Determinants of the overall response to furosemide: pharmacokinetics and pharmacodynamics

After an oral or i.v. dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On the average, approximately half as much reaches the intraluminal site of action with an oral compared with an i.v. dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose or after pretreatment with probenecid, amounts of drug are at the "steep" portion of the dose-response curve for longer periods of time. Our analysis shows that this is not the case. For furosemide, the amount of diuretic delivered into the urine that is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does i.v. administration. By so doing, total response to an oral dose approaches that of i.v. dosing despite delivering half the amount of drug to the active site, and after probenecid an i.v. dose causes a greater response than i.v. dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.     

Intensified controlled fish growth in tanks implementing a multipurpose flow device

Fish biomass (Tilapia sp.) were raised at high stocking density in 1-m(3) tanks containing 450 L of water. The water was changed continously by means of a jet flow regulator. The jet flow regulator maintained adequate dissolved oxygen (DO) and a low ammonia level, while the suspended solids were discarded. In such a system, an annual yield of above 15 kg/m(3) can be expected. The application of the jet flow regulator in aquaculture is discussed.     

Trial of the use of bleomycin in combination with other chemopreparations for treating the metastases of squamous cell cancer in various sites

The data on the treatment of 19 patients with squamous cell carcinoma of different sites are presented. A combination of chemotherapeutics, including methotrexate, adriamycin and bleomycin was used. The combination was effective and low toxic. It may be recommended for the treatment of the above form of carcinoma.     

The synthesis of ATP by the membrane-bound ATP synthase complex from medium 32Pi under completely uncoupled conditions

Previously, we demonstrated that isolated coupling factor 1 can reversibly synthesize bound ATP from "tightly bound" ADP and medium Pi (Feldman, R I., and Sigman, D. S. (1982) J. Biol. Chem. 25, 1676-1683). In order to ensure that the thermodynamic constants derived are relevant to coupled ATP synthesis, we have also studied the reaction on thylakoid membranes. The ATP synthase complex, uncoupled with 20 mM NH4Cl or 0.3% Triton X-100, synthesizes enzyme-bound ATP in a similar manner to coupling factor 1. The pH optimum is 6, the concentration of medium Pi for 50% saturation is 38 mM, and the equilibrium constant for the formation of ATP from bound ADP and Pi is 0.5. It is concluded that the active site responsible for the reaction is not appreciably altered by the dissociation of coupling factor 1 from the membrane or Fo. Thus, either enzyme form can be used to derive data relevant to the mechanism of ATP synthesis. The ability to measure bound ATP synthesis in an energizable system will allow us to probe the effect of membrane energization on the accumulated bound product.     

Determination of C distribution in photosynthetic serine and phosphoglycerate from grape leaves

Serine and phosphoglyceric acid are the classical marker intermediates of photorespiration and reductive carbon assimilation in C₃ plants. The present paper introduces a new and fast method for the determination of ¹⁴C distribution in these compounds by selective elimination of C-3 (NaIO₄) or C-1 (ninhydrin/ceric sulfate). Reproducibility of the procedure was found to be better than ±1% upon degradation of [U-¹⁴C]serine and [U-¹⁴C]glycerate standards.     

Lack of genotoxic properties of the hair-dye component N-methyl-amino-2-nitro-4-N',N'-bis-(2-hydroxyethyl)-aminobenzene, in mammalian cells in vitro, and in yeasts

N-Methyl-amino-2-nitro-4-N',N'-bis-(2-hydroxyethyl)-aminobenzene is a hair-dye ingredient. Its potential ability to induce gene mutations, in the yeast S. pombe and in cultured mammalian CH-V79 cells, mitotic gene conversion in the yeast S. cerevisiae, and unscheduled DNA synthesis in cultured human HeLa cells was evaluated. The chemical proved unable to induce detectable genotoxic effects according to these tests. The present data, together with others that show that the chemical is not mutagenic in Salmonella typhimurium or Drosophila, and is not clastogenic in mammalian cytogenetic assays (in vitro or in vivo), strongly support the non-genotoxicity of the chemical.