Furosemide and spironolactone reduce transmigration of leukocytes through endothelial cell monolayers

Furosemide and spironolactone reduce transmigration of leukocytes through endothelial cell monolayers. Leukocytes play a tremendous role during inflammation. Leukocytes migrate from intravascular space into the tissue to attack microorganisms. Various agents are able to influence leukocyte recruitment. The influence of diuretics, such as furosemide and spironolactone, on inflammatory processes is not well known. The aim of our study was to examine the influence of furosemide and spironolactone on leukocyte migration through endothelial cell monolayers (ECM). Human umbilical vein endothelial cells were cultured on microporous membranes achieving a monolayer. Polymorphonuclear leukocytes (PMNL) were used in a currently described migration assay. PMNL and/or ECM were pretreated with furosemide and spironolactone using therapeutic, as well as higher and lower, concentrations. Furosemide (76 +/- 7.2%) and spironolactone (70 +/- 7.7%) were able to inhibit PMNL migration through ECM significantly, when both cell types were treated simulating the situation after an iv injection. Furosemide and spironolactone were identified as potent inhibitors of leukocyte migration through ECM.     

Safety and efficacy of molgramostim as an adjunctive therapy in critically ill patients with severe sepsis

The aim of this uncontrolled, prospective, clinical study was to investigate the efficacy and safety of molgramostim administration in patients with severe sepsis. The subjects were 20 critically ill, mechanically ventilated patients with severe sepsis in a university intensive care unit (ICU). Molgramostim 300 microg s.c. was given every 12 h for 3 d. Treatment for severe sepsis was also administered as medically indicated. No adverse events (clinical or serum chemistry) were considered as drug related. Temperature (p = 0.334) and PaO2/FiO2 index (arterial oxygen tension/inspiratory oxygen fraction) (p = 0.178) were not significantly changed. Total leukocyte and neutrophil count increased significantly (p < 0.001) during drug administration. Simplified Acute Physiology Score II (SAPS II) was not significantly increased (p = 0.955), but there was a statistically significant decrease (p = 0.006) in Sepsis-related Organ Failure Assessment (SOFA) score. Death probability was not statistically different compared with mortality rate on day 28 and overall mortality (p = 0.238 and 0.700, respectively). There were statistically significant decreases (p < 0.01) in serum tumor necrosis factor-alpha (TNF-alpha), TNF-RII and interleukin-2 (IL-2), and an increase in TNF-RI levels between study entry and day 3. Mean ICU stay was 40.2 +/- 7.7 d. In conclusion, molgramostim administration may not affect serum chemistry and PaO2/FiO2 index, may decrease SOFA score but does not produce significant clinical benefit in terms of patients' outcome compared with death probability. It may also influence TNF-alpha, TNF-RI and TNF-RII serum complex levels. These changes may be attributed to the natural clinical course of sepsis or therapy applied.     

A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer previously treated with a cisplatin-based front line chemotherapy

PURPOSE: CPT-11 and gemcitabine are both active agents against non-small cell lung cancer (NSCLC). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of their combination in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Twenty-seven patients with histologically confirmed NSCLC, who had failed cisplatin-based front-line chemotherapy, were enrolled. The patients' median age was 56 years, 24 were male and 22 had a performance status (WHO) 0-1. Gemcitabine was administered on days 1 and 8, as a 30-minute i.v. infusion, at escalated doses ranging from 900 to 1200 mg/m2. CPT-11 was given over a 60-minute i.v. infusion on day 8 at escalated doses ranging from 200 to 350 mg/m2, following gemcitabine administration. The treatment was repeated every three weeks. RESULTS: The MTD was exceeded at dose-level 7 with CPT-11 350 mg/m2 and gemcitabine 1200 mg/m2, where all three enrolled patients presented DLTs (one patient grade 4 thrombocytopenia, one grade 3 diarrhea and one grade 3 asthenia). The recommended doses for future phase II studies are CPT-11 300 mg/m2 on day 8 and gemcitabine 1200 mg/m2 on days 1 and 8. A total of 107 treatment cycles were administered. Grade 3/4 neutropenia was observed in 13 (13%) cycles, febrile neutropenia in 3 (3%) and grade 3/4 thrombocytopenia in 2 (2%). Grade 2/3 diarrhea was seen in 6 (6%) cycles, grade 2/3 nausea and vomiting in 13 (13%) and grade 2/3 asthenia in 8 (8%). Other toxicities were mild. Among 23 patients evaluable for response, PR was achieved in one (4.5%), SD in 12 (52.5%) and PD in 10 (43%). CONCLUSION: The results of this phase I study clearly demonstrate that gemcitabine and CPT-11 can be efficiently combined in a low-toxicity regimen with doses equal or near monotherapy levels. Further studies are needed to evaluate the efficacy of this combination in both chemotherapy-naive and pre-treated patients with advanced NSCLC.     

