High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension.

PURPOSE: To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. RESULTS: The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 ± 1.7 µg/L, (2) the normalized C(max) (C(max, norm)) 79.1 ± 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 ± 1.6 µg · h/L and (4) the normalized AUC (AUC(norm)) 261.6 ± 1.7 g · h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm). CONCLUSION: The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

Subspecies of Pleurota bicostella (Clerck, 1759) revisited and descriptions of nine new species in the P. bicostella species group (Lepidoptera: Gelechioidea: Oecophoridae: Pleurotinae).

The identities of five subspecies of Pleurota bicostella (Clerck, 1759) are studied, and each is raised from subspecies to species: P. andalusica Back, 1973, stat. nov.; P. aragonella Chrétien, 1925, stat. rev.; P. asiatica Back, 1973, stat. nov.; P. illucidella Chrétien, 1915, stat. rev.; P. lepigrei Lucas, 1937, stat. rev. Nine new Pleurota species which all belong to the P. bicostella species group are described: P. agadirensis Tabell, sp. nov.; P. aprilella Tabell, sp. n.; P. karsholti Tabell, sp. nov.; P. kullbergi Tabell, sp. nov.; P. monochroma Tabell, sp. nov.; P. murina Tabell, sp. nov.; P. paragallicella Tabell, sp. nov; P. phaeolepida Tabell, sp. nov., all from Morocco; and P. dalilae Tabell, sp. nov. from Tunisia. Adult males and females, and their genitalia are illustrated. DNA barcodes of the aforementioned species are compared with those of all other Pleurotinae available to us in the BOLD database. Each of the presented and barcoded species has a unique BIN (Barcode Index Number).

World apheresis registry 2003-2007 data.

OBJECTIVES: Seventy-five centers from many countries have applied for a login code to the WAA apheresis registry. Fifteen centers from 7 countries have been actively entering data at the internet site from 2003 until 2007. We report on data from the registry so far. METHODS: This is a web-based registry. A link is available from the WAA homepage (www.worldapheresis.org). So far data from 2013 patients (12,448 procedures) have been included. A median of 6 treatments have been performed (range 1-140). Mean age 51 years (range 1-94 years; 45% women). Seven percent of the patients were < or = 21 years and 4% were < or = 16 years. RESULTS: The purpose of the apheresis procedure was therapeutic in 67% and retrieval of blood components in 33%. Main indications: neurological and hematological diseases, lipid apheresis and stemcell collection (autologous, and some allogeneic). Blood access: peripheral vessels (71%), central dialysis catheter through jugular (6.5%) or subclavian veins (6.7%), femoral vein (8%) and AV fistula (4%). ACD was used for anticoagulation in 73% of the procedures. Albumin was mainly used as replacement fluid. Adverse events (AE) were registered in 5.7% of the procedures. AE was graded as mild (2.5%), moderate (2.7%) or severe (0.5%). No death occurred due to treatment. The procedures were interrupted in 2.6%. Most frequent AEs were blood access problems (29%), tingling around the mouth (20%), hypotension (18%), and urticaria (9%). There were significant differences between the centers regarding mild and moderate AEs. Data indicate that centers using continuous infusion of calcium had fewer AEs. CONCLUSION: There was a limited number of severe AEs. Centers use various standard procedures for apheresis. By learning from the experience of others the treatment quality will improve further. In the near future, an update of the registry will enable more extensive evaluation of the data.

Structural and functional integrity of chondrocytes immediately following isolation.

Chondrocytes were isolated from costal cartilage in young rats after digestion with collagenase and hyaluronidase. The immediate survival of the cells was investigated with the use of different criteria for viability, namely structural integrity and metabolic activity. Structural integrity was studied by transmission and scanning electron microscopy, trypan blue exclusion and NADH oxidation. Metabolic activity was measured both as O2 consumption and as proline and sulphate incorporation, as indicators of collagen and proteoglycan synthesis. The cellular content of glutathione was also measured. The chondrocytes isolated were found to be structurally intact and metabolically active. Early after isolation the chondrocytes varied considerably in size similarly to the native tissue. A selective loss of the larger sized cells was observed during further incubation for 24 h.

Kinetic studies on epiphyseal growth cartilage in the normal mouse.

