Warfarin use in hemodialysis patients: what is the risk?

BACKGROUND: There is a paucity of data concerning the risks associated with warfarin in hemodialysis (HD) patients. We compared major bleeding episodes in this group with HD patients not receiving warfarin and with a cohort of non-HD patients receiving warfarin. METHODS: A retrospective review of 141 HD patients on warfarin (HDW), 704 HD patients not on warfarin (HDNW) and 3,266 non-dialysis warfarin patients (NDW) was performed. Hospital admissions for hemorrhagic events and ischemic strokes were examined as was hospital length of stay and blood product use. INR variability was also assessed. RESULTS: The incidence rates for major hemorrhage per 100 patient years was 10.8 in the HDW group as compared to 8.0 in the HDNW (p = 0.593) and 2.1 in the NDW (p < 0.001) groups. Mean units of red blood cell transfusions required was higher in patients on dialysis with no significant difference between HDW and HDNW groups. The risk of ischemic stroke per 100 patient years was 1.7 in the HDW group as compared to 0.7 in the HDNW groups (p = 0.636) and 0.4 in the NDW (p = 0.003). The HDW group had higher inter-measurement INR variability compared to the NDW group (p = 0.034). In patients with atrial fibrillation, HDW group had a higher incidence of ischemic stroke than the NDW group (2.2 versus 0.4 events per 100 patient years; p = 0.024). CONCLUSIONS: This study confirms the higher bleeding risk associated with HD/ESRD but suggests that warfarin use in these patients may not add significantly to this risk. We also demonstrated high rates of ischemic stroke in HD patients despite warfarin use. SUMMARY: Our study compares the frequency of major hemorrhage and secondarily, ischemic stroke in HD patients receiving or not receiving warfarin, with non-HD patients receiving warfarin. The major finding was that frequency of hemorrhage was higher in HD patients receiving warfarin than in non-HD patients receiving warfarin, but not different in HD patients with or without warfarin. A secondary finding was that INR variability was significantly higher in HD patients than non-HD patients on warfarin.

Elastolytic activity of human duodenal contents.

Elastolytic activity of human duodenal contents was determined using the new chromogenic substrate succinyl-trialanine-p-nitroanilide (Suc-Ala3-NAp). The mean output values after pancreatic stimulation with pancreozymin and secretin were significantly higher in controls than in subjects with impairment of other secretory values (volume, bicarbonate, amylase, lipase). Agar gel electrophoresis and chromatography on DEAE-Sephadex revealed one to two fractions which differed in mobility (cathodic and anodic fraction), elution with different NaCl concentrations (0.15 M, cathodic fraction; 0.3 M, anodic fraction), and in behaviour towards synthetic and natural substrate (Suc-Ala3-NAp) and elastin-Congo Red). The cathodic fraction cleaved both substrates, whereas the anodic fraction cleaved only Suc-Ala3-NAp. After trypsin and enterokinase treatment the anodic fraction behaved as the cathodic fraction on DEAE-Sephadex chromatography. The molecular weights (Sephadex G-100) and the Michaelis constants (Suc-Ala3-NAp) of both fractions were identical (24 500; 0.45 X 10(-3) M). These fractions represent probably diffenent activation forms of pancreatic elastase.

Antiemetic efficacy of three serotonin antagonists during high-dose chemotherapy and autologous stem cell transplantation in malignant lymphoma.

