Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?

The pharmacokinetics of midazolam and its metabolites were studied in 17 patients on mechanical ventilation in a general intensive care unit who were receiving a continuous intravenous infusion of midazolam, adjusted according to the level of induced sedation. Three patients were studied twice. Serum midazolam and alpha-hydroxymidazolamglucuronide levels were determined during and after infusion. The sedation level was scored on a four-point scale. Half of the observed patients were still drowsy or asleep 10 hours after termination of midazolam infusion. In only one patient was midazolam serum elimination half-life less than 2 hours and in six patients the half-life was greater than 10 hours. A wide range of midazolam serum levels was associated with adequate sedation, and similarly the midazolam levels at the moment of awakening were highly variable. The serum concentration ratio of midazolam/alpha-hydroxymidazolamglucuronide at the end of the infusion varied from 0.03 to 15.6. Renal function could account for only a part of this variation.     

Isolation of isoguanosine fromCroton tiglium and its antitumor activity

This paper describes the isolation of isoguanosine from Croton tiglium L. and its cytotoxic effect against several tumor cell lines in culture and newly reports that isoguanosine has an antitumor activity against implanted S-180 ascitic tumor mice. Isoguanosine is effective at the dose of 24 mg/kg/day x 5, with T/C value of 168%. Isoguanosine inhibits the growth of S-180 and Ehrlich solid tumor in mice at the optimal doses of 96 mg/kg/day x 12 and 48 mg/kg/day x 12, with 1-T/C values of 65% and 60%, respectively.     

Renal disease in POEMS syndrome: report on a case and review of the literature

POEMS syndrome is a multisystem disorder associated with plasmacell dyscrasias. This report describes a patient with POEMS-associatedrenal disease and reviews the literature on biopsy-proven renalinvolvement in POEMS syndrome. Our patient had glomerulonephritiswith membranoproliferative features on light-microscopy withoutcharacteristic findings on immunofluorescence, and with ultra-structural evidence of glomerular microangiopathy. Ultrastructuralevidence of microangiopathy was also found in vasa nervorum.In 20 other cases of POEMS- associated renal disease, 16 hadglomerular disease. Light-microscopy showed membranoproliferative-likeglomerulopathy in 14 patients and glomerular microan giopathyin two. Ultrastructural evidence of microangi opathy was presentin all 15 patients in whom electron- microscopy was done. Thus,in most patients with POEMS-associated glomerular disease acharacteristic lesion is present with evidence of endothelialinjury. As endothelial damage is also found in endoneural vessels,generalized endothelial injury may play a role in non-renalmanifestations of POEMS syndrome. In previous reviews manifestationsof the POEMS syndrome were similar for patients with or withoutmyeloma. Among patients with biopsy-proven glomerular disease,however, myeloma patients are underrepres ented. Whether thisrepresents a sampling error or has true pathophysiological significanceremains to be established.     

Isolation and identification of chondroitin sulfates from the mud snail

Chondroitin sulfates were isolated from the mud snail. For the quantitative analysis of enzymatic digestion products of isolated chondroitin sulfates, strong anion exchange-high performance liquid chromatography (SAX-HPLC) was performed. By the action of chondroitinase ABC, three unsaturated disaccharides 2-acetamide-2-deoxy-3-O-(β-D-gluco-4-enepyranosyluronic acid)-D-galactose (ΔDi-OS), 2-acetamide-2-deoxy-3-O-(β-D-gluco-4-enepyranosyluronic acid)-6-O-sulfo-D-galactose (ΔDi-6S) and 2-acetamide-2-deoxy-3-O-(β-D-gluco-4-enepyranosyluronic acid)-4-O-sulfo-D-galactose (ΔDi-4S) were produced from the mud snail chondroitin sulfates. The analysis showed that relative proportion of ΔDi-OS/ΔDi-6S/ΔDi-4S was 58.7/3.1/38.2. The immunomodulating activity of chondroitin sulfate was examined by cell proliferation assay and these results suggest that it might be a immunosuppressant.     

Establishment of a human hepatocellular carcinoma cell line highly expressing sodium iodide symporter for radionuclide gene therapy.

