Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives.

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.

Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia.

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.

3-[1-(2-Benzoxazolyl)hydrazino]propanenitrile derivatives: inhibitors of immune complex induced inflammation.

3-[1-(2-Benzoxazolyl)hydrazino]propanenitrile derivatives were evaluated in the dermal and pleural reverse passive Arthus reactions in the rat. In the pleural test these compounds were effective in reducing exudate volume and accumulation of white blood cells. This pattern of activity was similar to that of hydrocortisone and different from that of indomethacin. The structural requirements for inhibiting the Arthus reactions were studied by systematic chemical modification of 1. These structure-activity relationship studies revealed that nitrogen 1' of the hydrazino group is essential for activity and must be electron rich, whereas chemical modifications of other sites of 1 had only a modest effect on activity.

The effects of two dietary fiber supplements on gastrointestinal transit, stool weight and frequency, and bacterial flora, and fecal bile acids in normal subjects.

The effect of dietary supplements of sugar-cane fiber (bagasse), on stool weight, solids, and water content were studied in normal ambulant volunteers over a 9-mo period; a second inpatient study was done with bran supplements. The addition on 10.5 g of bagasse containing 5.1 g of crude fiber to a normal diet containing 3.7 g of crude dietary fiber daily raised the mean fecal weight from 88.3 +/- 6.4 g to 139.7 +/- 10.2 g/day (p less than 0.005). There was also a significant rise in fecal solids and fecal water, although the percentage of water in the stools remained unchanged. Bagasse supplements accelerated gastrointestinal transit when measured by the carmine marker technique. Radiopaque "shapes" showed a trend toward more rapid transit with bagasse supplements. Daily supplements of 39 g of wheat bran or 10.5 g of bagasse increased the total daily excretion of fecal bacteria, but there were no changes in bacteria excreted per gram of feces. The composition of the bacterial flora showed no change. There was increased excretion of fecal acid sterols on the bagasse supplement, but this failed to occur with bran. No changes attributable to fiber supplements occurred in the plasma triglycerides or cholesterol. Future work may define specific dietary fiber supplements for different therapeutic purposes. One fiber may be used as a bulk expander in diverticular disease and another as a hypocholesteremic fiber.

Metabolic responses to dietary supplements of bran.

During a metabolic ward study, the addition of dietary fiber in the form of wheat bran biscuits to the diet of five volunteer subjects resulted in an increase in the stool wet weight and fecal solids. The excretion of fecal solids was highly correlated with the intake of unavailable carbohydrates, and fecal losses of water were similarly correlated with fecal excretion of these constituents. The major component of the increase in fecal solids was due to the noncellulosic polysaccharide fraction of dietary fiber. There was an increased fecal excretion of nitrogen fat and energy by most subjects when the supplement was eaten. However, the increased loss of energy in the feces was only 40-80 kcal/day, and therefore a large supplemental intake of dietary fiber had only minor effects on energy metabolism. Supplemental fiber is thus unlikely to induce a useful loss of calories in the management of obesity. The addition of dietary fiber caused an increased excretion of most inorganic constituents, particularly sodium and phosphorus; increased excretion of iron and magnesium was also found in two subjects.

Effects of two types of dietary fibre on faecal steroid and lipid excretion.

Fibre supplements from wheat bran and sugar cane residue (bagasse) were added to the normal diet of volunteers for 12-week periods in a controlled metabolic study. Stool weights and stool fat excretion increased on both dietary fibres. Bagasse increased the daily loss of acid steroids, but bran failed to affect bile acid excretion. Decreased transit time without alteration in faecal flora occurred with bagasse. The raised excretion of bile acids and fatty acids failed to lower the plasma cholesterol and triglycerides after 12 weeks. Thus different fibre sources with variable components have dissimilar metabolic effects.

Absorption of slow-release iron and effects of ascorbic acid in normal subjects and after partial gastrectomy.

Radiolabelled tablets of slow-release iron and ferrous sulphate containing 50 mg of elemental iron were given to 28 patients, and iron absorption was studied using a whole body counter.There was no significant difference between the absorption of ferrous sulphate and that of slow-release iron in normal subjects, anaemic patients, anaemic and non-anaemic post-gastrectomy patients, or those with coeliac disease. Ascorbic acid potentiated iron absorption, especially in anaemic post-gastrectomy patients.The indications and hazards of slow release iron preparations are discussed.