Recombinant human erythropoietin for the correction of cancer associated anemia with and without concomitant cytotoxic chemotherapy.

BACKGROUND: Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied. METHODS: One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter. RESULTS: Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients. CONCLUSION: This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.

Quinidine-induced potentiation of cardiovascular effects of nitrendipine: functional aspects and possible molecular mechanisms.

The functional interaction between the dihydropyridine calcium channel blocker nitrendipine and quinidine was studied in isolated preparations from guinea-pig cardiac ventricle and in mesenteric arterial segments under a variety of experimental conditions. The negative inotropic potency of nitrendipine is clearly enhanced by quinidine (3 x 10(-6)-10(-4) mol/l) by up to two orders of magnitude, i.e. cardiac nitrendipine effects are potentiated. Vasorelaxant effects, however, remain largely unaffected (nitrendipine potency is increased by half an order of magnitude maximally). To elucidate the mechanism of this interaction, the ability of quinidine to potentiate the negative inotropic effect of a series of 12 dihydropyridines was compared with their voltage-dependence of action in guinea-pig left atria. No significant correlation is found (r = 0.18). Furthermore, quinidine inhibits rather than stimulates binding of tritiated nitrendipine, nimodipine or (S)-isradipine to isolated cardiac membranes. Therefore, the mechanism of the quinidine-nitrendipine interaction differs from those previously proposed for modulation of dihydropyridine binding by other drugs. We hypothesize that quinidine-occupied calcium channels adopt an intermediate affinity for nitrendipine, higher than in resting channels, but lower than the high affinity present with inactivated channels. Model calculations which are based on this assumption are able to reproduce all experimental findings of this study.

[Amalgam fillings in the deciduous and mixed dentition--a post-treatment evaluation of service life and quality]. / Amalgam-Füllungen im Milch- und Wechselgebiss--eine Nachuntersuchung zur Lebensdauer und Qualität.

295 amalgam fillings in deciduous teeth and 150 amalgam restorations in permanent first molars were examined in 112 child patients. The functional loss of restorations was corded and present fillings were assessed in view of marginal integrity, anatomy and surface condition. For primary molar amalgams the 4-year survival rates "estimate" ist ein Schätzwert--wenn der Autor es so gemeint hat, muss "estimate" stehenbleiben, andernfalls heisst es "iate" (= Quote) were 67% for Class 1 restorations and for 55% Class 2 fillings. After 4 years of placement 78% of the Class 1 restorations in permanent first molars were still intact.

Photobiological studies with dioxetanes in isolated DNA, bacteria, and mammalian cells.

1,2-Dioxetanes, efficient chemical sources of triplet excited carbonyl compounds, were observed to be genotoxic in isolated DNA, bacteria, and cultured mammalian cells. In superhelical DNA of bacteriophage PM2, various alkyl- and hydroxyalkyl-substituted dioxetanes (1) induced predominantly endonuclease-sensitive base modifications and only few single strand breaks. With a specific endonuclease a small fraction of the base modifications was identified as pyrimidine dimers. The psoralen dioxetane (2a) or PsD bound photochemically to calf thymus DNA at the alpha-pyrone ring of psoralen (fluorescence measurements). Photobinding was also observed when calf thymus DNA was incubated with psoralen and 3-hydroxymethyl-3,4,4-trimethyl-1,2-dioxetane. In Syrian hamster embryo fibroblasts and HL-60 cells, dioxetanes induced DNA single strand breaks. The alkyl- and hydroxyalkyl-substituted dioxetanes 1 and 2 were efficiently inactivated by cysteine, glutathione, ascorbic acid, tocopherol, NADH and FADH2. While dioxetanes 1 and 2 were not mutagenic in Salmonella typhimurium strain TA100, benzofuran dioxetanes 3 exhibited substantial effects. Further data imply that presumably a mutagenic intermediate with a lifetime of a few minutes is produced from the benzofuran dioxetane.

Induction of morphological transformation and micronuclei in Syrian hamster embryo fibroblasts by 1,2-dioxetanes. Correlation with single-strand breaks in HL-60 cells.

The photochemical genotoxic and cell-transforming potential of 4-hydroxymethyl-3,3,4-trimethyl-1,2-dioxetane (HTMD) and 3-(N-[4-pyridino]carbamoyl)methyl-3,4,4-trimethyl-1,2-dioxetane , (APD), in mammalian cell was studied. Both dioxetanes, which are efficient sources of triplet-excited ketones on thermal decomposition, induced morphological transformation in Syrian hamster embryo (SHE) fibroblasts. Unscheduled DNA synthesis in SHE and in HeLa cells could not be detected with these dioxetanes, but the number of micronuclei scored after the first mitosis was dose-dependently increased. Single-strand breaks but not Micrococcus luteus u.v.-endonuclease sensitive sites were observed by alkaline elution in HL-60 cells when treated with sub-lethal doses of HTMD and APD. A possible mechanism for the transformation mediated by DNA and chromosomal damage as well as the intermediacy of triplet carbonyls in these events are discussed.