Nitroimidazooxazoles(#) Part xxiv, Search for Antileishmanial Agents: 2,3-Dihydro-6-nitroimidazo[2,1-b]oxazoles as Potential Antileishmanial Agents.

A number of mono and bicyclic nitroimidazoles were screened for in vitro antileishmanial activity. Among these, compounds belonging to the class of nitroimidazo[2,1-b]oxazoles showed moderate to good activity. This class of compounds had been reported previously to have pronounced antitubercular activity, particularly CGI17341 (5a). In the present study (5a) and (5d) and (7) were found to be more potent antileishmanials in vitro than the standard and less toxic in relation to a reference compound. (7) Was earlier formulated to have the phenyl group located on C-2(5b).

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs.

On the existence of cytokines in invertebrates.

Based on the assumption that invertebrates, like vertebrates, possess factors regulating responses to infection or wounding, studies dealing with the evolution of immunity have focussed on the isolation and characterisation of putative cytokine-related molecules from invertebrates. Until recently, most of our knowledge of cytokine- and cytokine receptor-like molecules in invertebrates relies on functional assays and similarities at the physicochemical level. As such, a phylogenetic relationship between invertebrate cytokine-like molecules and vertebrate counterparts could not be convincingly demonstrated. Recent genomic sequence analyses of interleukin-1-receptor-related molecules, that is Toll-like receptors, and members of the transforming growth factor-beta superfamily suggest that the innate immune system of invertebrates and vertebrates evolved independently. In addition, data from protochordates and annelids suggest that invertebrate cytokine-like molecules and vertebrate factors do not have the same evolutionary origin. We propose instead that the convergence of function of invertebrate cytokine-like molecules and vertebrate counterparts involved in innate immune defences may be based on similar lectin-like activities.

Tumor-derived transforming growth factor-beta 1 and interleukin-6 are chemotactic for lymphokine-activated killer cells.

Adherent lymphokine-activated killer (A-LAK) cells are purified IL-2 activated natural killer (NK) cells with potent anti-tumor cytotoxic activity. They have been used in the adoptive immunotherapy of metastatic cancers. However, it has been shown that intravenously transferred LAK cells have a poor homing capacity to tumor sites. For the present study, the effects of tumor-derived factors on the in vitro migratory capacity of A-LAK cells was investigated. In a micropore migration assay the conditioned medium from 3LL Lewis lung carcinoma cell cultures was found to exert a strong chemotactic, but not chemokinetic effect on A-LAK cells. This effect was partially inhibited by neutralizing antibodies against the cytokines TGF-beta 1 and IL-6. A combination of the 2 antibodies completely suppressed the chemotactic activity of tumor-cell-conditioned medium. Purified TGF-beta 1 and recombinant IL-6 were chemotactic for A-LAK cells. Biological activities of both cytokines were detectable in the tumor-cell-conditioned medium. The in vivo relevance of these findings, with respect to tissue infiltration of NK cells and LAK cells in inflammation or cancer, remains to be elucidated.

The effect of dietary L-carnitine on the growth performance in fingerlings of the African catfish (Clarias gariepinus) in relation to dietary lipid.

The effect of dietary L-carnitine on the growth and growth efficiency of African catfish (Clarias gariepinus, Burchell 1822) fingerlings was investigated. Six dietary levels of L-carnitine, varying from the control level (about 125 mg/kg) to 3920 mg/kg, were each tested at two dietary lipid levels (96 and 155 g/kg). The diets were isonitrogenous and were fed to thirty-six experimental groups of 100 fish weighing 5 g at a feeding level of 25.2 g/kg live weight (w)0.8 per d, during 18 d. The average final weight varied from 19.1 to 28.0 g. At a dietary lipid level of 96 g/kg the metabolic growth increased from 30.8 to 36.5 g/kg w0.8 per d. At the higher dietary lipid level the metabolic growth increased from 30.9 to 35.4 g/kg w0.8 per d. To assess the dose-response relationship between dietary L-carnitine and growth performance in the African catfish a linear-plateau model was fitted to the experimental data. According to this model, metabolic growth was at a maximum at L-carnitine levels of 500 mg/kg and above at a lipid level of 96 g/kg and at L-carnitine levels of 684 mg/kg and above at a lipid level of 155 g/kg. The fitted maximum metabolic growth was higher at a dietary lipid level of 96 g/kg (35.9 g/kg w0.8 per d) than at 155 g/kg (34.7 g/kg w0.8 per d). Feed conversion improved significantly with increasing dietary levels of L-carnitine, reaching a fitted plateau at L-carnitine levels of 448.8 and 236.7 mg/kg respectively for the high and low dietary fat levels. Other growth efficiency variables, e.g. protein efficiency ratio, protein retention and energy retention improved accordingly. Taking into consideration that all fish received the same amount of feed, the results of the present study demonstrate that the positive effect of increased levels of dietary L-carnitine is the result of an improved feed utilization, probably because of a stimulated protein-sparing action.

Mechanisms underlying trypanosome-elicited immunosuppression.

T-cell proliferative responses of lymph node cells are profoundly suppressed during experimental infections of mice with Trypanosoma brucei. The active suppression of lymph node T-cell proliferative responses is attributed to the coexistence of at least two unlinked suppressive mechanisms that block different T-cell regulatory steps and operate through different effector mechanisms. The generation of prostaglandin-producing macrophages is entirely responsible for the suppression of IL-2 production whereas the induction of a prostaglandin-independent suppressive mechanism accounts for the suppression of the expression of IL-2 receptors (IL-2R). Both mechanisms are mediated by the cells that co-purify which macrophages. Despite an impairment at the level of T-cell proliferation, lymph node cells from T. brucei infected animals produce substantial amounts of interferon-gamma (IFN-gamma) and this lymphokine participates in the down-regulation of IL-2R expression. T-brucei-pulsed macrophage cell lines acquire concomitantly the potential to suppress T-cell proliferative responses and to stimulate CD8+ T-cells to secrete IFN-gamma. The sensibilization of CD8+ T cells by T. brucei-pulsed macrophages might be mediated by TNF-alpha. Collectively, these results indicate that the uptake of T. brucei by macrophages, either in vivo or in vitro, results in the generation of suppressive cells that annihilate T-cell proliferative responses. Furthermore, at least two cytokines (i.e., TNF-alpha and IFN-gamma) are released during these interactions. Besides playing a role in the pathway of T-cell immunosuppression, TNF-alpha and IFN-gamma could also contribute to immunopathological features that occur during trypanosome infections.