The synthesis of DNA was studied in the proximal tibial growth plate of 25-day-old healthy NMRI mice by using the thymidine analog bromodeoxyuridine (BrdUrd), which is incorporated into cells in the S-phase. Such cells were found only in the upper three fifths of the morphologically defined proliferating zone. This zone was therefore subdivided into a functional proliferating zone (the S-phase zone) where most, if not all, chondrocytes proliferate, and a remaining maturation zone. The BrdUrd containing immunoreactive cells could then be followed at different intervals and they were found at the chondro-osseous junction after only 36 h. By using double-labeling with BrdUrd and iododeoxyuridine (IdUrd) the duration of cell cycle components could be estimated; that is, the time for DNA synthesis (S-phase), second gap and mitosis (G2 + M-phase), and remaining first gap (G1). We determined an S-phase time of 7.1 h and an average cell-cycle duration of 36 h. The G2 + M-phase was estimated as 3.5-4 h, leaving an average G1-phase time of 25 h, which probably varies considerably between chondrocytes. By combining these data with morphometrical data regarding distances between cells, we calculated a total growth rate of 9.0 microm/h. Of this rate, 80% was entirely related to the process of hypertrophy--that is, longitudinal expansion without any corresponding increase in cell number--and 75 % was the result of processes outside the S-phase zone. Five percent of the growth was due to the expansion of cell distances within the S-phase zone. In this way longitudinal expansion can be studied at different levels in the growth plate and the data permit calculation of changes in volumes of the extracellular matrix. The largest increases in matrix volume occurred in the hypertrophic zone. These data may serve as a basis for further studies on matrix turnover in relation to growth.

Blood viscosity and peripheral vascular resistance in patients with untreated essential hypertension.

OBJECTIVES: The viscosity of blood is increased in patients with essential hypertension. The aim of the present study was to investigate the importance of the different variables of blood rheology to total peripheral resistance, and to elucidate whether inappropriate regulation of the formation of erythropoietin could be important. DESIGN: Nineteen consecutive patients with untreated essential hypertension were examined and compared with a group of matched healthy volunteers. METHODS: The haemorheologic variables were assessed by rotational viscometry and the haemodynamic variables by bioimpedance cardiography. The serum concentrations of erythropoietin were determined by radioimmunoassay. RESULTS: The whole blood viscosity and peripheral resistance index were elevated in the hypertensive group. The two variables were positively correlated with each other (r = 0.68, P = 0.0015). The plasma viscosity and erythrocyte aggregation tendency were increased and the erythrocyte deformability, measured as fluidity, was decreased in the hypertensive patients. In the male subpopulation (n = 12) the aggregation tendency was positively, and the deformability negatively, correlated with body mass index. The serum concentrations of erythropoietin were equal in the two groups. CONCLUSIONS: The increased total peripheral resistance in patients with essential hypertension may in part be explained by an increased blood viscosity, but the possibility of an opposite cause-effect relationship must also be taken into consideration. The haemorheological abnormalities observed in the present patients cannot be explained by high serum levels of erythropoietin.

DNA content in primary tumours and lymph node metastases in colorectal adenocarcinoma.

In 18 consecutive patients operated on for colorectal carcinoma of Dukes' stage C, the DNA patterns were determined in multiple samples of the primary tumours and in all detected lymph node metastases. Single-cell microspectrophotometry on Feulgen-stained smears of fine-needle aspirates was used. When the most aggressive DNA pattern was considered representative, 12 primary tumours (67%) were designated as aneuploid. The frequency of aneuploidy among the metastases was almost the same (63%). In 15 cases (83%) the DNA patterns displayed by the metastatic lymph nodes were also found in the corresponding primary tumour, while in the remaining three cases (17%) the DNA pattern in the lymph node metastases was not seen in any of the multiple samples from the primary tumour. The observed tumour DNA heterogeneity may reflect either the multicellular origin of the tumour cells or the continuous evolution and progression of a neoplasm of unicellular origin, and may partly explain the dissimilarities between the DNA patterns of the primary tumour and the lymph node metastases. Biopsy samples from a number of metastatic lymph nodes are therefore required to ensure representativeness and to permit an adequate analysis of the prognostic role of the DNA ploidy status in lymph node metastases from colorectal cancer.

Crystal inhibition: the effects of polyanions on calcium oxalate crystal growth.

The inhibition of calcium oxalate crystal growth by the glycosaminoglycans, chondroitin sulphates and heparin, by the low-molecular-weight heparin analogue pentosan polysulphate and by Tamm-Horsfall glycoprotein extracted from human urine, was measured by using a seeded crystal procedure and compared with the inhibition by pyrophosphate. It was found that the most pronounced inhibition was obtained with the polyanions with the highest charge density, i.e., heparin and pentosan polysulphate. Tamm-Horsfall glycoprotein caused an inhibition of a similar magnitude as urinary chondroitin sulphates. Urinary polyanions with a high affinity to Sepharose 4B were more efficient inhibitors than those with a low or no affinity to the gel. It is concluded that urinary polyanions are important inhibitors of calcium oxalate crystal growth and that the potency of inhibition increases with the charge density.

