Dose-titration to confirm the level of fenbendazole for control of Raillietina cesticillus in broiler chickens

A total of 452 broiler chickens, naturally infected with Raillietina cesticillus, were allotted into six treatment groups. One group was fed unmedicated broiler ration (Group 1), and the other five groups were fed broiler ration containing fenbendazole at 180 ppm for 3 days (38.5 mg/kg body weight [BW]), 240 ppm for 3 days (50.9 mg/kg BW), 120 ppm for 6 days (52.2 mg/kg BW), 180 ppm for 6 days (79.9 mg/kg BW), or 240 ppm for 6 days (104.3 mg/kg BW). Fenbendazole was 100.0% efficacious against R. cesticillus when administered in the diet at 240 ppm for 6 days; 99.9% at 240 ppm for 3 days and at 180 ppm for 6 days; 99.5% at 120 ppm for 6 days; and 96.9% at 180 ppm for 3 days. Fenbendazole treatment had no adverse effect on weight gain or feed intake.     

Phenomenon of life span instability in Drosophila melanogaster: I. Nonrandom origin of life span variations in successive generations

The dynamics of life span (LS) and fecundity in Drosophila melanogaster, strain D-32, were analyzed in a series of successive generations. Highly reliable variations in both fitness components were found. On initial inspection the variations would be characterized as random or irregular wherein mean values differed up to threefold. The variance in longevity is greater in females than in males. By use of mathematical procedures we have shown a scale regularity in LS distributions for all generations. Such regularity, in spite of considerable differences in absolute values (mean and maximum LS), suggested that the origin of LS instability is nonrandom.     

Synthesis and evaluation of 4-amino-substituted 7-methoxy (and 7-hydroxy)- 11-methyl (and 5,11-dimethyl)-10H-pyrido [2,3-b] carbazoles and 4-amino- substituted 11-methyl (and 5,11-dimethyl)-10H-pyrido[3',4':4,5] pyrrolo [3,2-g] quinolines, two new series related to antitumor ellipticine derivatives

2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reacted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl-1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected alcohols. Reduction of these intermediates with triethylsilane trifluoroacetic acid and subsequent cyclodehydration then led to 4-chloro-7-methoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the corresponding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11-dimethyl)-10-unsubstituted derivatives of these two series was performed through an independent pathway, involving condensation of conveniently substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone systems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performed in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H- pyrido [2,3-b] carbazoles (25d-e) were obtained from 7-methoxy precursors (25a-b), by demethylation with boron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubstituted derivatives and in vivo antitumor evaluation of the most active compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor properties in two experimental models shown to be sensitive to ellipticines. The place of the pyridinic nitrogen atom in these series has thus been demonstrated to play a crucial role in antitumor activity.     

Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine

BACKGROUND: Substantial hematologic toxicity limits the use of azathioprine. OBJECTIVE: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. DESIGN: Prospective cohort study. SETTING: Two rheumatology units. PATIENTS: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. MEASUREMENTS: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. RESULTS: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). CONCLUSION: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.     

Tolyporphins J and K, two further porphinoid metabolites from the cyanobacterium Tolypothrix nodosa

Two new porphinoids, tolyporphins J (1) and K (2), have been isolated from the terrestrial cyanobacterium, Tolypothrix nodosa (HT-58-2) and identified by NMR and mass spectral analysis. The activities of tolyporphins J and K in cell sensitization and drug accumulation assays for multidrug resistance (MDR) reversal were compared with those of tolyporphin A. Unusual NMR spectroscopic shifts were observed for tolyporphin J (1) in CDCl3.     

Metabolic delivery of ketone groups to sialic acid residues. Application To cell surface glycoform engineering

The development of chemical strategies for decorating cells with defined carbohydrate epitopes would greatly facilitate studies of carbohydrate-mediated cell surface interactions. This report describes a general strategy for engineering the display of chemically defined oligosaccharides on cell surfaces that combines the concepts of metabolic engineering and selective chemical reactivity. Using a recently described method (Mahal, L. K., Yarema, K. J., and Bertozzi, C. R. (1997) Science 276, 1125-1128), we delivered a uniquely reactive ketone group to endogenous cell surface sialic acid residues by treating cells with the ketone-bearing metabolic precursor N-levulinoylmannosamine (ManLev). The ketone undergoes highly selective condensation reactions with complementary nucleophiles such as aminooxy and hydrazide groups. The detailed quantitative parameters of ManLev metabolism in human and nonhuman-derived cell lines were determined to establish a foundation for the modification of cell surfaces with novel epitopes at defined cell-surface densities. Ketones within the glycoconjugates on ManLev-treated cells were then reacted with synthetic aminooxy and hydrazide-functionalized carbohydrates. The remodeled cells were endowed with novel lectin binding profiles as determined by flow cytometry analysis. The simplicity and generality of this method make it well suited for use in the study of carbohydrate-mediated cell surface interactions.