The aim of this study was to compare antiemetic efficacy of three serotonin antagonists, granisetron, tropisetron and ondansetron, during conditioning for autologous stem cell transplantation (ASCT). Forty-five malignant lymphoma patients (mean age 38 years, M:F 30:15), undergoing the highly emetogenic regimen BEAM prior to ASCT, were randomized to receive IV granisetron (G) 3 mg once a day, IV tropisetron (T) 5 mg once a day, or IV ondansetron (0) 8 mg twice daily, for six days. The treatment groups were comparable with respect to age, sex and previous experience of nausea and/or vomiting. Nausea and/or emesis control failure was defined as a nausea lasting > or = 4 hours and/or > or = 3 episodes of vomiting/24 h, emesis control failure as > or = 3 episodes of vomiting/24 h. Both the period of chemotherapy (6 days) and the whole period of observation (10 days) were evaluated. Nausea and/or emesis control failure occurred in 24% of patients during the period of chemotherapy and in 51% of patients throughout the whole period of observation, while emesis control failed in 2% and 27% of patients, respectively. The efficacy of three serotonin antagonists was comparable during the chemotherapy period (5 patients with nausea and/or emesis control failure in the granisetron group, 2 in the tropisetron group and 4 in the ondansetron group,p = 0.40). When evaluating the whole period of observation, the antiemetic response to G and T was significantly better than to O, nausea and/or emesis control failure having occurred in 7 (47%) patients treated with G, 5 (33%) patients treated with T, and 12 (80%) patients treated with O, p = 0.03. The results concerning emesis control failures were similar, G 4 (27%), T 1 (7%), O 7 (47%), p = 0.04. Headache was the only frequent side effect of serotonin antagonists (30% incidence). All three serotonin antagonists sufficiently controlled nausea and vomiting during high-dose chemotherapy (BEAM) administration in 67-87% of patients. In comparison with ondansetron, both tropisetron and granisetron proved to be more effective after ASCT, when emetogenic factors other than chemotherapy alone participated.

Comparative study of the estimation of exocrine pancreatic function using p-(N-acetyl-L-tyrosyl)- and p-(N-benzoyl-L-tyrosyl)aminobenzoic acid.

A comparative study using the oral test with chymotrypsin substrates p-(N-acetyl-L-tyrosyl)- and p-(N-benzoyl-L-tyrosyl) aminobenzoic acid (Ac-Tyr-PAB and Bz-Tyr-PAB) was carried out in 43 adults divided into four groups comprising controls (n = 18), chronic pancreatitis (n = 13), after acute pancreatitis (n = 7), and celiac sprue (n = 4), after separate administration of both derivatives and determination of PABA urinary output in 6 and 8 hours. Both derivatives were diagnostically comparable. The specificity of both derivatives in the investigated group in 6 and 8 hours was 100%, and test sensitivity in patients with chronic pancreatitis, was in 6 hours 90.9% for Ac-Tyr-PAB and 72.7% for Bz-Tyr-PAB, and 8 hours 81.8% for both compounds. Differentiation between the controls and the chronic pancreatitis group was better in Ac-Tyr-PAB, as adjudged by the sensitivity and significance of the Student t-test criterion.

A new method of testing pancreatin therapy in vivo by the use of a peroral chymotrypsin substrate 4-(N-acetyl-L-tyrosyl)aminobenzoic acid.

The efficacy of pancreatin in vivo was determined in 14 patients with advanced pancreatic insufficiency using a peroral test with 2 g of chymotrypsin substrate, 4-(N-acetyl-L-tyrosyl)aminobenzoic acid, the Lundh test meal and 1000 ml tea. Chymotrypsin hydrolysis was quantified by 4-aminobenzoic acid excreted in 6-hr or 8-hr urine samples. After a control test without pancreatin, one or two tablets of Panpur (Nordmark-700 mg of pancreatin and 50 mg of bile per tablet) were applied simultaneously with the Lundh meal on repeated examinations. The urinary excretion of 4-aminobenzoic acid was restored to normal values in 5 subjects during both sampling periods. With this method, stimulated and substituted chymotrypsin is measured at the same time. The conditions of the tests, both with and without pancreatin replacement, are fully comparable and thus the significance of factors modifying the activity of enzymic components in the digestive tube is limited. The method appears appropriate for the institution of an effect pancreatin therapy and its control in vivo.

Effect of new oligopeptide inhibitors of elastase on acute experimental pancreatitis in the rat.

