Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Studies on the effect of dietary orotic acid on mouse liver carcinogenesis induced by diethylnitrosamine.

The present study was designed to determine whether orotic acid, a liver tumor promoter in the rat, also promotes liver carcinogenesis in the mouse. Eight-week-old male BALB/c mice were initiated with diethylnitrosamine (90 mg/kg i.p.). One week later they were divided into 2 groups and given either a basal diet or the basal diet containing 1% orotic acid (OA). They were killed at 6 or 10 months after the administration of the carcinogen. At 6 months, no nodular lesions were seen in mice whether or not they were exposed to OA. However by 10 months 100% of mice in both groups developed hepatic nodules. OA neither shortened the latent period for the appearance of the nodular lesions not did it increase the size of the nodules. Although BALB/c mice exhibited an increase in uridine nucleotides and a decrease in adenosine nucleotides in the liver upon exposure to OA, the magnitude of the change was less compared with that seen in the rat liver. The resistance of BALB/c mouse to the tumor-promoting effects of OA may reflect in part the resistance of the mouse to OA-induced nucleotide pool imbalance.

Effects of maternal anti H-Y antibodies on fetal gonadal development.

C57BL/6 inbred female mice preimmunized by serial injections of isogeneic male spleen cells were mated and the effects of the circulating anti H-Y antibodies on the fetal gonads and on their fertility were studied. Female mice receiving injections of saline formed one control group and those given female spleen cells a second control group. The experiment was carried out three times and since observations were similar and reproducible the data of all three sets were pooled. There was no significant change in the birth weights of newborns, total number of conceptions or sex ratio in the study group compared to either of the controls. There was no difference in the mean live birth rate between the study group and both the controls. Although the incidence of stillbirths in the study group was higher than that in both controls the difference was not statistically significant. In the study group there were no histopathological changes in the gonads from female pups compared to ovaries from the controls. In contrast, the gonads of male pups showed mild to severe structural disorganization in the study group, but not in the female spleen cell injected group. In spite of the morphological changes in the testes, the newborn male pups had a normal anogenital distance and testicular descent suggesting that Leydig cell function was normal.

Euglycemic and hypolipidemic activity of PAT5A: a unique thiazolidinedione with weak peroxisome proliferator activated receptor gamma activity.

The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine analog of thiazolidinedione, have been evaluated in different animal models. Administration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of troglitazone and comparable to that of rosiglitazone. In addition, PAT5A showed better lipid-lowering activity than troglitazone or rosiglitazone. A similar profile was seen in ob/ob mice. In high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. An in vitro peroxisome proliferator activated receptor gamma (PPARgamma) transactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPARalpha- or PPARdelta-activating properties. Ex vivo study in db/db mice treated with PAT5A showed decreased activity of liver glucose 6-phosphatase, a key enzyme in gluconeogenesis. A 28-day probe toxicity study in Wistar rats did not show any treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas rosiglitazone treatment increased liver and heart weights. Our results indicate that PAT5A is a potent insulin sensitizer and hypolipidemic compound with a weak PPARgamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mechanisms not related to PPAR activation.

Membrane lipids and protein-bound carbohydrates status during the maturation of reticulocytes to erythrocytes in type 2 diabetics.

BACKGROUND: The reticulocyte maturation process is an ideal model for the study of biochemical alterations seen during final stage of erythropoiesis under disease conditions. In this study, determined whether type 2 diabetes has any effect on membrane lipids and protein-bound carbohydrates during the maturation of reticulocytes to erythrocytes. SUBJECTS AND METHODS: Lipids (cholesterol and phospholipids) and protein-bound carbohydrates (hexose, hexosamine and sialic acid) were extracted and estimated in plasma, membrane of reticulocytes and erythrocytes from 20 treated but uncontrolled type 2 diabetic volunteers and age matched controls. RESULTS: Plasma, membranes of reticulocytes and erythrocytes of diabetics showed increase in cholesterol (35.7%, 8.7% and 16.4%); phospholipids (43.4%, 18.8% and 8.2%); hexose (34.1%, 19.3% and 8.2%) and decrease in hexosamine (11.9%, 7.3% and 14.7%); and sialic acid (34.1%, 19.3% and 32.0%) compared to controls. As reticulocytes matured to erythrocytes, cholesterol, phospholipids, hexosamine and sialic acid levels were decreased; C/P ratio and hexose levels were increased in both controls and diabetics. However, these alterations were more intensified in diabetics. CONCLUSION: These alterations in diabetic patients may indicate the existence of one or both of the following conditions: acceleration of maturation processes and/or decreased red blood cell life span.