To evaluate the possibility of radionuclide gene therapy and imaging in hepatocellular carcinoma cancer, we investigated the iodine accumulation of a human hepatocellular carcinoma cell line, SK-Hep1, by transfer of human sodium iodide symporter (hNIS) gene. By targeting NIS expression in SK-Hep1, we could also investigate whether these cells concentrate 99mTc-pertechnetate and 188Re-perrhenate as well as 125I in vitro and in vivo. METHODS: The hNIS gene was transfected to human hepatocellular carcinoma SK-Hep1 cell lines using lipofectamine plus reagent. The uptake and efflux of 125I, 99mTc-pertechnetate, and 188Re-perrhenate were measured in the transfected and parental cells. Biodistribution was studied in nude mice bearing SK-Hep1 and SK-Hep1-NIS at 10 and 30 min and at 1, 2, 6, 16, and 23 h after injection of 125I, 99mTc- pertechnetate, or 188Re-perrhenate. In tumor imaging studies, the nude mice were intravenously injected with 188Re-perrhenate and imaged with a gamma-camera equipped with a pinhole collimator at 30 and 60 min after injection. The survival rate (%) was determined by the clonogenic assay after 37 MBq/10 mL (1 mCi/10 mL) 131I and 188Re-perrhenate treatment. RESULTS: SK-Hep1-NIS, stably expressing the NIS gene, accumulated 125I up 150 times higher than that of SK-Hep1. Iodine uptake of SK-Hep1-NIS is completely blocked by perchlorate. NIS gene transfection into SK-Hep1 also resulted in 112- and 87-fold increases of 99mTc-pertechnetate and 188Re-perrhenate uptake, respectively. Iodide efflux from SK-Hep1-NIS was relatively slow, with only 10% released during the initial 5 min, and 60% remained at 25 min. In the biodistribution study using SK-Hep1-NIS-xenographed mice, the tumor uptake of 125I, 188Re-perrhenate, and 99mTc-pertechnetate was 68.0 +/- 15.0, 46.2 +/- 9.1, and 59.6 +/- 16.2 %ID/g (percentage injected dose per gram) at 2 h after injection, respectively. After 188Re-perrhenate injection in SK-Hep1 and SK-Hep1-NIS-xenographed nude mice, whole-body images clearly visualized the SK-Hep1-NIS tumor, whereas the control tumor was not visualized. The survival rate (%) of SK-Hep1-NIS was markedly reduced to 46.3% +/- 10.1% and 28.9% +/- 5.2% after 37 MBq/mL (1 mCi/10 mL) 131I and 188Re-perrhenate treatment compared with the survival rates of the parental cells. These results demonstrated that SK-Hep1-NIS could be selectively killed by the induced 131I and 188Re-perrhenate accumulation through NIS gene expression. CONCLUSION: NIS-based gene therapy using beta-emitting radionuclides has the potential to be used in hepatocellular carcinoma management.     

Management of congenital tracheal stenosis

Objectives: Congenital tracheal stenosis is a rare disease. Various methods for treatment exist but there is still much debate as to the appropriate surgical procedure. We present our surgical experiences of patch tracheoplasty and slide tracheoplasty as viable methods for the treatment of congenital tracheal stenosis. Methods: From 1994 to 2002, 13 patients were diagnosed with congenital tracheal stenosis. Eight patients (7 symptomatic and 1 asymptomatic) had their stenosis corrected, three by means of pericardial patch tracheoplasty, four by slide tracheoplasty, and one by resection and anastomosis. Concomitant operations were performed on six patients to treat congenital cardiovascular disease. Five patients showing no significant symptoms did not undergo tracheal surgery and received only cardiac procedures. A retrospective review of the hospital course, complications, and long-term results was conducted. Results: Among the patch tracheoplasty group, every patient suffered from granulation tissue formation. One patient died of respiratory acidosis and one was hospitalized due to recurrent granulation tissue, which required frequent bronchoscopy. The third patient from this group is free of all symptoms. Among the slide tracheoplasty group, one patient died of anastomosis disruption. The three remaining patients are alive and well. The one patient who received resection and anastomosis is alive without symptoms. Conclusions: Surgical repair of long-segment congenital tracheal stenosis exhibited high mortality and morbidity rates. Every patient that underwent pericardial patch tracheoplasty suffered from troublesome granulation tissue. As slide tracheoplasty provided relatively good results in the short and mid-term follow-up periods, it seems to be a preferred method for the treatment of long-segment congenital tracheal stenosis.