Acute experimental pancreatitis was induced in male Wistar rats by retrograde injection of 0.4 ml 2% sodium taurocholate into the common choledochopancreatic duct. Prophylactic intraperitoneal injection of 20 mg glutaryl-trialanine-ethylamide, Glt-(Ala)3-NH-Et, 30 min. before induction of pancreatitis reduced the amount of fat necroses and the activity of amylase and lipase in ascites. Repeated intraperitoneal injection of this inhibitor decreased pancreatic hemorrhage. Simultaneous administration of 20 mg Glt-(Ala)3-NH-Et intraperitoneally, and 10 000 KIU of aprotinin intravenously was followed by the most extensive inhibitory effect. Prophylactic and repeated administration of both inhibitors also reduced the area of pancreatic hemorrhage. The same mode of administration of 20 mg undecenoyl-aspartyl-dialanyl-proline-ethylamide, UDE-Asp-(Ala)2-Pro-NH-Et, intraperitoneally and 20 000 KIU of aprotinin intramuscularly, resulted in selective inhibition of fat necroses in all localizations. Glt-(Ala)3-NH-Et and UDE-Asp-(Ala)2-Pro-NH-Et are considered effective inhibitors of various macroscopic and biochemical signs of acute pancreatitis in the rat during short-ferm experiments, if administered prophylactically or early after induction of the disease.

[Separation of hematopoietic progenitor cells from peripheral blood in patients with hemato-oncologic malignancy]. / Separace hemopoetických progenitorových bunek z periferní krve (PBPC) u pacientu s hematoonkologickými malignitami.

BACKGROUND: Transplantations of haematopoietic progenitor cells from peripheral blood (PBPC) are able to ensure haematopoietic and immunological reconstitution as well as stable long term engraftment. Autologous PBPC are administered after previous myeloablative chemotherapy to patients with haematological and non-haematological malignancies. The objective of the submitted study was to follow-up the results of autologous separations of PBPC in patients with a good effect of mobilisation therapy. The authors evaluated in PBPC concentrates the content of cell parameters needed for transplantation. In the subsequent part of the trial they mention the times of engraftment after autologous transplantation. METHODS AND RESULTS: The authors evaluated parameters of 26 separations of PBPC in 11 haematooncological patients with a good effect of mobilisation therapy and with concentration of CD 34+ cells higher than 20 x 10(3)/ml of peripheral blood. The separations of PBPC were implemented on the Cobe Spectra and Baxter CS 3000 Plus equipment under a standard regime with processing of 12 l blood, i.e. 2.7 total blood volumes of the patients. In the mentioned group of patients already from one separation an adequate amount of CD 34+ cells for their transplantation was obtained. Transplantation doses were prepared on average from two separations and amounted as regards MNC/kg, CD 34+ cells/kg and CFU-GM/kg to 4.3 x 10(8), 17.1 x 10(6) and 2.5 x 10(4). The assembled parameters correspond to, or in some parameters exceed, recommended amounts for their transplantation. CONCLUSIONS: In well mobilised patients under the regime of standard separations adequate amounts of progenitor cells for their autologous transplantation were obtained. Transplantation doses were prepared from two collections. Investigation of pre-separation concentration of CD 34+ cells in the peripheral blood is a reliable indicator for starting PBPC separation. Early post-transplantation results indicate the time of engraftment 10 days on average and minor need of substitution therapy with blood products.

[Predictive features of positron emission tomography after two cycles of induction therapy in malignant lymphoma]. / Prediktivní vlastnosti pozitronové emisní tomografie provádené po druhém cyklu indukcní terapie maligních lymfomu.

BACKGROUND: Positron emission tomography (PET) is a modern functional imaging method, recently introduced to clinical oncology. The aim of our study was the evaluation of prognostic value of PET performed in malignant lymphoma patients after two cycles of chemotherapy. METHODS AND RESULTS: From 9/99 to 11/00 PET was performed in 37 patients with malignant lymphoma (9x m. Hodgkin, 21x HG + IG-NHL, 7x LG-NHL; 26x new diagnosis, 11x relaps of disease). Freedom from progression interval (FFP) and overall survival (OS) were evaluated. Attenuation corrected PET imaging was done by dedicated ECAT EXACT PET scanner from base of the skull to the upper thighs 1 hour after intravenous administration of 18-FDG (7.6 +/- 1.3 MBq/kg). Statistical analysis was done using Kaplan-Meier method. Significance of differences between groups was determined by log-rank test on the level of 5%. After the induction therapy, 30 patients were in complete remission, 3 patients in partial remission and in 4 cases progression of disease were observed. Progression of disease was seen in 4 patients. Median follow up of living patients was 7 months (1-13 months) from the end of therapy. Progression, resp. relapse of disease occurred in 13 patients during this period, two patients died. PET performed after the second course of therapy was positive in 18 patients and negative in 19 patients. Two progressions, resp. relapses of disease were documented in PET-negative group and 11 in PET-positive group. FFP was significantly different in PET positive and PET negative groups (p < 0.05). The negative and positive predictive values of PET for malignant lymphoma relapse or progression were estimated 89%, 63% respectively. CONCLUSION: Regardless the short follow-up period, our preliminary results reflect very good prognostic value of PET performed after the second course of chemotherapy in malignant lymphoma patients.