Establishment and characterization of a paclitaxel-resistant human non-small cell lung cancer cell line.

We have established a paclitaxel-resistant mutant cell line called H460/TAX which was derived from human non-small cell lung cancer (NSCLC) H460. A 64-fold greater resistant was shown in our assay as compared with the parental cells. High specificity of drug resistance was also observed since this mutant was not cross-resistant to several other anticancer drugs. Drug accumulation in H460/TAX was significantly less than that in H460. Many endogenous protein profiles were intact, including the expression level of P-glycoprotein, multidrug resistance-associated protein, the 70 kDa heat shock proteins as well as the phosphorylation of Bcl-2 in H460/TAX cells, except that the total amount of alpha- and beta- tubulins was higher in H460/TAX than in H460 cells. Higher drug concentration and longer treatment for paclitaxel were required in H460/TAX to exert the phosphorylation of keratin 19 which was then accompanied by reorganization of the intermediate filament and the microtubule networks. Since all of the aforementioned factors involved in paclitaxel-resistance in other systems were not found to be significantly altered in H460/TAX, there must be other paclitaxel-resistance mechanisms(s) which remains to be identified in human lung cancers.

Benzohydroxamic acid as a reductometric titrant determination of manganese in ores and alloys.

Benzohydroxamic acid has been employed as a reductometric titrant for the determination of manganese in various ores and alloys. The determination is based on the fact that benzohydroxamic acid reduces Mn(VII) quantitatively to Mn(II) in 1.5N sulphuric acid.

Spectrometric determination of arsenic in zinc concentrates and other lead-zinc smelter roasted products.

In the zinc electro-winning process arsenic is considered a "problem impurity". Its determination should be fast, accurate and simple to help in-plant control for its effective removal during the iron purification stage. Such a method is presented which is applicable to all zinc concentrates, lead concentrates and smelter residues, with various compositions and matrix components. Results for certified reference samples and for recovery of standard additions are very good.

Spectrophotometric determination of arsenic by molybdenum blue method in zinc-lead concentrates and related smelter products after chloroform extraction of iodide complex.

The most popular and widely applied method for determination of arsenic in ore concentrates is by spectrophotometry of arsenomolybdic acid reduced to molybdenum blue. While applying this method, several authors have developed procedures which varied in the decomposition, separation of arsenic and in the final colour development. Data regarding interference from germanium is inadequate. The present paper describes a procedure, which combines the best features of the previous procedures and is simple, less time consuming and interference-free compared to earlier procedures. This method has been applied to zinc-lead concentrates and related smelter products.

Immunostimulatory activity of Picrorhiza kurroa leaf extract.

A 50% ethanolic extract of Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae) leaves (PKLE) was found to stimulate the cell-mediated and humoral components of the immune system as well as phagocytosis in experimental animals. PKLE elicited a dose-related increase in SRBC, induced 4 h (early) and 24 h (delayed) hypersensitivity reactions in mice and rats, and horse serum induced Arthus reaction in guinea pigs. It also enhanced the humoral immune responses in mice and rats and phagocytic function of the cells of the reticuloendothelial system in mice. PKLE exhibited no mitogenic activity but augmented the responsiveness of murine splenocytes to T cell mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A) and B cell mitogen lipopolysaccharide (LPS E. coli).

Antinociceptive and anti-inflammatory activity of a flavonoid isolated from Caralluma attenuata.

Luteolin-4'-O-neohesperidoside, i.e. luteolin-4'-O-[alpha-(L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside)] has significant anti-inflammatory action. It is more potent than ibuprofen. Its antinociceptive activity is less pronounced when compared with its anti-inflammatory activity.

Acetic acid and phenylquinone writhing test: a critical study in mice.

