A phase I and pharmacokinetic study of gemcitabine given by 24-h hepatic arterial infusion.

PURPOSE: This study was performed to assess the toxicities, the maximum-tolerated dose (MTD), the pharmacokinetics and the anti-tumour activity of gemcitabine given by 24-h hepatic arterial infusion (HAI). PATIENTS AND METHODS: Patients with liver malignancies received gemcitabine by 24-h HAI, weekly x 3, every 4 weeks. On day 1 or day 8 of the first cycle, patients received one administration by 24-h intravenous infusion for pharmacokinetic comparison and to determine hepatic extraction. RESULTS: Thirteen patients received gemcitabine at the dose levels of 75, 135 and 180 mg/m(2). The MTD was 180 mg/m(2) with thrombocytopaenia as the dose-limiting toxicity. Pharmacokinetic analysis showed a significantly lower maximum gemcitabine plasma concentration (C(max): HAI, 26, 80 and 128 nM, respectively; IV, 229, 264 and 293 nM, respectively) and area under the plasma-concentration-versus-time curve (AUC(0-24h): HAI, 386, 1247 and 2033 nmol x h/L, respectively; IV, 3526, 4818 and 5363 nmol x h/L, respectively) during HAI, compared with intravenous infusion (both P<0.001). Additionally, the mean hepatic extraction ratios of gemcitabine at the 75, 135 and 180 mg/m(2) dose level were 0.89, 0.75 and 0.55, respectively. Hepatic extraction decreased linearly with increasing dose. The C(max) and AUC(0-24h) of 2',2'-difluoro-2'-deoxyuridine, the deaminated product of gemcitabine, were similar for HAI and intravenous infusion. Seven patients had stable disease for a median duration of 9 months (range: 2-11 months). CONCLUSIONS: Gemcitabine given by 24-h HAI was well tolerated and resulted in significantly lower systemic gemcitabine plasma concentrations than intravenous infusion due to a relatively high hepatic extraction.

Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery.

Hip replacement surgery (HRS) is associated with a high frequency of deep vein thrombosis (DVT). At the same time there is a substantial systemic and local activation of coagulation. This study indicates that discontinuation of thromboprophylaxis one week after surgery may allow a second wave of coagulation and fibrinolysis activation to occur. An almost parallel increase in plasma TAT and D-dimer levels between the 6th and the 35th postoperative day may indicate late DVT formation. Repeated bilateral ascending venography is though to be necessary to evaluate the suitability of using selected activation markers of the coagulation and fibrinolytic systems as indices of DVT formation.

Refinements of pre-, intra-, and postoperative care to prevent complications of vaginoplasty in male transsexuals.

In the period of 1980 to 1992, primary genital reassignment surgery was performed for 200 male-to-female transsexuals aged 18 to 71 years. For this, the penile and scrotal skin inversion technique was used. Because, apart from minor complications in 32 patients, neovaginal obliteration was encountered only twice and early in this series, we believe it is worthwhile to report in detail our pre-, intra-, and postoperative measures. Discontinuation of hormonal treatment may prevent venous thrombosis. The preoperative rectal rinse and antibiotics are believed to be of importance to avoid rectovaginal fistulae. A soft and pliable intravaginal Vaseline tampon may prevent sloughing of the inverted skin. Intermittent daily neovaginal dilatation may successfully ensure neovaginal depth and width and, in our opinion, is superior to a long-term continuous intravaginal stent.

Does Lp(a) lipoprotein inhibit the fibrinolytic system?

Lp(a) lipoprotein contains a unique apolipoprotein, apolipoprotein (a), that has a striking homology with plasminogen. This homology has brought forward speculations as to an inhibitory effect of Lp(a) lipoproteins on fibrinolysis. The present investigation was undertaken to study the influence of Lp(a) lipoprotein on the fibrinolytic system. In an in vitro model, we have studied the influence of purified Lp(a) lipoprotein on plasminogen activation by tissue plasminogen activator (t-PA) in the presence of soluble fibrin. Increasing concentrations of Lp(a) lipoprotein (0-32 mg/dl) did not inhibit plasminogen activation by t-PA in the presence of thrombin or bathroxobin digested fibrinogen. When purified Lp(a) lipoprotein was added to whole blood, the degree of fibrin degradation obtained following standardized coagulation, as evaluated by the generation of D-dimer, was not reduced. D-dimer levels in plasma and in serum after standardized coagulation, as well as conventional parameters for evaluation of the fibrinolytic system, were determined in 10 individuals with high and 10 individuals with low levels of Lp(a) lipoprotein. No differences in the fibrinolytic parameters were observed between the groups. Thus, we found no evidence that Lp(a) lipoprotein interferes with the fibrinolytic process in the present experiments.

A novel principle for assessment of stimulated fibrinolysis.