Continuous arteriovenous hemofiltration in the treatment of 100 critically ill patients with acute renal failure: report on clinical outcome and nutritional aspects.

The clinical outcome for 100 consecutive patients with multiorgan failure including acute renal failure (ARF) was studied. Fifty-eight of the patients had acute renal failure due to complications during and after major surgery. Seventy-three of the patients had a urine output of less than 400 ml/24 hours. The majority of the patients also had complications such as septicemia or respiratory insufficiency and required vasopressor infusions. All patients were treated with continuous arteriovenous hemofiltration (CAVH). The duration of the CAVH treatment varied between a few hours and 90 days, with a mean of 8 days. The mean ultrafiltration volume per 24 hours was, on the average, 12 liters. CAVH resulted in adequate uremic control in 89 cases, but additional treatment with intermittent hemofiltration was necessary in 11 patients. The total survival rate was 45% including survival rates as high as 54% in patients with ARF complicating abdominal aortic surgery. Only three patients were referred for chronic dialysis therapy. In a subgroup of 17 patients with ARF complicating abdominal aortic surgery the nutritional aspects during CAVH were studied. It is concluded that during CAVH therapy it is possible to give adequate nutritional support even to hypercatabolic and anuric patients.

Outcome of renal transplantation in patients treated with erythropoietin.

The introduction of treatment with recombinant human erythropoietin (rhEPO) has raised the possibility of deleterious effects on early kidney graft function. Due to renal anemia, the great majority of patients waiting for kidney transplantation until now have had a low hematocrit. It has been suggested that a low hematocrit is beneficial for early kidney graft function by protecting the transplanted kidney from so-called reperfusion damage, which results in delayed onset of renal function. We have retrospectively examined the early function of 26 kidney grafts transplanted to uremic patients with rhEPO corrected anemia. Compared with a randomized control group no significant differences were seen in the rate of immediate onset of graft function, graft survival or serum levels of creatinine one year after transplantation. We conclude that the reversing of anemia by rhEPO in recipients of cadaver kidneys does not impair early graft function.

Pharmacokinetics of intravenous cefuroxime during intermittent and continuous arteriovenous hemofiltration.

The pharmacokinetics of cefuroxime were determined in ten patients during intermittent hemofiltration (IHF) and in three patients during continuous arteriovenous hemofiltration (CAVH). All patients received a bolus dose of 1.5 g of cefuroxime intravenously and the concentrations of cefuroxime in serum and ultrafiltrate were followed during the hemofiltration period and up to 16 hours after injection of cefuroxime. During IHF the mean terminal half-life of cefuroxime was 1.6 +/- 0.3 hours compared with a terminal half-life of 21.7 +/- 5 hours after treatment. The total cefuroxime clearance was 120 +/- 22 ml/min. The hemofiltration clearance represented 86% of the total clearance and the hemofiltration process removed in average 63% of the dose. During CAVH the terminal half-life of cefuroxime was 7.9 +/- 2.2 hours. The total plasma clearance for cefuroxime was 32 +/- 7.5 ml/min where the CAVH-treatment represented only 34% of the total clearance. From these data we suggest that a full loading dose (1.5 g of cefuroxime) should be given after each intermittent hemofiltration treatment when performed every second day. In CAVH, where nonrenal clearance will influence the dosage scheme significantly, we suggest an initial dose of 1.5 g of cefuroxime to be followed by a supplementary dose of 750 mg every 20-24 h.

Acute effects of whole-body vibration. Stabilography and electrogastrography.

The influence of whole-body vibration on postural control and stomach motility was investigated. Fifteen subjects were exposed to two vibration signals (3 and 6 Hz random) while sitting for 1 h on a vibration simulator. A control situation, ie, sitting for 1 h without vibration, was also included. Stabilographic recordings before and 1 and 15 min after the sitting showed that exposure to these frequencies had no effect on postural control. Electrogastrographic (EGG) measurements before and during the sitting showed that, for 3 Hz, there was an initial increase in activity which decreased towards normal values. For 6 Hz there was a significant increase in activity for EGG frequencies of 0.05 and 0.13 Hz. The results imply that stomach motility can be affected by whole-body vibration in certain frequency ranges.

