Clinical implications of mycotoxins and Stachybotrys

There has been considerable interest and concern in recent years regarding the potential health effects of mycotoxins in the indoor environment. Although the existence of mycotoxins has been known for several decades, relatively little is known about their effects in humans. What is known comes almost exclusively from studies of ingestion as the route of exposure. This review summarizes what is known regarding health effects of mycotoxins in general and specifically examines the evidence for the role of indoor exposure to the fungi of the genus Stachybotrys as a cause of disease in humans. Much work remains to be done in the area of mycotoxin research. The risk of health effects from ingestion seems much more widespread than from indoor airborne exposure, although the latter has received considerably more media attention. Rigorously controlled studies are needed to clarify these issues.     

Novel pyrazolo[3,4-d]pyrimidine nucleoside analog with broad-spectrum antiviral activity.

A novel nucleoside analog, 4(5H)-oxo-1-beta-D- ribofuranosylpyrazolo[3,4-d]pyrimidine-3-thiocarboxamide (N10169), was evaluated in cell culture and in animals for antiviral activity against DNA and RNA viruses. The compound was highly active against strains of adeno-, vaccinia, influenza B, paramyxo-, picorna-, and reoviruses, with 50% inhibition of virus-induced cytopathology at 1 to 10 microM. Lesser or no antiviral effects were observed against herpes simplex, cytomegalo-, corona-, influenza A, vesicular stomatitis, and visna viruses. Drug potency against certain viruses was highly cell line dependent (N10169 was highly active in HeLa cells but was much less potent in Vero cells). This was correlated, in part, to differences in levels of adenosine kinase activity in these cell lines, since adenosine kinase appears to phosphorylate N10169 to its active form. N10169 was inhibitory to proliferating cells at antiviral concentrations, whereas stationary-phase monolayers tolerated higher concentrations (less than or equal to 100 microM). Exogenous uridine was able to reverse the virus-inhibitory effects of the compound, leading to the discovery that N10169 5'-monophosphate is a potent inhibitor of cellular orotidylate decarboxylase. N10169 was evaluated in mice that were infected intraperitoneally with banzi virus or inoculated intranasally with influenza B virus, and in hamsters that were infected intranasally with vaccinia virus. In each model, intraperitoneal injection of N10169 (100 to 300 mg/kg per day for 7 days) twice daily was ineffective, whereas intraperitoneal injection of ribavirin showed some benefit in the influenza B and banzi virus infection models.     

Genotoxic effects of monocrotophos,an organophosphorous pesticide,on an estuarine bivalve, Meretrix ovum

Genotoxicity studies evaluate the effects of pollutants on organisms and consequently, their implications on human health. Meretrix ovum was exposed to different concentrations of monocrotophos, viz. 5.5, 11.0 and 16.5 mg/L continuously for four different time periods viz. 2, 3, 7 and 14 days. Gills of these animals were collected immediately after exposure at the above time intervals and analyzed for genotoxic effect employing micronucleus test and effect on somatic growth by estimating the total RNA/DNA ratio. Data were analyzed employing Student’s ‘t’ test and ANOVA. Significant increase of micronuclei observed in the present study in a dose dependant manner indicates the possible chromosomal damage induced by monocrotophos in this species and thereby reveals its genotoxic potency. Significant reduction of the total RNA/DNA ratio observed in a time dependant manner indicates a considerable retardation of somatic growth in monocrotophos treated mussels. Results of the present study indicate that monocrotophos is genotoxic on M. ovum and also induces a pollution stress related retardation of somatic growth of this mussel. Further, this study indicated the possibility of using MN test in bivalves as a marker for screening/monitoring the genotoxic potential of pollutants in aquatic ecosystems.     

Therapy of infections caused by dematiaceous fungi

Dematiaceous fungi are responsible for a wide variety of clinical syndromes, from local infections due to trauma, to disseminated infection in immunocompromised patients. These fungi are unique owing to the presence of melanin in their cell walls, which imparts the characteristic dark color to their spores and hyphae. Melanin may also be a virulence factor in these fungi. Therapy depends upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Azoles such as itraconazole and voriconazole have the most consistent in vitro activity, although newer agents may also play a role in therapy in the future.     

Cure of disseminated zygomycosis with cerebral involvement using high dose liposomal amphotericin B and surgery.

We present a case of cerebral zygomycosis that did not respond to standard treatment with amphotericin B or amphotericin B lipid complex. The patient was eventually cured through a combination of surgery and the use of high dose liposomal amphotericin B. Since penetration of the central nervous system by amphotericin B is poor the application of high dose therapy may be useful in cases of cerebral zygomycosis.     

Synthesis and antitumor evaluation in mice of certain 7-deazapurine (pyrrolo[2,3-d]pyrimidine) and 3-deazapurine (imidazo[4,5-c]pyridine) nucleosides structurally related to sulfenosine, sulfinosine, and sulfonosine

7-Deaza (pyrrolo[2,3-d]pyrimidine) and 3-deaza (imidazo[4,5-c]pyridine) congeners of sulfenosine (5a and 9), sulfinosine (6a and 10), and sulfonosine (7a) have been prepared and evaluated for their antileukemic activity in mice. Amination of 2-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-th ion e (4a) and its 2'-deoxy analogue (4c) with a chloramine solution gave the corresponding 4-sulfenamides (5a and 5c, respectively), which on selective oxidation with m-chloroperoxybenzoic acid (MCPBA) gave the respective diastereomeric 2-amino-7-beta-D-ribofuranosyl-pyrrolo[2,3-d]pyrimidine-4-sulfinamide (7-deazasulfinosine, 6a) and its 2'-deoxy derivative (6c). A similar amination of 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (4b) gave the corresponding 4-sulfenamide derivative (5b). Oxidation of 5b with 1 molar equiv of MCPBA furnished (R,S)-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine- 4- sulfinamide (6b), whereas use of excess of MCPBA afforded the corresponding sulfonamide derivative (7b). Treatment of 3-deaza-6-thioguanosine (8) with a chloramine solution gave 3-deazasulfenosine (6-amino-1-beta-D- ribofuranosylimidazo[4,5-c]pyridine-4-sulfenamide, 9). Controlled oxidation of 9 with MCPBA afforded 3-deazasulfinosine (10). As gauged by increases in the mean postinoculation life spans of L1210 inoculated mice, none of these nucleosides exhibited biologically significant activity (T/C greater than or equal to 125). Even so, antileukemic activity appeared to be influenced, albeit not uniformly, by structural modifications in the base and carbohydrate moieties of sulfenosine and sulfinosine. Thus, while several of the compounds were lacking in cytotoxic activity, eight others (4c, 5a, 5c, 6a, 6b, 7b, 9, and 10) were estimated to have reduced body burdens of viable L1210 cells by 16-77%.