Current Medicinal Chemistry - Volume 12, Issue 15, 2005

During the past decade, combined highly active antiretroviral therapy (HAART) consisting of the nucleoside, non-nucleoside and protease inhibitors has improved the outlook for HIV-infected individuals. However, despite the clinical improvement associated with HAART, current antiviral drug regimens are not able to eradicate HIV due to the persistence of virus in cellular reservoirs (predominantly long-lived memory CD4+ T cells and cells of the macrophage lineage) and anatomical sanctuary sites (brain and possibly testis). Detailed knowledge of viral reservoirs is essential for the effective design of therapeutic eradication strategies such as immunostimulation of virus-persistent reservoirs and better penetration of antiretroviral drugs into sanctuary sites. The recent therapeutic approaches undertaken thus far, including immune activation, intensification protocols combined with HAART, antiretroviral treatment during seroconversion, structured treatment interruptions, activation of latent infection or targeted killing of viral reservoirs have failed to completely eradicate the virus. This review provides an evaluation of the current HAART regimens exploring the reasons for their inability to eradicate HIV from cellular reservoirs and anatomical sanctuary sites. We also provide examples of therapeutic strategies that aim to eradicate the virus, flush out reservoirs and increase antiretroviral drug concentration in these cells and tissue compartments.

Serotonin is a neuromediator, well-know for its implication in mood regulation, anxiety, depression and, insomnia as well as in normal human function such as sleep, sexual activity and appetite. In this way, serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists and pharmaceutical companies. Among 5-HTRs, the 5-HT1A subtype is the best studied, and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT1A receptor sites such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines and aryloxyalkyl-amines.

New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some antiatherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of lowdensity lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.

Oncogenic conversion of receptor protein tyrosine kinases (RTK) is a frequent feature of malignant cells. This knowledge has fostered efforts to develop target-specific low molecular weight therapeutics able to obstruct RTK signalling. The clinical efficacy of the ABL- and KIT-inhibitors are paradigmatic of the power of this approach. Here, we focus on small-molecule inhibitors for RTKs involved in human cancer. In particular, we examine the KIT, MET and RET receptors that are targeted by genetic alterations in both sporadic and familial human tumours.

There is an increasing number of studies utilizing dendritic cell (DC) based therapies for cancer. With a powerful antigen-presentation capability, DCs have the potential to overcome tumor tolerance and induce anti-tumor immunity, when loaded with tumor antigens. In order to optimize this approach, methods have aimed to enhance immunopotency of therapeutic DCs. A thorough understanding of DC immunobiology would accelerate this process and provide advantageous procedures to increase anti-tumor responses. This review contains an analysis of recent advances on DC subsets, phenotypic characterization, localization, surface receptors and their ligands. The events of immune induction via DCs, involving initial recognition and uptake of antigens, migration, subsequent activation and maturation are revisited. Furthermore, the current methods used for DC-based cancer immunotherapy, including DCs pulsed with tumor antigens in forms of DNA, RNA, peptides, proteins and lysates, or DCs fused with tumor cells are summarized. Respective preclinical and clinical trials are in progress and hold promise for developing effective cancer vaccines.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific β-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-α (TNF- α), and interleukin- 1 β] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a β-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-α serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-g in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- β release or augmenting NK activity in depressed patients.

Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries, but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore, expansion of novel anti-HIV drugs and targets will be critical in the coming years. In this context, discovering anti-HIV agents from natural sources and particularly from plants, may highlight the principle of a nutritional antioxidant antiretroviral diet. In this paper, we review the putative anti-HIV activity of simple caffeic acid derivatives, together with their antioxidant properties. Toxicity, metabolism and bioavailability, when known, will also be detailed. Wellknown caffeic acid derivatives, such as chicoric, rosmarinic and lithospermic acids, may be designed as future leads multitarget anti-HIV compounds and the plants and vegetables containing them as potent nutritional therapeutic supplementation source. They are not expected to replace the actual antiretroviral therapy, but more likely, to complete and perhaps lighten it by adapted diet.