The distribution of lead in human hemopoietic tissue and spongy bone after lead poisoning and Ca-EDTA chelation therapy

Two iliac crest needle biopsies were taken from a 43-year-old lead-poisoned woman during and after completion of a Ca-EDTA treatment. By atomic absorption spectroscopy the first and second biopsy were found to contain 56, respectively 41.6 g lead/g wet tissue. In both biopsies 36% of the lead was extractable in 0.1 N HCl. Electron microbeam X-ray analysis proved to have too low sensitivity for quantitation of the lead in these biopsies. Laser microbeam mass analysis (LAMMA), performed only on the second biopsy, revealed a high and fairly constant residual lead concentration in all bone marrow cell nuclei (approximately 55 g/g) and a low lead concentration in the cytoplasm of the same cells (4–12 (g/g). The extracellular bone matrix lead was greatly concentrated in the superficial 3–6 m osteoid zone of the bony trabeculae and totally absent from deeper parts of the mineralized matrix. The LAMMA results are in good agreement with those of subcellular fractionation experiments and atomic absorption spectroscopy, provided that the relative volume fraction of nucleus and cytoplasm is accounted for. The high residual osteoid lead after completed chelation therapy indicates that lead has a stronger affinity for the organic than the mineral components of bone matrix.     

Intestinal 5-Fluorouracil Absorption: Use of Ussing Chambers to Assess Transport and Metabolism

We have employed an in vitro system to study transport and metabolism of organic molecules by gastrointestinal tissues. Such a system would aid in the evaluation of the potential for oral delivery of organic molecules. Transport and metabolism of 5-fluorouracil (5-FU) were studied using rabbit intestinal preparations. Unidirectional fluxes and metabolism were measured in vitro in Ussing chambers under short-circuit conditions. Results from these studies reveal that in ileum, proximal, and distal colon, steady-state fluxes of 5-FU (10 µM added to both bathing solutions) are established after 30 min and remain constant for at least 110 min. Transport of 5-FU under sink conditions with 10 µM 5-FU present in the mucosal or serosal bathing solution alone demonstrated similar rates of transport as under nonsink conditions. The concentration dependence of 5-FU fluxes indicates that the mucosal (m)-to-serosal (s) flux is composed of both a saturable and a linear component over the range of 1–100 µM in the ileum, whereas the s-to-m flux in the ileum and both fluxes in the colon are linear functions of concentration. Over the concentration range employed and the time course of these studies, 5-FU had no effect on the electrical properties of the ileum or colon. In the ileum, the m-to-s but not the s-to-m flux of 5-FU was reduced by (1) serosal ouabain (0.1 mM); (2) reduction of the bathing solution Na concentration; and (3) addition of uracil, thy mine, thymidine, uridine, 2-deoxyuridine, or uridine-5-monophosphate. These results indicate that 5-FU absorption in the ileum occurs by a Na-dependent mechanism that is inhibited by uracil and structurally related compounds. In distal colon, no evidence for an active transport mechanism was obtained. High-performance liquid chromatography (HPLC) analysis reveals that both ileum and distal colon metabolize 5-FU to more polar compounds. Metabolism in ileum is quantitatively greater than in distal colon. Metabolites are found predominantly on the side to which transport has occurred, suggesting that metabolism occurs concomitantly with transport. Since the intestinal cells metabolize 5-FU to more polar compounds and active absorption is inhibited in a competitive manner by related compounds, these results may provide an explanation for the variable oral activity reported for 5-FU.     

Fresh gas flow in the Bain circuit during laparoscopy

Twenty-two women were studied during laparoscopy with abdominal insufflation of carbon dioxide. A bain anaesthetic breathing circuit was used with a fresh gas flow (VFG) of 110 ml.min-1.kg-1, and controlled ventilation was applied with a minute ventilation (VE) of 175 ml.min-1.kg-1. Arterial blood gases were analysed at the end of the operation. Nineteen of the women (86 per cent) were found to have a PaCO2 within the range for normocapnia (i.e., 4.7-5.9 kPa (35-45 mmHg), two were hypocapnic with a PaCO2 of 4.4 and 4.5 kPa (33 and 34 mmHg) respectively and one was found to have a PaCO2 of 6.2 kPa (46.5 mmHg). It was concluded that the carbon dioxide absorbed from the abdomen during laparoscopy demands fresh gas flows that are higher than normally used in the Bain circuit if a PaCO2 within the normal range is to be obtained. A simultaneous increase in VFG and VE of about 45 per cent is sufficient to achieve normocapnia.     

