Monoclonal antibodies against bovine tissue factor, which block interaction with factor VIIa

Two monoclonal antibodies that recognize bovine tissue factor (coagulation factor III) have been obtained following the fusion of hyperimmune mouse spleen cells with NS-1 plasmacytoma cells. Both antibodies, TF1-E2 and TF1-F7, have gamma 1 heavy chains and lambda light chains. TF1-E2 and TF1-F7 have each been used to purify bovine tissue factor from a crude detergent extract of bovine brain by immunoaffinity chromatography. Both antibodies inhibit tissue factor procoagulant activity and block the association of factor VIIa with tissue factor. The association of TF1-F7 and tissue factor solubilized in Triton X-100 was measured under equilibrium conditions. The Kd for this antibody-antigen interaction was 2.1 +/- 0.2 nmol/L. TF1-E2 effectively competes with TF1-F7 for tissue factor binding, indicating that the monoclonal antibodies recognize overlapping sites on the protein. These antibodies will be useful reagents for large-scale purification and for structure-function studies of bovine tissue factor. In particular, since they appear to bind to the same region of the tissue factor molecule as factor VIIa, they will be useful as specific probes for studying the kinetics of tissue factor-initiated coagulation and for immunocytochemical localization of tissue factor in bovine cells.     

Improvement of pressure flow parameters with finasteride is greater in men with large prostates. Finasteride Urodynamics Study Group

PURPOSE: We assess the effect of finasteride, a 5alpha-reductase inhibitor, on objective voiding parameters in men with lower urinary tract symptoms and benign prostatic enlargement on digital rectal examination (known as clinical benign prostatic enlargement) in a double-blind placebo controlled multicenter study using strict standard pressure flow study techniques. MATERIALS AND METHODS: A modification of the Abrams-Griffiths nomogram was used by 1 reader to ensure that all patients met objective criteria for bladder outlet obstruction at baseline. After performing a pressure flow study patients with obstruction were randomized 2:1 to receive 5 mg. finasteride (81) or placebo (40) daily. A second pressure flow study was performed at month 12. At baseline and month 12 free urinary flow studies and transrectal ultrasound were performed, and International Prostate Symptom Score questionnaires were completed. Patients were treated between May 1994 and July 1996. RESULTS: Finasteride caused a significant decrease (-8.1 cm. water) in detrusor pressure at maximum flow (p <0.05 versus placebo p = 0.02), increase (+1.1 ml. per second) in maximum flow rate (p <0.05 versus placebo p = 0.02) and decrease (-22.8%) in prostate volume (p <0.05 versus placebo p <0.001). Men with prostates larger than 40 cc had greater improvement in detrusor pressure at maximum flow (between group difference -14.5 cm. water, 95% confidence interval -26.2 to -2.6, p = 0.02) and maximum flow rate (mean treatment effect +1.6 ml. per second, 95% confidence interval -0.2 to 3.0, p = 0.02) compared to those with prostates 40 cc or less (between group differences not significant). CONCLUSIONS: Finasteride treatment resulted in improvements in urodynamic parameters, which were greater in men with large prostates.     

Relevance of neoadjuvant and adjuvant treatment for patients with resectable liver metastases of colorectal carcinoma

Background: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. Methods: The databases Medline and Cancerlit (1982–1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. Results: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m² for 5 days every 28 days) and folinic acid (200 mg/m² for 5 days every 28 days) was compared with observation only. Neither in the intention-to-treat nor in the as-treated analysis was median survival time (34.5 months versus 40.8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. Conclusion: Despite several theoretical reasons for post- or preoperative treatment in resectable patients, every approach should be tested using of controlled studies. Received: 2 March 1999 Accepted: 28 June 1999     

3-[123I]Iodo-L-alpha-methyl tyrosine transport into human fibroblasts and comparison with Ewing's sarcoma cells

The cellular transport systems and the transport kinetics of [123I]IMT uptake into non-malignant extracranial cells were characterized for the first time. Human fibroblasts were chosen as non-malignant extracranial cells as they are found ubiquitous in the body. [123I]IMT is exclusively transported into fibroblasts via the sodium independent system L. An apparent Michaelis constant K(m) = 116.2 +/- 18.9 microM and a maximum transport velocity V(max) = 191.6 +/- 13.9 pmol x (10(6) cells)(-1) x min(-1) were calculated for the sodium-independent transport. These results were compared with those determined in two malignantly transformed extracranial cell lines, the human Ewing's sarcoma cell lines VH-64 and CADO-ES-1.     

