1-Methylnicotinamide stimulates cell growth and inhibits hemoglobin synthesis in differentiating murine erythroleukemia cells

Exposure of murine erythroleukemia cells (MELCs) to nicotinamide (NA) or its synthetic analog N′-methylnicotinamide (N′-MN) reduces cell growth and induces terminal differentiation, marked by increased heme and globin accumulation. On the contrary, 1-methylnicotinamide (1-MN), the primary metabolite of excess NA, was found to stimulate cell growth and reduce spontaneous differentiation of cultured MELCs. Log phase MELCs exhibited up to 50% higher cell density above untreated cells when cultured for up to 96 h with 2.5 mM 1-MN. When combined with NA or several chemically-unrelated inducers of hemoglobin synthesis in cultured MELCs, 1-MN reduced the globin mRNA levels and heme accumulation by 40–80%. 1-MN was able to inhibit heme production if present during only the first 24–48 h after NA exposure. Pre-treatment with 1-MN could not confer resistance of cells to effects of NA, suggesting the inhibition is reversible. Commitment to differentiate in semisolid medium by the most potent inducer, 5 mM N′-MN, was inhibited up to 95% by 2.5 mM concentrations of 1-MN. It appears that 1-MN has opposing effects on growth and induction of differentiation than those seen in MELC cultures exposed to NA or N′-MN.     

Cerebrospinal Fluid Penetration and Pharmacokinetic/Pharmacodynamic Parameters of Intravenously Administered Colistin in a Case of Multidrug-Resistant <Emphasis Type="Italic">Acinetobacter baumannii</Emphasis> Meningitis

Described here is a case of meningitis caused by multidrug-resistant Acinetobacter baumannii susceptible only to colistin, which was treated successfully with intravenous colistin sulfomethate sodium (5 mg/kg/day). The levels of colistin in serum and cerebrospinal fluid and the pharmacokinetic/pharmacodynamic parameters of colistin were determined. In this case, intravenously administered colistin penetrated cerebrospinal fluid (25% of serum levels) at levels sustaining bactericidal concentrations. Electronic Publication     

Growth inhibition of Entamoeba histolytica by rat colon components.

Susceptibility to invasive amebiasis has been suggested to be due to intrinsic amebic factors and/or to such host factors as intestinal microflora, mucus and colonic redox potential. We investigated the effect of rat colon components on the growth of axenically cultured E. histolytica trophozoites. Extracts of rat colon tissue produced a 57% amebic growth inhibition. The main growth inhibitory components were precipitated by 65% ammonium sulfate and were heat-sensitive. These components were partially separated by ultrafiltration and gel filtration chromatography. Thus, we found colonic components (Mr 50-100 kDa) that produced strong growth inhibition (75%). These results suggest that rat colonic products may play an active role in resistance to amebic infection.     

Experimental models of hypersensitivity pneumonitis.

Experimental models of hypersensitivity pneumonitis are important tools for the study of the pathogenesis of this disease. In this paper we review the characteristics of the main animal models developed until now. The HP models in rats seem to be particularly appropriate for studying pigeon fancier's disease and the HP induced by chemicals, as well as for studying mediators of acute lesions induced by immunocomplexes. However, the HP models developed in rats are of less value in the evaluation of other aspects of the pathogenesis of this clinical entity in humans. The murine models of HP offer several advantages: the ease and simplicity of intranasal administration, the ability to produce acute and subacute pulmonary lesions similar to those found in humans, the possibility of reproducing lesions similar to those of nonaffected exposed subjects and the possibility of pharmacologically modulating the process. Their disadvantages lie in the different pulmonary lymphocyte response and the difficulty in reproducing a model of chronic fibrosis. The HP models in rabbits are extraordinarily useful for evaluating the immunological mechanisms through which subjects repeatedly exposed to the antigen do not develop clinical manifestations. However, the rabbit has several immunological differences when compared to humans, and the effect of some immunomodulators in this animal is different. The models of HP in guinea-pigs have as advantages the ease in handling the animals, the possibility of pharmacological manipulation, and the ability to induce an acute phase that is very similar to that observed in humans. The drawback, however, is the low lymphocyte response and the striking eosinophilic reaction that contrast with the bronchoalveolar data found in HP in humans. In conclusion, there is no ideal model to reproduce all the findings observed in humans, suggesting that the experimental animal and the method of developing HP should be selected on the basis of concrete research aims.     

Membrane-coated fiber array approach for predicting skin permeability of chemical mixtures from different vehicles.

A membrane-coated fiber (MCF) array approach was developed for quantitative assessment of skin absorption from chemical mixtures, which was based on the similarity in the absorption mechanisms of the MCF membrane and the stratum corneum of the skin. A set of probe compounds were used to detect the relative molecular interaction strengths of chemicals with the vehicle and the membranes, which provided a linkage between the skin permeability (log k) and MCF partition coefficients (log KF). A predictive model was established via multiple linear regression analysis of the data matrix of experimentally measured log k value and log KFm values; log k=a0+a1 log KF1+a2 log KF2+...+an log KFm, where m is the number of diverse MCFs. Twenty-five probe compounds and three MCFs (polydimethylsiloxane for lipophilic, polyacrylate for polarizable, and CarboWax for polar interactions) were used to demonstrate the model development processes in the MCF array approach. The skin permeability of the probe compounds was measured with conventional diffusion cell experiments using dermatomed porcine skin. Three predictive models were established for skin permeability prediction from chemical mixtures in water, 50% ethanol, and 1% sodium lauryl sulfate (SLS) with R2 values of 93, 91, and 83, respectively. The log k and log KF values were considerably altered by the addition of ethanol or SLS into the dose vehicle; however, their correlations to skin permeability remained strong under various conditions. These results suggested that the experimentally based MCF array approach can be used to predict skin absorption from chemical mixtures in different vehicles or formulations.