Studies were planned to establish the dose-effect relationship with both acetic acid and phenylquinone and to find out suitable concentrations for these two chemicals for pre- and post screening. The LD50 of acetic acid and phenylquinone were found to be 3.16% and 0.23%, respectively. Based on the studies conducted, the prescreening and postscreening concentrations of 0.5% is recommended for acetic acid, while for phenylquinone, prescreening concentration of 0.005% and postscreening concentration of 0.02% is advocated. Using this criterion in the acetic acid writhing test, analgin was the most potent analgesic while aspirin was the least. However, suprofen was most potent and paracetamol least among analgesics employed against phenylquinone induced writhing.

Prognosis in intra-abdominal sepsis.

Peritonitis is a common surgical problem with a high mortality rate. Recent advances have not brought down the mortality rate. Eighty six patients with intra-abdominal sepsis were studied for factors affecting prognosis. The factors which significantly affected prognosis were: duration of illness, source of infection and APACHE-II score. Further, among the factors contributing to APACHE II score, statistical analysis using logistic regression identified some factors which individually affect outcome. Our results indicate that mortality rate is high in patients with long duration of illness, postoperative peritonitis and organ system insufficiency.

A rapid method for evaluation of analgesic and anti-inflammatory activity in rats.

Carrageenin (2%) was used to produce edema and hyperalgesia; indomethacin, phenylbutazone, aspirin, ibuprofen, analgin, paracetamol and phenacetin were tested at different doses for anti-inflammatory and analgesic activity in the same rats as the peak for the edema reached at the end of 3rd hr and for the hyperalgesia at the end of 4th hr. Indomethacin, phenylbutazone and ibuprofen reduced edema and increased the pain threshold. Analgin and aspirin increased the pain threshold relatively at a low dose. Paracetamol and phenacetin were inactive in the doses tested. Carrageenin (2%) was observed to possess both phlogistic and allogenic properties.

Immunotherapeutic modification by an ayurvedic formulation Septilin.

Effect of Septilin, an ayurvedic formulation proven to be effective in the therapy of chronic infections, was investigated on the phagocytic system and humoral response in rats and mice. Septilin exhibited significant protection in E. coli-induced abdominal sepsis in normal mice and in Staphylococcus aureus-induced sepsis in neutropenic mice. It significantly reduced the viable E. coli cells when incubated with neutrophils in rats. Septilin stimulated the phagocytic function of the reticuloendothelial system in mice. In normal rats, Septilin enhanced anti-SRBC hemagglutination antibody titre by 5.7-fold and showed significant protection in cyclophosphamide-induced humoral suppression.

IDPH-8261--a new nonsteroidal antiinflammatory agent.

IDPH-8261, methyl alpha-methyl-4-(3-thienyl)benzeneacetate, exhibited marked anti-inflammatory activity in acute, subacute and chronic models of inflammation. In rats, IDPH-8261 exhibited a dose related inhibition of carrageenin-induced rat paw edema and the inhibition was greater than ibuprofen, phenylbutazone, but was three times less than indomethacin. It exhibited anti-inflammatory activity in normal and adrenalectomized rats. It also exhibited the activity against various phlogistic agents. IDPH-8261 exhibited AI activity in subacute granuloma tests. In adjuvant-induced established polyarthritis. IDPH-8261 exhibited anti-arthritic effect at a very low dose (ED50 = 4 mg/kg, p.o.). Ulcerogenic liability was the lowest (UD50 = 180 mg/kg, p.o.), when compared to reference standard drugs. Low toxicity and high efficacy may make this compound a potentially useful therapeutic agent.

[Whole soy bean flour: use of a methodology of response surface for the study of nutritional aspects]. / Farinha de soja integral: aplicação da metodologia da superfície de resposta para estudo de aspectos nutricionais.

Cotyledons of soybeans (Glycine max) of the Paraná variety were subjected to hydrothermal processing. Response surface methodology was used to evaluate the conditions which provided a product of the highest protein quality. The processing variables used in the experimental design were: soaking time (0 - 8 hr); blanching time (5 - 35 min) and bicarbonate concentration (0 - 0.5 g%) in blanching water. Biological evaluations of protein quality were done using the NPR. The mathematical model developed does not distinguish between treatments (p less than 0.05) in the experimental region studied.