Plasminogen receptors. Turning Salmonella and Escherichia coli into proteolytic organisms.

We evaluated in vitro the hypothesis that bacterial adhesiveness to the mammalian extracellular matrix and the activation of plasminogen on bacterial plasminogen receptors promote bacterial penetration through basement membranes. We used the strain SH401 of Salmonella enterica serovar Typhimurium, which adheres to the high-mannose chains of laminin, a major glycoprotein of basement membranes, and expresses plasminogen receptors. Bacterium-bound plasmin was able to degrade laminin and extracellular matrix preparations as well as to potentiate the penetration of bacteria through a reconstituted basement membrane. The results suggest that metastatic tumour cells and bacterial pathogens use similar mechanisms to penetrate through tissue barriers.

Plasmapheresis in HLA-immunosensitized patients prior to kidney transplantation.

Immunosensitization against the human lymphocyte antigen (HLA) is a problem in most transplant centers. It prolongs the waiting list time in addition to risk of frequent acute rejections. To avoid these problems, various pretransplantation approaches have been attempted e.g. plasmapheresis (PP). The present retrospective study reports our experience with PP in this respect over a 5 year period. Twenty-three chronic hemodialysis patients with circulating panel reactive antibodies (> or = 50%) and previous kidney graft rejections were treated with 12 PP each. In addition to this, immunosuppression with cyclophosphamide and prednisolone were administered on the first day of PP and after tapering continued until transplantation. HLA-antibodies, as measured by the panel reactive antibodies and the antibody titer, decreased from about 70% to 30% (p < 0.001) and 5 steps of titerdilution, respectively with PP and immunosuppressive drugs; Twenty-two patients were transplanted with cadaveric grafts. Eight grafts were lost due to irreversible rejection, and one due to the patient's death 2 months after transplantation. The cumulative five-year graft survival at the time of follow-up was 59%. Adequate kidney function (serum creatinine mean 150 mumol/l) was observed in all grafts (n = 3) still functioning 60 months posttransplant. We conclude that pretransplantation plasmapheresis together with immunosuppressive drugs (cyclophosphamide and prednisolone) is useful in the removal of HLA antibodies in immunized patients awaiting kidney transplantation. It can be considered a valuable approach to increase the chances of successful transplantations.

Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study.

A therapeutic removal of antibodies may be achieved by immunoadsorption (IA) or by plasma exchange (PE). The aim of this prospective randomised study was to compare the efficacy of these different techniques with regard to treatment of patients with rapidly progressive glomerulonephritis (RPG) having at least 50% crescents. Forty-four patients with a RPG were included for treatment either by IA or PE (with albumin as substitution for removed plasma). All patients were additionally treated with immunosuppression. A median of 6 sessions of PEs were performed in 23 patients compared with 6 IAs in 21 patients. Goodpasture's syndrome (GP) was present in 6 patients (PE 3, IA 3). All of them started and ended in dialysis, two died. Among the remaining 38 patients (26 men, 12 women) 87% had antibodies to ANCA. Creatinine clearance for PE versus IA were at a median at start 17.1 and 19.8 ml/min, and at 6 months 49 and 49 ml/min, respectively. At 6 months 7 of 10 patients did not need dialysis (remaining: IA 0/5 and PE 2/5, n.s.). The extent of improvement did not differ between the groups. Three patients died during the observation period of 6 months (IA 2; PE 1, on HD). Although no difference was found between the IA or the PE group this study shows that the protocol used was associated with an improved renal function in most patients (except for Goodpasture's syndrome) whereas 70% of them could leave the dialysis program.

Calcium acetate used as phosphate binding treatment in uremic hyperphosphatemia.

Due to toxic side effects of aluminum-containing agents for treatment of uremic hypophosphatemia, much interest has been focused upon aluminum-free phosphate binder alternatives. From results of experimental studies with calcium acetate, this salt has been suggested as a possible effective and safe phosphate binder. In the present study, calcium acetate was used during a mean of 11 months for serum phosphate control in 30 uremic patients previously treated with aluminum and/or calcium carbonate. Satisfactory control of serum phosphate was achieved during the study (mean phosphate concentration +/- SE: 2.15 +/- 0.12 mmol/l compared to prestudy 2.23 +/- 0.19 mmol/l). Mean serum concentrations of calcium, alkaline phosphatase and parathyroid hormone did not change significantly during the study. Serum aluminum decreased significantly (p less than 0.01). Moderate hypercalcemia was observed in 6 patients. Calcium acetate treatment was withdrawn in 2 patients due to gastrointestinal discomfort. It is concluded that calcium acetate seems to be an effective phosphate binder alternative with relatively few side effects.

