Haemodynamic and renal effects of urodilatin in healthy volunteers

Urodilatin (ANF(95-126)), an analogue of the atrial natriuretic factor (ANF(99-126)), has recently been isolated from human urine. To study haemodynamic and renal effects of synthetic urodilatin, 18 healthy male volunteers (age 26.1 +/- 0.8 years; X +/- SEM) received i.v. bolus injections of urodilatin at doses of 1, 2 or 4 micrograms kg-1 body weight (bw) (n = 6 per dosage group). Urodilatin dose-dependently increased heart rate and cardiac index. A dose-dependent increase in plasma cyclic GMP levels was also observed. Urinary cyclic GMP excretion, urine flow and natriuresis increased 7-fold, 5-fold and 4-fold, respectively. Renal effects were not different between dosage groups. Compared with ANF(99-126), after urodilatin the reduction in mean pulmonary arterial pressure (PAP) was more pronounced (2 micrograms kg-1, n = 6; ANF -1.8 +/- 0.5, URO: -5.5 +/- 1.1 mmHg, P less than 0.05). Furthermore, after urodilatin the reduction of PAP lasted continuously from 2 up to 90 min after injection, while ANF(99-126) produced only a transient decrease of PAP. Similarly the reduction of pulmonary capillary wedge pressure (PCWP) by urodilatin from 9.3 +/- 1.2 to 3.8 +/- 0.9 mmHg (P less than 0.05) was also sustained up to 90 min post administration. These data in healthy volunteers suggest that, due to prolonged reduction of PAP and PCWP with increases of cardiac index and reduction of systemic vascular resistance, urodilatin might exhibit beneficial effects in cardiovascular disease.     

Three-Year Experience with a Stylet for Lead Extraction: A Multicenter Study

The extraction of chronically implanted and infected pacemaker and defibrillator leads is an important issue. This article describes the experience gathered between 1990 and 1994 by seven European centers regarding a locking stylet that is uniformly applicable for a wide variety of internal pacing coil diameters. This interventional locking stylet for lead extraction has an outer diameter of 0.4 mm (0.016 inches). The stylet consists of a hollow shaft in which an inner traction wire is embedded. At the tip of the inner traction wire an anchoring mechanism, which can be opened by retraction, is applied. Removal attempts were made for 150 leads, 110 in ventricular and 40 in atrial positions. Results : Complete removal was possible in 122 cases (81 %). Partial removal was possible in 18 cases (12%). Failure to remove the lead with the extraction stylet was experienced in 10 cases (7%). In seven patients, the leads were removed by cardiothoracic surgery; 3 defective leads were left in place. There were no serious complications associated with the procedure. None of the patients died. Conclusion : The experience with this extraction stylet for lead removal has shown good results. Despite a low complication rate thus far, each case for lead removal should be judged on the individual basis of benefit-to-risk ratio.     

Biopharmaceutics: Submicron Oil-in-water Emulsion Formulations for Mefloquine and Halofantrine: Effect of Electric-charge Inducers on Antimalarial Activity in Mice

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine. The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg^?1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg^?1 for dicetylphosphate, 17 mg kg^?1 for phosphatidylserine, 23 mg kg^?1 for oleic acid and 27 mg kg^?1 for stearylamine, again after subcutaneous administration. This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.     

The fusion of TEL and ABL in human acute lymphoblastic leukaemia is a rare event

We have recently identified a common ALL patient which harboured a chromosomal fusion between the TEL gene on chromosome 12 and the ABL gene on chromosome 9. We designed an RT-PCR assay to screen 186 adult ALL and 30 childhood ALL patients for this novel translocation. We were unable to identify any additional cases with a TEL/ABL fusion product.     

Expression of intercellular adhesion molecule 1 (ICAM-1) in childhood acute lymphoblastic leukaemia: correlation with clinical features and outcome

To investigate whether expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in childhood acute lymphoblastic leukaemia (ALL) has an impact on the biological behaviour of the disease, we evaluated 751 children of the ALL-BFM 90 trial with B-cell precursor- ( n  = 6777) or T-cell-ALL ( n  = 74) for CD54 expression within immunological subgroups, its correlation to certain clinical features, and therapy outcome.
The highest percentage of patients expressing CD54 was found in common- and pre-B-ALL (76.1% and 61.4%, respectively). There was intermediate expression in pre-pre-B-ALL (47.8%), and the lowest expression was detected in T-ALL (12.2%).
A significant positive correlation could be demonstrated between low CD54 expression (< 20% stained blasts) and high peripheral leucocyte counts, central nervous system (CNS) involvement, and splenomegaly at the time of diagnosis ( P  < 0.01). In addition, CD54 expression was a favourable but not independent prognostic factor. Event-free survival estimate at 4.5 years was 86% for CD54⁺ patients ( n  = 463), compared with 78% for CD54⁻ patients ( n  = 241) ( P  < 0.01). These findings demonstrate that CD54 expression has an impact on dissemination patterns and outcome of childhood ALL, and emphasizes the potential relevance of adhesion mechanisms in influencing clinical characteristics and prognosis of haematological malignancies.     

STUDIES ON THE COSUBSTRATE SITE OF PROTEASE SOLUBILIZED NADPH-CYTOCHROME P450 REDUCTASE

Modification of the protease solubilized NADPH-cytochrome P450 reductase (= NADPH-cytochrome c reductase) at the critical SH group in the cosubstrate binding site affects K^NADPH_m but not V for the cytochrome c reduction. The increase of K^NADPH_m is dependent on the size and the charge of the substituent introduced. Substitution of the cosubstrate site SH by the CN-, S₂ O₃- and the (N-ethyl) succinimido group effects a 3-, 7- and 23-fold increase of K^NADPH_m respectively. The critical SH group in the NADPH binding region can be specifically radiolabeled by N-ethyl (2,3-¹⁴C) maleimide after preincubation of the reductase with unlabeled NEM in the presence of 1 mM NADP+. The selective reaction at the essential cysteine in the cosubstrate site is demonstrated by peptide mapping of the thermolytic digest and urea SDS gel electrophoresis of the cyanogen bromide fragments of the reductase. Protease solubilized NADPH-cytochrome P450 reductase is inactivated by reagents directed to histidine, orginine and lysine residues. NADP (H) (1 mM) and 2′-AMP (1 mM) give effective protection only for the reaction of 1, 2-cyclohexanedione (12 mM). The functional role of the basic amino acid residues for the cosubstrate binding by the NADPH-cytochrome P450 reductase cannot be established therefore by the modification experiments described. The number of NADPH binding sites in the NADPH-cytochrome P450 reductase is determined to one site/mol reductase by titration of the enzyme with NADP+ monitored by CD-spectroscopy.