After venous occlusion (VO), D-dimer levels were measured by means of an ELISA technique, in citrated plasma clotted by thrombin and in serum from whole blood. D-dimer levels increased with duration of incubation (30 min to 24 hours). D-dimer values, both in clotted plasma and in serum (n = 12), incubated 4 hours at room temperature, correlated well with euglobulin clot lysis time (ECLT) (r = -0.85 and -0.89, respectively, p less than 0.002) and tissue plasminogen activator (t-PA) activity, (r = 0.82 and 0.83, respectively, p less than 0.002). D-dimer concentrations from plasma and serum (n = 25) were compared (r = 0.90, p less than 0.001). Healthy volunteers (n = 65) were tested to establish reference values in serum from post-occlusive whole blood samples incubated 4 hours prior to centrifugation. Finally, a patient group (n = 62) was examined. For the whole material (n = 152) such D-dimer concentrations correlated well with both ECLT (r = -0.85, p less than 0.001) and t-PA activity (r = 0.81, p less than 0.001). D-dimer levels in serum were determined by a latex agglutination test as well. These semi-quantitative values also correlated significantly with both ECLT (r = -0.86, p less than 0.001) and t-PA activity (r = 0.87, p less than 0.001). We conclude that measurement of D-dimer as described above, represents a simple and accurate method for assessment of global fibrinolytic activity following VO. The latex agglutination test is particularly suitable as a screening procedure.

Comparison of thrombin-antithrombin complex (TAT) levels and fibrinopeptide A following thrombin incubation of human plasma using hirudin as an inhibitor of TAT formation.

Following incubation of citrated plasma with human thrombin, the interaction of thrombin with antithrombin III was measured as thrombin-antithrombin complex (TAT) concentration. Comparison was made to thrombin activity on fibrinogen, assayed as fibrinopeptide A (FPA). Light scattering studies were included to evaluate polymerization of fibrin. Hirudin, at a final concentration of 100 U/ml, effectively inhibited TAT generation at final thrombin concentrations below 0.4 NIH U/ml. Hirudin by itself did not affect the TAT ELISA analysis. TAT and FPA values correlated closely (r = 0.83, p less than 0.001) and may equally well represent in vitro thrombin activity.

Comparison of methods for detecting soluble fibrin in plasma. An in vitro study.

The ability of the COA-SET Fibrin monomer (COA-SET FM) test to detect soluble fibrin was evaluated by comparing the results of the COA-SET FM test with fibrinopeptide A (FPA) determinations following thrombin incubation of plasma or whole blood. In addition, two semiquantitative tests (erythrocytes-agglutination test (FM-test) and ethanol gelation test (EGT] were included in the study. Under the experimental conditions used, the COA-SET FM test proved less sensitive than the FPA-assay. There was a strong correlation between the results obtained by the two tests (r = 0.86, p = 0.0001). When solely regarding low levels of soluble fibrin, however, the correlation was weaker (r = 0.59, p = 0.0003). The FM-test was less sensitive than the COA-SET FM test, but more sensitive than EGT at normal and low fibrinogen concentrations. At high fibrinogen concentrations, however, EGT proved more sensitive than the FM-test. Knowing that 1-2 moles of FPA are released per mole of fibrin monomers formed, a discrepancy was observed between the FPA concentrations and the fibrin monomer concentrations as determined by the COA-SET FM test, the FPA levels being 2-25 times higher than the fibrin monomer levels. The discrepancy was greatest at incipient fibrinogen-fibrin transformation and at high plasma fibrinogen levels. This may suggest that fibrinogen in some way interfered with the stimulating effect of fibrin on the t-PA catalyzed activation of plasminogen, the principle upon which the COA-SET FM test is based.(ABSTRACT TRUNCATED AT 250 WORDS)

No discriminating power in FPA measurements during fibrinaemia in hip replaced patients generating DVT.

Fibrinaemia following total hip replacement was evaluated in eighteen patients, grouped according to a negative and a positive fibrinogen uptake test (FUT), after having excluded two patients due to a false negative test, using phlebography as reference. The ethanol gelation test (EGT) was employed for detection of circulating soluble fibrin, and the conversion of fibrinogen to fibrin was evaluated by the level of fibrinopeptide A (FPA). Eight patients were cleared with respect to thrombosis, whereas ten had a positive FUT. All patients developed a positive EGT, irrespective of thrombosis, coinciding with the postoperative increase in fibrinogen. FPA increased to approximately twice its preoperative level in both groups of patients, but reached its maximum earlier in patients with thrombosis. However, this parameter had no discriminative value in this type of postoperative thrombosis, possibly due to massive thromboplastin release in both groups.

Does preincubation of the red blood cells contribute to the capability of the osmotic fragility test to detect very mild forms of hereditary spherocytosis?

During incubation for 24 h at 37 degrees C, erythrocytes from patients with hereditary spherocytosis (HS) undergo a greater increase in osmotic fragility than do normal cells, and this procedure has been recommended for differentiating more clearly between patients with very mild HS and normal subjects. The greater effect of preincubation on erythrocytes from patients with HS was confirmed, but, except in cases demonstrating a markedly increased osmotic fragility before incubation, this effect was outweighed by a simultaneous loss of test precision. It therefore seems that preincubation does not significantly contribute to the capability of the osmotic fragility test to detect very mild forms of HS.

Failure of ouabain to influence the osmotic fragility in hereditary spherocytosis.

No effect of 3 mumol ouabain on the osmotic fragility of red blood cells in subjects suspected of being carriers of hereditary spherocytosis, as well as in patients with overt disease could be demonstrated. These results are in disagreement with a recent report. Some possible explanations for these discrepant results are discussed. It is concluded that ouabain probably adds little to the diagnostic capability of the osmotic fragility test.