Current Pharmaceutical Design - Volume 15, Issue 11, 2009

This special issue of “Current Pharmaceutical Design” covers a broad range of topics with the unifying theme - novel approaches to conquer a disease and improve well-being of a patient. Most, if not all of these, are approaches that already have passed the preclinical stage and have been applied in clinical practice. In order to assemble this issue the Editor picked original investigators working all over the world in order to make it truly international and to provide a representative sample of projects that are undertaken on a global scale. The individual topics of this issue cover every major global disease. The articles in this issue are listed in the alphabetical order according to the surname of the first author. The team of Batdelger et al. [1] from Mongolia, Thailand and USA, review the current trend in therapeutic vaccines and summarize their own contribution to immunotherapy of hepatitis B and C - two most common serious, infectious diseases that affect globally over 500 million people or roughly 10% of global population. AIDS is another global disease affecting 30 million people. Armenian group of Davtyan et al. [2] describe their own approach to combat AIDS - an anti-inflammatory as well as antiviral combination therapy that they have successfully developed and applied in their own country. Kucherov et al. [3] from Belarus describe results of their drug screening effort for potential anti-HIV agents among affordable, locally-manufactured drugs that have been used for unrelated diseases. As a result they were able to discover six new compounds, three of which can be deployed immediately since they have been used safely by physicians for other clinical conditions.

Franciscan missionary Giovanni Di Plano Carpini traveled in 1245 to a country named Yeke Tartar, to visit a certain man called Genghis Khan. His journey's report narrated peculiar dietary habits of the locals: “they eat anything, even lice”. Little that Carpini knew, he had actually documented the earliest known to us record of oral vaccination against blood-borne infections - an approach that is still used occasionally in the present-day Mongolia for therapy of hepatitis. Currently, efforts aimed at developing therapeutic hepatitis vaccines have switched to more palatable path, but we may still benefit from the insight of medieval Mongols. This review provides an update on development of hepatitis B and C vaccines as related to immunotherapy of hepatitis. Immune therapy is a fast-moving field but the results so far failed to pitch woo. Current trends in research on therapeutic vaccine candidates and liver immunology are discussed. We subscribe to the idea that viral hepatitis is essentially an autoimmune disease generating immune-mediated liver damage. Therapeutic vaccines need to be designed in such a way that self-destructive immunity of the host is targeted not the virus, which is not cytopathic.

An ideal antimicrobial should be not toxic and possess board spectrum antiviral, antibacterial, antifungal activity, excluding resistance and should affect pathogen-mediated damage of host physiology including immune, nervous and endocrine systems. With the purpose of a combination of nonspecific antimicrobial action of molecular and ionized iodine with systemic immune-modulating property of the negatively charged polysaccharides a complex drug of iodine and lithium on a template of a α-dextrin liquid crystal was designed. The physicochemical model of iodine-lithium-α-dextrin (ILαD) is based on the human blood and the stereochemistry of moving equilibred systems of dynamically balanced organic polymers conformation complexed with the iodine and lithium molecules. Here we reviewed the antibacterial, antiviral, immune-modulating and anti-inflammatory mechanisms in vivo and in vitro as well as pharmacokinetics, metabolism, chronic toxicity, cumulative properties, embryo toxicity and carcinogenicity of ILαD. Clinical efficacy, tolerability and safety of ILαD monotherapy have been evaluated in HIV-infected patients, administered intravenously for a total of 12 infusions in 4 cycles. ILαD therapy contributes to anti-HIV and anti-inflammatory effects, resolution of dermatological and neurological pathology and dramatically improves the quality of life reflecting on enhanced treatment adherence. ILαD appears to be safe and perspective for an adjuvant therapy of bacterial and viral infections, including HIV/AIDS, hypothyroid, autoimmune and inflammatory diseases for controlling pathogen production from infected cells, immune response, inflammation and metabolism.

In vitro screening of 307 drugs with various clinical indications (cardiotropic, neurotropic, antibacterial, etc.) has revealed 6 compounds which displayed remarkable antiretroviral activity. Three of these drugs had a tendency to have undesirable side effects and were thus excluded from further consideration. Remaining three, i.e., Xantinol Nicotinate, Tardiferon, and Trental may become valid candidates for inclusion into antiviral regimens such as HAART. In vitro tests have shown that xantinol and trental display synergistic effect with azidothymidine, inhibit the replication AZT-resistant strains of HIV, and have no competing undesirable activities. These compounds should be evaluated in safety studies to determine optimal doses for patients with HIV. If these studies confirm in vitro results these compounds may become valid candidates as safe and affordable means to be added into the arsenal of antiretroviral drugs.