Effect of human hydrosalpinx fluid on the development of mouse embryos and role of the concentration of growth factors in culture medium with and without hydrosalpinx fluid.

The aim of this study was to investigate the effect of human hydrosalpinx fluid (HF) on the development and blastulation of mouse embryos and the role of the concentration of growth factors in culture medium with and without HF. In total, 2100 mouse embryos were cultured. Female mice were induced to superovulate and then mated with males. Two-cell-stage embryos were recovered from the oviduct and cultured in Ham's F-10 medium with bovine serum albumin and HF. Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) were analyzed by quantitative enzyme immunoassay. Mean blastulation index of 1.11, 0.97 and 0.98 was found at HF concentration of 5%, 20% and 30%, respectively (p = 0.8). The mean value of EGF in the control culture medium without HF was 11.2 pg/ml, which was statistically significantly different from that in culture medium containing HF (p < 0.001). The mean value of IGF-I in the control group without HF was 1.30 pg/ml and was not statistically significantly different from that in culture medium containing HF. Development of the two-cell-stage embryos was not affected at low (< 30%) HF concentrations. In conclusion, the present study demonstrates that even apparently normal blastulation is affected by any concentration of HF because of low embryonic EGF.     

Stapled Hemorrhoidectomy Under Local Anesthesia: Tips and Tricks

Stapled hemorrhoidectomy—a new, evolving technique—is considered to be safe and painless. General and spinal anesthesia are the “gold standard” anesthetic techniques for the procedure. The stapled hemorrhoidectomy under local anesthesia is described. Emphasis is given in few tips and tricks for safe and successful application of the local anesthesia.     

Arg16 homozygosity of the beta2-adrenergic receptor improves the outcome after beta2-agonist tocolysis for preterm labor

BACKGROUND: Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor. METHODS: Sixty white women with preterm labor between 24 and 34 weeks' gestation were treated for 48 hours with intravenous hexoprenaline. The effect of tocolysis and outcome of pregnancy were recorded. The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined. A control group of 116 women delivered at term was also genotyped. RESULTS: Preterm labor was not associated with beta(2)AR genotype at codon 16 (17% of patients with preterm labor were Arg16 homozygotes versus 19% of control subjects) or codon 27. Gestation was significantly prolonged in Arg16 homozygotes (median, 69 days; interquartile range, 63-79 days) compared with the other 2 genotypes (median, 58 days; interquartile range, 2-72 days) (P = .04). Tocolysis was 100% successful in delaying delivery for 48 hours in Arg16 homozygotes (n = 10), just failing to achieve statistical significance (P = .069). In contrast, only 37 of 50 women carrying 1 or 2 glycine alleles (74%) had delivery delayed by more than 48 hours with tocolysis. Neonatal outcomes were significantly better in babies born to mothers homozygous for arginine than in women with 1 or 2 Gly16 alleles. CONCLUSIONS: This is the first study examining the pharmacogenetics of beta(2)AR agonist therapy for preterm labor. It appears that Arg16 homozygosity improves pregnancy outcome after beta(2)-agonist tocolysis. The relatively low frequency of Arg16 homozygotes in our population limited the power of this investigation. Future assessments of tocolytic therapy may need to assess beta(2)AR genotype.