Renal tissue gas tensions during hemorrhagic shock

To evaluate the development of renal hypoxia during hemorrhagic shock, fourteen dogs were induced in this study. The animals were divided equally into a group in which mean arterial pressure (MAP) was kept at 50mmHg (group 1), and into another where MAP was kept at 40mmHg for 180mim (group 2). Renal tissue gas tensions were determined by a mass spectrometer. In the 50-mmHg group, renal tissue oxygen tension (Pr_{O 2}) dropped for 15min following hemorrhage, remained constant for 90min, then fell further for 150min before a plateau was established. In the 40-mmHg group, the Pr_{O 2} dropped for 90min before reaching a plateau. The second Pr_{O 2} decline occurred at the same level in both the 50-mmHg group and the 40-mmHg group. The point at which the same Pr_{O 2} level occurred for each group suggests the cessation of oxygen consumption and the conditions of renal hypoxia. It is assumed that renal hypoxia occurs in 120min at a MAP of 50-mmHg and in 60min at a MAP of 40mmHg.(Murakawa K, Izumi R, Kobayashi A: Renal tissue gas tentions during hemorrhagic shock. J Anesth 3: 10–15, 1989)     

Absorption and presystemic glucuronidation of 1-naphthol in the vascularly fluorocarbon emulsion perfused rat small intestine

Summary Using the isolated vascularly fluorocarbon emulsion perfused rat small intestine some factors which determine the extent of the intestinal glucuronidation of 1-naphthol to 1-naphthol--d-glucuronide were studied. Increasing the luminal 1-naphthol concentration resulted in a concomitant increase in the 1-naphthol appearance in the vascular perfusate. In contrast, the total appearance of 1-naphthol--d-glucuronide increased less than proportional to the increase in the luminal 1-naphthol concentration. About 88% of the total amount of 1-naphthol--d-glucuronide excreted was released into the vascular perfusate. The capacity-limited intestinal glucuronide efflux is most likely due to saturation of the excretory mechanism for 1-naphthol--d-glucuronide. Decreasing the vascular flow rate influenced both the appearance of 1-naphthol and 1-naphtol--d-glucuronide in the vascular perfusate, whereas the appearance of 1-naphthol--d-glucuronide in the luminal perfusate was essentially flow-independent. A noradrenaline-induced change in the haemodynamic state of the vascular bed (with the total flow kept constant) resulted in a marked decrease in the 1-naphthol vascular concentration. The vascular 1-naphthol--d-glucuronide concentration was only slightly affected. These results indicate that changes in blood flow and blood flow distribution within the intestinal wall can affect the extent of presystemic intestinal metabolism by interfering with the absorption of the parent compound and the efflux of formed conjugates. These parameters can be of paramount importance for causing variable intestinal first-pass effects of drugs in vivo. Send offprint requests to M. H. de Vries at the above address     

In vitro absorption of some chlorinated paraffins through human skin

The in vitro absorption of chlorinated paraffins, Cereclor S52 and Cereclor 56L (present in a cutting fluid), has been measured through human skin. During 56 h continuous skin contact no Cereclor S52 was detected to have been absorbed and only a very slow rate of Cereclor 56L absorption (mean rate, 0.04 g/cm/h) was measured. This rate was only apparent after more than 7 h continuous skin contact. These chlorinated paraffins were very poorly absorbed through human skin and human dermal exposure should not cause significant systemic levels.     

Rectal Absorption Enhancement of Des-Enkephalin-γ-Endorphin (DEγE) by Medium-Chain Glycerides and EDTA in Conscious Rats

The stability of the neuroleptic peptide des-enkephalin--endorphin (DEE; Org 5878) in the rectal lumen and the rectal bioavailability of DEE were investigated in conscious rats. Furthermore, the influence of peptidase inhibition, peptidase saturation, and absorption enhancement on DEE bio-availability were evaluated. Na₂EDTA (0.25%, w/v) prolonged the degradation half-life of DEE in the ligated colon from 33 ± 7 to 93 ± 45 min. Without adjuvant, tritium-labeled DEE was absorbed from the rat rectum to a very low extent (0–4%). After administration of an excess of unlabeled DEE or with Na₂EDTA, comparable results were obtained. The medium-chain glyceride preparation MGK markedly enhanced the rectal DEE bioavailability, up to 8–20%, which was further increased to 10–44% by coadministration of Na₂EDTA. No substantial influence of varying the rectal delivery rate was observed. The results suggest that absorption enhancement and enzyme inhibition both are essential for effective increase of rectal peptide bioavailability.     

免疫磁珠法分离白血病转基因小鼠骨髓造血干细胞

本文分离转基因小鼠骨髓造血干细胞。运用针对小鼠干细胞表面特异表达的干细胞抗原 1(stemcellantigen 1,Sca 1)的单克隆抗体和包被于磁颗粒表面的第二抗体 ,采用磁吸附细胞分选方法 (MACS )分离小鼠骨髓造血干细胞 ,用流式细胞术 (FACS )检测MACS分离后骨髓细胞中干细胞 (Sca 1阳性细胞 )比例 ,监测细胞分选效果。结果显示MACS分离后骨髓细胞中Sca 1阳性细胞所占比例达 85 %以上 ,涂片观察发现细胞组成和细胞形态学特征与FACS所得结果一致。MACS可以从转基因小鼠全骨髓细胞中分离出Sca 1阳性的骨髓造血干细胞 ,细胞纯度可达 85 %以上。     

A multiple-pathway model for the diffusion of drugs in skin

A mathematical model for the diffusion of drugs in skin is presented.The penetration of the drug by both transcellular and intercellularpathways, as well as its interchange between these pathways,is considered. A pharmacologically motivated asymptotic limitis identified and analysed to obtain, in particular, an analyticalexpression for the flux of drug to the blood at steady state.Relevant model data is discussed, and some numerical resultsare also presented.