Regulatory T lymphocytes (Tregs) are specialized for immune suppression and are important regulators of the immune response in various settings. Tregs actively suppress enteroantigen-reactive cells and contribute to the maintenance of intestinal immune homeostasis. Distinct Treg subsets coexist in the intestinal mucosa and mesenteric lymph nodes. Disturbances in Treg number and function are associated with immune-mediated disorders. Therefore, Tregs are potential targets for immunotherapies. The gut mucosal immune system is the largest lymphoid organ in the body. This site has continuous antigenic challenges from food antigens, antigens of the abundant normal bacterial flora, and pathogens. Despite this constant antigenic stimulation, controlled inflammatory responses and suppression of inflammation appear to be the rule. The gut immune system differentiates the antigenic signals from the high background noise of food and bacterial antigens. This tight regulation required to maintain homeostasis is achieved through multiple non-immune and immune factors. Oral tolerance is a mechanism in which the gastrointestinal immune system inhibits or promotes its reaction toward an orally administered antigen. Mucosal tolerance is attractive as an approach to the treatment of autoimmune and inflammatory diseases; the benefits of using an oral tolerance approach are: lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. Multiple mechanisms of tolerance are induced by oral antigen administration. Recent data suggest that oral antigen administration of antigens may promote activation of different types of regulatory T lymphocytes, enabling treatment of immune mediated disorders. This review summarizes the recent data on induction of regulatory T-cells by oral antigen administration as a possible mechanism of oral tolerance.

Dengue viruses cause 50-100 million cases of acute febrile disease every year, including more than 500000 reported cases of the severe forms of the disease-dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Attempts to create conventional vaccines have been hampered by the lack of suitable experimental models, the need to provide protection against all four serotypes simultaneously and the possible involvement of virus-specific immune responses in severe disease. Live attenuated D2 16681-PDK53 vaccine was first developed from Mahidol University, Thailand. This vaccine induced both humoral and cell-mediated immunity and lack of reactogeneticity in humans. Infectious cDNA clones of the virulent D2 16681 virus and its attenuated D2 16681-PDK53 were constructed. The attenuated virus elicited neutralizing antibodies in mice and monkeys and developed viremia in monkeys. At molecular level, patterns of cytokines which are immunological mediators released from human mononuclear cells obtained from dengue naive and immune donors infected with this attenuated virus compared with virulent virus were studied. In dengue naive PBMC, the virulent and attenuated clones induced alternation in expression of 25 and 24 versus 13 and 18 genes out of 268 genes on day 1 and 3. In dengue immune PBMC, the virulent and attenuated clones induced alternation in expression of 33 and 38 versus 25 and 29 genes on days 1 and 3. Up-regulation of IL-1β, IL-6, IL-8, IL-10, IFN-α, IFNγR, MIP-1α, MIP-1β, MIP-2α, VEGF and down-regulation of IL-4, IL-4R, IL-RII, MIF, RANTES, IGF-1, GM-CSF-2 were shown. This review pointed out the infectious clones of the attenuated D2 16681-PDK53 was safe and induced both neutralizing antibodies in vivo and cytokine gene expression in vitro at molecular level. Furthermore, the phenotypic markers of ideal dengue vaccine could be included the alteration of cytokine gene expression and cytokine production in human mononuclear cells.

Inflammation is a general term used to describe various pathological processes with diverse causes that can include infection, trauma, or an autoimmune response. Due to its many causes, the inflammatory response involves multiple and varied mediators, including vasoactive amines, free radicals, and both lipidic and peptidic mediators. Medicinal plants and the compounds derived from them are a good source of new and specific inhibitors of the inflammatory process. The past decade has witnessed many important discoveries in this field, with new findings challenging the more traditional views of pharmacologists. Various studies, for example, have demonstrated the positive effects of plantderived phenolics, which act as anti-oxidants, free radical scavengers, and inhibitors of nitric-oxide synthase, cyclooxygenase, and lipoxygenase. The anti-inflammatory activity of chalcones has been correlated with the induction of heme oxygenase-1 while phlorotannins have been found to inhibit matrix metalloproteinase, which is implicated in arthritis, chronic inflammation, and wrinkle formation. Sesquiterpene lactones have been studied as inhibitors of NF-κB activity and the relationship between their chemical structure and pharmacological activity has been clearly established. Recently, cucurbitacins have been described as inhibitors of JAK -STAT and NF-AT functions related to inflammation; they were also found to induce apoptosis of cells involved in the inflammatory response. This review focuses mainly on the effects of natural products on transcription factors, which are the most promising targets for designing new active drugs against inflammation and cancer.