Increased oxidative stress in the mouse adriamycin model of glomerulosclerosis is accompanied by deposition of ferric iron and altered GGT activity in renal cortex

Chronic renal failure evolves inevitable towards glomerular and tubulo-interstitial sclerosis. This pathological process involves a disturbed redox status of the kidney tissue, leading to irreversible damage. In this study we investigate in an adriamycin model of chronic renal failure in mice the evolution of in vivo hydrogen peroxide production, and the possible role of gamma-glutamyl transpeptidase and ferric iron in the process. Histological changes and ferric iron deposits are evaluated by histochemical staining. To evaluate oxidative stress residual catalase activity, TBARS formation and gamma-glutamyl transpeptidase activity are measured spectrophotometrically. While catalase activity remains the same, a decreased residual catalase activity indicates an increased formation of hydrogen peroxide. Both the activity of gamma-glutamyl transpeptidase and TBARS formation is increased at early stages of the disease. Ferric iron is clearly present in the proximal tubule. Twenty days after adriamycin injection all parameters decrease, probably due to the destruction of the tissue. Our data show the involvement of oxidative stress in the progression of adriamycin induced renal failure in mice. Both radical production and oxidative damage are measurable, while the altered activity of gamma-glutamyl transpeptidase and the deposition of ferric iron suggest the involvement of these factors in the development of a disturbed redox status in the kidney cortex.     

Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment

Background. The pharmacokinetics of remifentanil, an opioidanalgesic metabolized by non-specific esterases, and its principalmetabolite, remifentanil acid (RA), which is excreted via thekidneys, were assessed as part of an open-label safety studyin intensive care unit (ICU) patients with varying degrees ofrenal impairment. Methods. Forty adult ICU patients with normal/mildly impairedrenal function (creatinine clearance [CL_cr] 62.9 (SD) 14.5 mlmin^–1; n=10) or moderate/severe renal impairment (CL_cr14.7 (15.7) ml min^–1; n=30) were included. Remifentanilwas infused for up to 72 h, at a starting rate of 6–9µg kg^–1 h^–1 titrated to achieve a target sedationlevel, with additional propofol (0.5 mg kg^–1 h^–1)if required. Intensive arterial sampling was performed for upto 72 h after infusion. Pharmacokinetic parameters obtainedby simultaneous modelling of remifentanil and RA data were statisticallycompared between the two groups. Results. Remifentanil pharmacokinetics were not significantlyaffected by renal status. RA clearance in the moderate/severegroup was reduced to about 25% that of the normal/mild group(41 (29) vs 176 (49) ml kg^–1 h^–1, P<0.0001).Metabolic ratio, a predictor of the ratio of RA to remifentanilconcentrations at steady state, was approximately eight-foldhigher in the moderate/severe group relative to the normal/mildgroup (116 (110) vs 15 (4), P<0.0001). Maximum RA levelsapproached 700 ng ml^–1 in the moderate/severe group. Conclusions. Although RA accumulates in patients with moderate/severerenal impairment, pharmacokinetic modelling predicts that RAconcentrations during a 9 µg kg^–1 h^–1 remifentanilinfusion for up to 15 days would not exceed those reported inthe present study, for which no associated prolongation of µ-opioideffects was observed. Br J Anaesth 2004; 92: 493–503     

Laser treatment of benign prostatic obstruction: basics and physical differences

Context

Laser treatment of benign prostatic obstruction (BPO) has become more prevalent in recent years. Although multiple surgical approaches exist, there is confusion about laser-tissue interaction, especially in terms of physical aspects and with respect to the optimal treatment modality.

Objective

To compare available laser systems with respect to physical fundamentals and to discuss the similarities and differences among introduced laser devices.

Evidence acquisition

The paper is based on the second expert meeting on the laser treatment of BPO organised by the European Association of Urology Section of Uro-Technology. A systematic literature search was also carried out to cover the topic of laser treatment of BPO extensively.

Evidence synthesis

The principles of generation of laser radiation, laser fibre construction, the types of energy emission, and laser-tissue interaction are discussed in detail for the laser systems used in the treatment of BPO. The most relevant laser systems are compared and their physical properties discussed in depth.

Conclusions

Laser treatment of BPO is gaining widespread acceptance. Detailed knowledge of the physical principles allows the surgeon to discriminate between available laser systems and their possible pitfalls to guarantee high safety levels for the patient.     

Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.