric to move from pharmacogenomics science to pharmacogenomics practice

Integration of pharmacogenomic data at the point of care is the next essential step in translating years of research into evidence-based decisions that impact the care of an individual patient. The use of clinical recommendations for pharmacogenomic data help clinicians to better select and monitor drug therapy. However, a systematic rubric for utilizing the data ensures a thorough implementation of the information in a way that may improve the application of the new scientific discoveries. NAVAGATE is a set of eight questions to ask when considering a pharmacogenomic test or test result when caring for a patient. The series of questions are meant to inform prescribing or dispensing when obtaining or employing pharmacogenomic data for these steps within the medical-care framework. In this article two key examples are used to exemplify the benefits of following a systematic process to evaluate the utility of the new scientific data.     

Early metabolic changes in response to lung injury: extrapolation from animals to humans

The pulmonary capillary endothelium provides a nonthrombogenic, semipermeable barrier between pulmonary blood and tissues. In recent years, particular attention has been focused on the ability of these cells to metabolize a variety of circulating biologically active substances either by interiorizing the substance through specific membrane transport processes or by directly altering the substance by way of enzymatic activity at the plasma membrane. Serotonin, norepinephrine, and several prostaglandins are examples of biologically active substances that are removed from the circulation by the pulmonary endothelium by way of specific transmembrane transport processes. Concomitant with the increased interest in metabolic functions of the pulmonary endothelium, there has been a growing awareness of the central role of endothelial cell abnormalities in the pathogenesis of various lung injuries and disease states. During the past several years, considerable evidence has accumulated in support of the hypothesis that alterations in the metabolic functions of the lung provide a method of detecting lung injury in vivo, and tests of the metabolic functions of the lung have progressed from in vitro systems to animal models to humans. This paper reviews some of the evidence responsible for this progression and discusses some of the limitations inherent in the extrapolation of lung metabolism studies from animal models to humans. In this discussion, particular emphasis is placed on the pulmonary uptake and metabolism of serotonin, norepinephrine, and prostaglandins E and F by mammalian lungs.     

Lectins: from basic science to clinical application in cancer prevention

Many physiological functions are attributable to lectin-carbohydrate interactions. Lectins are currently being studied for their ability to destroy tumour growth by binding to specific carbohydrate motifs on cancer cells. Cell-surface molecules, including growth factor receptors are often glycosylated, and lectins may act by binding to these. Certain lectins effect the proliferation of intestinal epithelial cells. This effect is cell-type and lectin specific and occurs in the intestine of intact animals, in human colonic explants and colorectal cancer cell lines. Lectins present in mammalian tissue are involved in cell-matrix adhesion, differentiation, lymphocyte circulation and immunomodulation. Mammalian lectins contribute to detection, diagnosis and prognosis of tumour cells, and can be targeted for therapy. New lectins of plant and mammalian origin that have one or more of these functions are currently being developed as tools that could be used to target tumour cells.