Interferons are first immunomodulatory molecules that have been shown to display a wide range of applications due to their antiviral, antibacterial, antitumor, and inflammatory activities. Natural and recombinant interferons are among most common biologic therapeutics worldwide. Interferon inducers, however, are less known and have been mostly developed and used in former socialist countries. Despite the fact that they are virtually unknown to the Western world, they represent a substantial market share of modern pharmacopoeia in former socialist republics. This review provides a brief description of most popular interferon inducers including Amyxin, Amizon, Anandin, Arbidol, Blasten, Cycloferon, Galavit, Groprinosine, Hepon, Immunoxel, Dzherelo, Kagocel, Larifan, Ligfol, Likopid, Mebavin, MIGI-KLP, V-5 Immunitor, SCV-07, Milife, Neovir, Poludan, Ragocin, Ridostin, Thymogen and Savratz, some of which were in use for several decades for the same clinical indications as for interferons. The variety and choice offered by the pharmaceutical industry behind the former “iron curtain” certainly deserves the appreciation, familiarity and application prospects for medical and research investigators worldwide.

The mycobacteria are one of a number of genera making up the aerobic Actinomycetales. Their antigens demonstrable by immuno-precipitation methods can be divided into four groups. The group i antigens, common to all mycobacterial species, cross-react with their counterparts in animal cells, largely derived from mitochondria. Notable amongst these antigens are the heat-shock, or stress, proteins and possibly bacterial sugars. Tests of cell-mediated immunity show that people can be separated by their responsiveness in skin-test, or lymphocyte proliferation techniques, into four categories of responders. Category 1 individuals respond to all mycobacterial reagents through recognition of the group i antigens. Many chronic diseases are associated with a lack of cell-mediated responsiveness to the group i antigens, and have a raised antibody titre to them. This reflects a predominance of T helper 2 activity and reduced T helper 1 responsiveness as part of the pathogenesis of their diseases, which include chronic bacterial, viral and parasitic infections, allergies, autoimmunities and neoplasms. Packaged together, the group i antigens and the cell-wall adjuvants of selected aerobic Actinomycetales make potent immuno- modulatory reagents. An example is heat-killed Mycobacterium vaccae, useful in both prevention and treatment of disease. Treatment with such reagents results in alleviation of disease, restoration of cellular responsiveness to the common mycobacterial antigens and a decrease in antibody titres to them. This new approach to treatment for such a wide range of diseases has few disadvantageous side effects and can accompany other non-immunosuppressive therapies.

Southern Africa is burdened with Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis (M.tuberculosis) infections as well as conditions of iron (Fe) overload. Highly Active Antiretroviral Therapy (HAART) is used to treat HIV-infection, many drugs exist for the treatment of tuberculosis (new solutions are also being sought because of the existence of multi drug resistant strains of M.tuberculosis) and Fe chelators are commonly used to treat Fe overload. Chelators have also been shown to inhibit the multiplication of numerous microorganisms and hence there are publications suggesting a role for chelators like desferrioxamine (DFO) in the dual treatment of microorganism infection and excess iron. Excess iron fuels pathogen survival which in turn lowers host cell functionality (manifested as altered proliferation, cytokine secretion, etc); withholding iron (via a chelator) reverses the process, even more so when the cells are chelated for longer periods of time. Chelation with DFO is reviewed here by commenting on its immunomodulatory effect.

The divergence and antigenic shifts in influenza viruses represent significant challenges for the development of effective vaccines and antiviral drugs against influenza viruses. In view of current challenges and/or deficiencies in the influenza pandemic influenza preparedness, novel antiviral strategies which are robust and can respond to constant viral mutations, are particularly needed to combat future pandemic threats. Toll-like receptor-3 (TLR-3) is an integral part of the host's innate immune system and serves as an important signaling pathway for the recognition of dsRNA for the triggering of antiviral and inflammatory responses to combat viral infections. This review examines dsRNA including Poly ICLC and liposome-encapsulated Poly ICLC (LE Poly ICLC) as TLR-3 agonists for their antiviral activity against seasonal and highly pathogenic avian influenza (HPAI) viruses. Furthermore, their roles in attenuating the antiviral and inflammatory cytokines in the host will also be explored. Preclinical studies in experimental animals suggest Poly ICLC and liposome-encapsulated Poly ICLC are safe and offer broadspectrum protection against both seasonal and HPAI viruses, as well as other respiratory viruses including respiratory syncytial virus and SARS. Preliminary results from recent studies suggest these drugs up-regulate the production of interferons (-α, -β, and -γ), and tumor necrosis factor (TNF-α) but downregulate some proinflammatory cytokines including IL-2 and IL-4. Taken together, these results suggest these TLR-3 agonists have a promising role to play as safe, effective and broadspectrum anti-influenza drugs that could complement other antiviral drugs to combat seasonal, zoonotic and pandemic influenza viruses. The clinical safety of these drugs and their efficacy in pre-clinical studies may provide sufficient justification for regulatory agencies to consider their fast track development for use in future outbreaks of pandemic influenza or of other emerging respiratory pathogens.