Continuous peritoneal dialysis in children with acute renal failure.

Continuous peritoneal dialysis (CPD) was performed in 13 children with acute renal failure (ARF) in our intensive care units (ICU). The median age was 6 months (range 3 days to 77 months). Sixty-nine percent of the patients (9/13) were below the age of 12 months. CPD was performed for a median duration of 5 days (range 1-35 days). In 62% of the patients (8/13), the cause of ARF was acute tubular necrosis (ATN) due to cardiac surgery. The outcome of CPD regarding total survival was 54% (7/13). A high mortality was registered (83% of the deaths [5/6]) within the first year of life, which suggests a worse prognosis if ARF occurs at this age. Half of the total deaths (3/6) were among the cardiac surgery patients. Peritoneal equilibration tests (PET) were performed utilizing measurement of urea and glucose transport through the peritoneal membrane at short intervals during a period of 45-60 min from the start of treatment. Short dwell times of 5-20 min were found to be sufficient for adequate uremic control until a satisfactory daily urine production was noted. CPD is a useful and simple treatment modality for ARF in critically ill ICU children. Equilibration tests are useful and should be considered for optimization of CPD treatment in critically ill children with ARF in order to achieve the goal of controlling uremia and fluid overload, and giving nutritional support.

Outcome of continuous arteriovenous haemofiltration (CAVH) in one centre.

Continuous arteriovenous haemofiltration (CAVH) has been adopted as the treatment of choice for acute renal failure (ARF) in critically ill patients in the intensive care units of Uppsala University Hospital since 1982. To know the outcome of CAVH during the last one and a half year this retrospective study was done on those patients seen in July 1987-December 1988. Forty patients aged 2 months-84 years (mean 57 years) were included. Treatment duration was 1-31 days (mean 10 days, patients with treatment duration less than 24 h were excluded). The majority of ARF causes were due to major surgery because there are two big cardiothoracic and vascular surgical centres with a high turnover in this hospital. In this study CAVH was found useful in the management of ARF in critically ill patients within the limits of its capacity of urea clearance. There is a notable improvement in the number of survivors in this study (55%) when this is compared to a previous study (45%) in a similar group of patients and in the same centre.

Treatment of acute renal failure in intensive care patients by continuous arteriovenous hemofiltration (CAVH): two years' experience in two centres.

The study objective was to evaluate the outcome of continuous arteriovenous hemofiltration (CAVH) as a first choice treatment for acute renal failure (ARF) in critically ill intensive care patients in two centres with a long experience in the field of continuous renal replacement therapies. Sixty consecutive intensive-care ARF patients from Uppsala Centre and 71 consecutive ARF patients from Vicenza Centre were included during a period of two years. Their age range was 58 +/- 16 and 52 +/- 15 years in Uppsala and Vicenza, respectively. CAVH was performed in the postdilution form using different types of hemofilters. Three choices of vascular access were utilised in each centre, namely: the Buselmeier shunt, femoral vessel catheter and the Scribner shunt. The pre-treatment serum urea level (mean +/- SD) in the Uppsala patients (30 +/- 14 mmol/l) was significantly higher (p < 0.001) than that of the Vicenza patients (17 +/- 10 mmol/l). The Uppsala patients had a longer treatment duration than the Vicenza patients; 8 +/- 6 vs 5 +/- 5 days (p < 0.05) perhaps because they were much older than the Vicenza patients (p < 0.05) in addition to their multi-organ failure. However, the total outcome of CAVH in the two centers was not significantly different (52 and 58% patient's survival in Uppsala and Vicenza, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Tubular proteinuria in renal calcium stone formers.

The incidence of tubular proteinuria measured as urinary excretion of beta 2-microglobulin was evaluated in 68 consecutive renal calcium stone formers, 14 of whom had impaired urinary acidification capacity. During normal conditions 13% of these stone formers had tubular proteinuria. There was no statistical difference in the incidence of tubular proteinuria between subgroups with proximal or distal acidification defects. During transient metabolic acidosis induced by an ammonium chloride load a pronounced increase in beta 2-microglobulin excretion was noticed in all patient groups but especially in those with urinary acidification defects. In stone formers with normal acidification capacity the degree of acidosis-induced beta 2-microglobulinuria was moderate but a small group of patients exhibited a large urine excretion of beta 2-microglobulin. This finding may reflect a latent tubular defect of importance for stone genesis.