[Effect of clodronate in patients with multiple myeloma. Evaluation of specific markers of bone resorption]. / Ucinek klodronátu u pacientu s mnohocetným myelomem. Hodnocení specifickými markery osteoresorpce.

BACKGROUND: In adjuvant therapy of patients with multiple myeloma among others anti-absorption properties of bisphosphonates are used. The objective of the present investigation was to evaluate the effect of long-term oral treatment route clodronate on the bone metabolism in this condition. As markers of bone reabsorption, assessment of pyridinoline and deoxypyridinoline in urine was used. METHODS AND RESULTS: We investigated in an open clinical trial 22 patients with multiple myeloma with bone changes confirmed on X-ray who had a normal calcium and creatinine serum concentration: the control group (A) comprised 13 patients (mean age 59 years, range 38-74 years), the experimental group (B) 9 patients (mean age 54 years, range 42-60 years). The patients in both groups were treated by chemotherapy, to group B concurrently clodronate 3 x 800 mg was administered by the oral route. No statistically significant differences were found between the two groups during the mean follow up period after assessment of the diagnosis (27 vs. 40 months) nor in the clinical stage of the disease. After intervals of 0, 3 and 12 months the excretion of pyridinoline and deoxypyridinoline in urine was assessed by liquid chromatography. At the same time also other parameters of osteoresorption were assessed (urinary calcium and hydroxyproline excretion). At the onset of the investigation the pyridinoline and deoxypyridinoline excretion in groups A and B did not differ statistically (pyr; 120.63 +/- 23.76 vs. 136.23 +/- 22.13 mumol/mmol creatinine. d-pyr: 19.61 +/- 3.65 vs. 22.76 +/- 5.40 mumol/mmol creatinine). After three months in group B a statistically significant drop of excretion of both metabolites was recorded (pyr. to 84.11 +/- 38.67 mumol/mmol creatinine, d-pyr. to 15.23 +/- 6.10 mumol/mmol creatinine). Their significantly reduced excretion persisted also after one year (pyr. 85.52 +/- 60.96 mumol/mmol creatinine, d-pyr. 12.6 +/- 6.56 mumol/mmol creatinine). CONCLUSIONS: Using specific markers, pyridinoline and deoxypyridinoline, the authors proved the favourable effect of long-term administration of clodronate on the bone metabolism in patients with multiple myeloma.

[Renal impairment in monoclonal gammapathies. Clinical study]. / Postizení ledvin u monoklonálních gamapatií. Klinická studie.

BACKGROUND: Renal involvement is an important and frequent complication in patient with monoclonal gammapathy (MG), especially in multiple myeloma (MM). Light chain proteinuria produces many renal manifestations, the most serious form is acute renal failure, which occurs in 5-10% of patients with MM. The frequency and form of renal involvement was determined in a group of patients with MG. The disturbances observed were correlated with the concentration and type of paraprotein in serum and urine. METHODS AND RESULTS: We investigated 82 patients, 37 men and 45 women with an average age of 63.5 years. Apart from standard nephrologic tests the aminoaciduria/24 h and urine acidification capacity was determined. In some patients renal biopsy was performed. Proteinuria was observed in 66 cases (80.5%), in 54 of them of Bence-Jones type. Nephrotic syndrome developed in 4 patients, in all cases the renal amyloidosis was present. Renal insufficiency was diagnosed in 39 patients (47.5%), mostly in MM. In 14 cases was renal insufficiency reversible, in 14 remain stable and in 11 progressed during the course of disease. Irreversible progression developed in terminal phase of disease in most cases. Acute renal failure was observed in 6 patients, only in four of them further course of renal disease could be evaluated. In half of these 4 patients the renal failure was reversible. CONCLUSIONS: Higher frequency of proteinuria and renal insufficiency was detected in patients with light chain paraprotein of lambda type, or biclonal kappa+lambda type. Aminoaciduria was diagnosed in 40% of patients, we did not observe complete Fanconi's syndrome. Incompleted form of renal tubular acidosis we diagnosed in 52% of cases without other signs of renal involvement.

