Current Drug Targets - Volume 2, Issue 4, 2001

Current theories of dopaminergic and noradrenergic mechanisms, which are thought to be of importance in the regulation of attention are reviewed. A biphasic model of dopaminergic function is described, in which tonic dopamine exerts a suppressive influence on subcortical dopamine systems by altering tonic / phasic dopaminergic relationships. Noradrenergic mechanisms are of importance in modulating sensory processing at the prefrontal cortical level. The work of Silberstein and colleagues utilizing Steady-State Visually Evoked Potential, during the course of an A-X Continuous Performance Task enables examination of the spatial distribution and dynamics of electrical brain activity during the task. The maintenance of activation in the interval between A and X provides a measure of working memory, thought to be related to prefrontal-parietal activation, which is facilitated by administration of methylphenidate to children with ADHD, suggesting that working memory may be a core deficiency in children with ADHD. While tonic dopamine activity in vental striatum / accumbens gates inhibitory activity, dorsolateral prefrontal-parietal connections allow maintenance of working memory required for goal completion.

Given the current global epidemic of obesity there is a demand for new anti-obesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as ‘appetite suppressants’ with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin / GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with life style changes and dietary intervention may be critical in dealing with the rising world epidemic of obesity.

Gene therapy, the expression in cells of genetic material that has therapeutic activity, holds great promise for the treatment of a number of human diseases. A gene delivery vehicle, or vector, that may be of viral or non-viral origin, is generally used to carry the genetic material. Viral vectors have been developed that exclude immunogenic genes while taking advantage of the genes responsible for proficient integration of the viral genome into that of the host. In this way, viral vectors improve the probability of long-term expression of the therapeutic gene, whereas non-viral vectors, that are not as efficient at introducing and maintaining foreign gene expression, have the advantage of being non-pathogenic and non-immunogenic. Although thousands of patients have been involved in clinical trials for gene therapy, using hundreds of different protocols, true success has been limited. A major limitation of gene therapy approaches, especially when non-viral vectors are used, is the poor efficiency of DNA delivery to the nucleus a crucial step to ensure ultimate expression of the therapeutic gene product. Here we review existing gene delivery approaches and, in particular, explore the possibility of enhancing non-viral gene delivery to the nucleus by incorporating specific nuclear targeting sequences in vectors, using a range of different strategies.

This review discusses the Ca2+-activated K+ channels of intermediate conductance (IK channels), and their historical discovery in erythrocytes, their classical biophysical characteristics, physiological function, molecular biology as well as their role as possible molecular targets for pharmacological intervention in various diseases. The first described Ca2+-activated K+ channel ever - the so-called Gardos channel from human erythrocytes - is an IK channel. The “I” denominates the intermediate conductance that distinguishes the IK channels from the related Ca2+- activated K+ channels of small (SK) or large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4) enabled a detailed mapping of the expression in various tissues. IK channel expression is found predominately in cells of the blood, in epithelia and endothelia. An important physiological role of IK channels is to set the membrane potential at fairly negative values and thereby to build up large electrical gradients for the passive transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling Tlymphocyte proliferation.The molecular cloning of IK and SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its therapeutic value, but new drug candidates are entering the stage.It is discussed whether pharmacological modulation of IK channels may be beneficial in sickle cell anemia, cystic fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune diseases.

Efforts to interfere with the initiation and promotion of breast and other cancers by endocrine manipulation are not new. It is of obvious benefit to cancer patients to administer substances that combine minimal general toxicity with maximal oestrogen inhibition. Raloxifene is a relatively recent addition to a group of compounds loosely designated as antioestrogens, which implies their ability to antagonize oestrogen effects via competitive binding to the various receptors. This is a reductionist simplification, since their effect varies and ranges from interaction with lipid transduction cascades, covalent binding to proteins and DNA, regulation of growth factors, erbB2, mdr1 and probably p53 expression, complexing with E-cadherin / catenin to active induction of apoptosis and many other effects on the genome. Also, the action of most antioestrogens is not solely antagonistic and different compounds do exert some agonistic effects in various tissues. Apart from some “pure” antioestrogens, the benzothiophene derivative Raloxifene has been found to combine a high degree of selective oestrogen suppression with several other desirable characteristics, such as reduction of bone demineralisation and antiatherogenic effects without endometrial stimulation. It is well tolerated, has been successfully tested as a chemopreventive agent for breast cancer in certain groups of the population and does not prevent ovulation in women with normal menstrual cycles. Certainly, Raloxifene is only another forerunner of upcoming “designer” oestrogen modulators, but it represents a welcome addition to the therapeutic choices available for the control of some menopausal problems as well as for the prevention and treatment of breast cancer, as outlined in the following brief review.

Tuberculosis (TB) kills more youth and adults than any other infectious disease in the world today. The emergence of new strains of Mycobacterium tuberculosis resistant to some or all current antituberculosis drugs is a serious and crescent problem. The resistance is often a corollary to HIV infection and drug-resistant TB is more difficult and more expensive to treat, besides to be more likely fatal. Thus, it is still necessary to search for new antimycobacterial agents. The identification of novel targets need the identification of biochemical pathways specific to mycobacteria and related organisms. Many unique metabolic processes occur during the biosynthesis of mycobacterial cell wall components. In this report, we examine one of these attractive targets for the rational design of new antituberculosis agents - the mycolic acids.