PubMed · 7285552
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I McMillan, C E Minder. 1981. Parameter estimation for the one compartment open model.. https://doi.org/10.1016/0010-4809(81)90046-x
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PURPOSE: The aim of this study was to investigate the pharmacokinetics of tissue plasminogen activator (tPA) under the conditions of an isolated extracorporeal circuit. METHODS: Plasma levels of tPA were measured in the perfusion solution and in central venous blood before, during, and after the perfusion in seven patients undergoing regional hyperthermic fibrinolytic perfusion with tPA in addition to surgical thrombectomy for extended deep venous thrombosis. RESULTS: After 15 minutes of fibrinolytic perfusion, the level of tPA in the perfusion solution was 10,427 +/- 4432 ng/mL, and after 30 minutes the maximum level of 19,726 +/- 5630 ng/mL was reached. After 60 minutes when the perfusion was discontinued, tPA concentrations dropped to 15,931 +/- 4818 ng/mL. In central venous blood, tPA levels increased to a maximum of 230.7 +/- 89.6 ng/mL after 60 minutes of perfusion, which represented 1.4% of the concentration measured in the perfusion solution at the same time. With disconnection of the extracorporeal circuit, the tPA levels in central venous blood decreased rapidly and reached a level of 24.1 +/- 8.7 ng/mL after 120 minutes. CONCLUSION: The use of regional hyperthermic fibrinolytic perfusion in the treatment of extended deep venous thrombosis makes it possible to achieve extremely high concentrations of tPA in the perfusion solution. At the same time, the entry of the fibrinolytic agent into the systemic circulation is minimized.
During pregnancy, insulin-like growth factors (IGFs) are important for growth of fetal and maternal tissues. One of the IGF binding proteins, IGFBP-1, is thought to regulate their activity within the local environment of the placenta. IGFBP-1 usually exists as a phosphorylated, high affinity species, which sequesters IGFs, thereby inhibiting their actions. This study has investigated the mechanisms that release IGF from IGFBP-1 at the maternal-fetal interface. Under basal conditions, human decidualized endometrium produces both non-phosphorylated (np) and phosphorylated (p) isoforms of IGFBP-1; however, in the presence of IGF-II, which is a trophoblast secretory product, npIGFBP-1 was preferentially produced. Furthermore, we found that trophoblast, presumably via placental alkaline phosphatase, can de-phosphorylate pIGFBP-1. Since npIGFBP-1 has decreased affinity for IGF-I, these effects should enhance IGF-I bioavailability. In addition, we found that decidual cells produce a protease, which cleaves IGFBP-1, but only when it is non-phosphorylated; [(125)I]-npIGFBP-1 is proteolysed into 14 and 17 kDa fragments which have markedly reduced affinity for IGF. We therefore propose paracrine modulation of IGFBP-1 at the maternal-fetal interface involving a multi-step process of de-phosphorylation and proteolysis; this will result in enhanced IGF bioavailability and is likely to represent an important mechanism for controlling fetal and maternal tissue growth.
We have previously hypothesized that sulfide inhibits Hg methylation by decreasing its bioavailability to sulfate-reducing bacteria (SRB), the important methylators of Hg in natural sediments. With a view to designing a bioassay to test this hypothesis, we investigated a number of aspects of Hg methylation by the SRB Desulfobulbus propionicus, including (i) the relationship between cell density and methylmercury (MeHg) production, (ii) the time course of Hg methylation relative to growth stage, (iii) changes in the bioavailability of an added inorganic Hg (Hg(I)) spike over time, and (iv) the dependence of methylation on the concentration of dissolved Hg(I) present in the culture. We then tested the effect of sulfide on MeHg production by this microorganism. These experiments demonstrated that under conditions of equal bioavailability, per-cell MeHg production was constant through log-phase culture growth. However, the methylation rate of a new Hg spike dramatically decreased after the first 5 h. This result was seen whether methylation rate was expressed as a fraction of the total added Hg or the filtered Hg(I) concentration, which suggests that Hg bioavailability decreased through both changes in Hg complexation and formation of solid phases. At low sulfide concentration, MeHg production was linearly related to the concentration of filtered Hg(I). The methylation of filtered Hg(I) decreased about fourfold as sulfide concentration was increased from 10(-6) to 10(-3) M. This decline is consistent with a decrease in the bioavailability of Hg(I), possibly due to a decline in the dissolved neutral complex, HgS(0).