Demonstration of "hetero-beta-galactosidase" "in situ".

A method for the histochemical demonstration of "hetero-beta-galactosidase" was elaborated. The enzyme is demonstrated in cryostat sections by the semipermeable membrane technique. Pairs of membranes--one pre-washed in saline--are used. The most sensitive method is post-coupling demonstration with 6-Br-2-naphthyl-beta-D-glucoside. The incubation time must be short, to avoid diffusion. The method allows cellular localization. The method with alpha-naphthyl-beta-D-glucoside and hexazonium-p-rosaniline is less sensitive, but localization is better. Indigogenic methods are the least sensitive. The enzyme is localized in the supranuclear zone of differentiated enterocytes of the human, monkey and rabbit small intestine, with maximum activity in the jejunum. The activity of the enzyme is low in patients with coeliac sprue, in the active phase of the disease. In isolated lactase deficiency it is normal. In the kidney, the enzyme is localized chiefly in the cytoplasm of the proximal tubule cells.

Immunohistochemical localization of intestinal glycosidases.

The presence of antigenic determinants of the following enzymes was detected in enterocytes by the indirect immunofluorescence method: 1. lactase in human biopsy material, 2. sucrase-isomaltase during ontogenesis in the rat. 1. Lactase: The antigenic relationship between rat and human lactase, demonstrated with the isolated enzymes, was utilized for the histochemical localization of human lactase. The indirect immunofluorescence method, using guinea pig antiserum to rat lactase, demonstrated the presence of human lactase in the enterocyte brush border. The usefulness of this method for clinical practice resides in the possibility of detecting enzymatically inactive protein immunologically related to lactase in cases of lactase deficiency, thereby facilitating more detailed classification of these diseases. 2. Sucrase-isomaltase: Guinea pig antiserum to rat sucrase-isomaltase (SI) was prepared. It was used to demonstrate antigenic determinants of the enzyme in the enterocyte brush border of the rat during ontogenesis. Structural SI protein is already present in 3-day-old rats, whereas enzyme activity can first be demonstrated histochemically from the 11th day of life and biochemically, in vitro, not until about the 18th day. We consider that this technique can be used for studying the biogenesis of membrane-bound enzymes.

Determination of pancreatic elastase with new chromogenic substrates-p-nitroanilides of N-acyltripeptides.

Mal-, Suc- and Glt-(Ala)3-NAp were prepared as new substances for determining pancreatic elastase. The kinetic constants show them to be more satisfactory than the previously described Ac-(Ala)3-NAp. The mean elastase output values after pancreozymin and secretin stimulation of the exocrine pancreas were significantly higher in the control subjects than in patients in whom other secretion values were altered. In agar electrophoresis, hog pancreatic elastase (Merck) formed a single cathodal fraction. One cathodal and one anodal fraction were found in human duodenal contents. Serum, plasma, alpha1-antitrypsin and alpha2-macroglobulin inhibit pancreatic elastase. Elastase-alpha1-antitrypsin complexes are enzymatically inactive, whereas the enzymatic activity of elastic-alpha2-macroglobulin complexes is partly preserved. Both types of complexes are stable and are not dissociated to a major extent in the presence of an excess amount of the other inhibitor.

[Positron emission tomography (PET) in patients with malignant lymphomas--indications for the method as presented in case reports]. / Vyuzití pozitronové emisní tomografie (PET) u nemocných s maligními lymfomy--indikace metody prezentované formou kazuistických sdelení.

Positron emission tomography is a modern functional imaging method recently available also in the Czech Republic. The authors try to present indications of this method in the form of case-histories of patients with malignant lymphomas.