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Purpose: In the absence of specific recommendations on blood transfusion in elderly subjects, we carried out a survey to assess transfusion practices in geriatric medicine., Methods: A descriptive, national, cross-sectional survey was conducted in 14 French geriatric departments (12 teaching hospitals and two general hospitals). In each department, five patients receiving transfusions were randomly selected in order to analyze their characteristics, the indications of blood transfusion, the criteria for and the methods of transfusion compared with Afssaps recommendations on transfusion thresholds., Results: Data were analyzed for 70 patients (mean age 86+/-7 years, sex ratio female to male 1.8, with an average of five+/-two pathologies and six+/-three treatments). The indicators of poor tolerance included confusion (23 %), somnolence (22 %), acute heart failure (17 %) or coronary heart disease (16 %), and differed from the Afssaps criteria in the majority of cases. The transfusion threshold that were considered in the absence of poor tolerance (45 % of transfusions) differed from that recommended by Afssaps in 26 % of cases. The main adverse event in transfusion recipients was heart failure., Conclusion: When criteria for poor anaemia tolerance or transfusion thresholds are considered, transfusion practices in geriatric subjects have specific features. Further studies are needed to validate the appropriateness of the practices described in this survey.

We recently showed in a rat model of dichromate-induced acute renal failure (ARF) that the elimination but not the distribution of pralidoxime was altered resulting in sustained plasma pralidoxime concentrations. The aim of this study was to compare the efficiency of pralidoxime in normal and acute renal failure rats against paraoxon-induced respiratory toxicity. Ventilation at rest was assessed using whole-body plethysmography after subcutaneous administration of either saline or paraoxon (50% of the LD(50)), in the control and ARF rats. Thirty minutes after administration of paraoxon, either saline or 50mg/kg of pralidoxime was administered intramuscularly. ARF had no significant effects on the ventilation at rest. The effects of paraoxon on respiration were not significantly different in the control and ARF group. Paraoxon increased the total time (T(TOT)), expiratory time (T(E)) and tidal volume (V(T)), and decreased the respiratory frequency (f). In paraoxon-poisoned rats with normal renal function, pralidoxime had a significant but transient effect regarding the T(TOT) and V(T) (p<0.05). In the ARF group, the same dose of pralidoxime significantly decreased the T(TOT), T(E), and V(T) and increased f during 90 min (p<0.01). In conclusion, pralidoxime had partial and transient effects towards paraoxon-induced respiratory toxicity in control rats; and a complete and sustained correction in ARF rats.

There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague-Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received pralidoxime methylsulfate (50mg/kg of pralidoxime base) intramuscularly. Blood specimens were sampled during 180min after the injection. Urine was collected daily during the 3 days of the study. Plasma pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of pralidoxime.

Imatinib (Glivec, Gleevec, STI571) is a small tyrosine kinase inhibitor that is currently in phase II clinical trials in patients with recurrent glioblastoma. Its therapeutic benefit is minimal, although it is greater in some patients when combined with hydroxyurea. Imatinib is transported by human and rodent ATP-binding cassette (ABC) transporters like P-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP). We have investigated whether ABC transporters determine the pharmacokinetics of imatinib and its pharmacological active metabolite CGP74588 in rat C6 glioma cells. ABC transporter expressions were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). C6 cells express high concentrations of the Pgp-encoding gene Mdr1b and a 10-fold smaller amount of the Pgp-encoding gene Mdr1a. The relative expression of ABC transporter genes are: Mdr1b>Mrp4>Mrp1>Mrp5>Mdr1a>Mrp3>Mrp2>Bcrp. The accumulation of imatinib into C6 cells increased linearly with the extracellular concentration of imatinib (0.5-50microM) and was not increased by zosuquidar (selective Pgp inhibitor) or elacridar (inhibitor of both Pgp and Bcrp). In contrast, there was less CGP74588 than imatinib in C6 cells and its concentration increased with the extracellular concentration in a sigmoid fashion. Lastly, 10microM valspodar (selective Pgp inhibitor), elacridar and zosuquidar all increased the accumulation of CGP74588 by 2.5-fold. Thus CGP74588 is readily transported by the Pgp in rat C6 gliomas cells, which raises the question of the role of Pgp in the resistance of recurrent glioblastomas to imatinib.

It has been shown that some cytochrome P450-dependent enzyme activities could present daily fluctuations, particularly CYP3A isoenzymes which are enhanced during the dark period. The aim of this study was to investigate whether age and photoperiodic conditions at different circadian stages could influence these fluctuations. Young mature (10 weeks) and old (22 months) Wistar rats were initially exposed to light-dark cycles 12:12 during 4 weeks, and secondly 18:6 for either one week or six weeks. Erythromycin N-demethylase (CYP3A-dependent), 7-ethoxycoumarin O-deethylase (CYP1A-dependent) and aniline 4-hydroxylase (CYP2E-dependent) activities were determined in liver and kidney microsomes at different hours after darkness onset (HADO). In addition, liver and kidney GSH, GSHPx, ATP, TBARS were determined. During the LD 12:12 cycle, while no significant modification was observed in CYP1A- and 2E-dependent enzyme activities as functions of HADO, erythromycin N-demethylase activity (CYP3A-dependent) showed a significant increase during the second third of the dark period in both young and old rats. After switching to a LD 18:6 cycle, this variation was still observed during second third of the dark period, to a lesser but still significant degree, with no difference between one week and six weeks exposure to the new photoperiod. It can be noted that the old rats showed a significantly lower level of erythromycin N-demethylase activity than the young rats, in parallel to a decrease in GSH, GSHPx and ATP, and an increase in TBARS. These results confirm the lower resistance of old animals to oxidative stress. The observed variations in metabolism parameters underline the need for study designs in pharmaco-toxicology taking into account the possible risks induced by circadian changes, especially in aged subjects.

Purpose: Atrial fibrillation and venous thromboembolism are particularly frequent in the elderly. Whether or not prescribe oral anticoagulant treatment in the elderly is therefore a common question for the physician. Despite the benefits of anticoagulation demonstrated in clinical trials, oral anticoagulant therapy is underused in the elderly., Current Knowledge and Key Points: Indications for oral anticoagulation are discussed specifically in the elderly with a literature review. Only the length of anticoagulation treatment after a venous thromboembolism remained a purpose of discussion regarding the severity of the pathology. The frequency of systemic thromboembolism in nonvalvular atrial fibrillation is increasing with age. Oral anticoagulation reduces this risk. This benefice is to compare with the increasing rate of major bleeding complications in the elderly and in patient who had stroke, hyper-tension, diabetes mellitus or gastrointestinal bleeding. The objective of this article is to focus on the mode to measure oral anticoagulant benefice/risk ratio in the elderly and to propose several ways to minimize the risk for bleeding., Future Prospects and Projects: The potential drug side effect severity of oral anticoagulation must lead to find the "reasonable" clinical indications in term of benefice/risk ratio and what measures should be take to increase the safety of oral anticoagulation in the elderly. The comprehensive geriatric evaluation should be considered as a decision-aid tool in long-term oral anticoagulation in the frail elderly. Anticoagulation clinics, informatics'-prescription coupled with dose-adaptation decision-aid adapted to the elderly should be helpful in this research of quality. Finally, prescribers education supports must insist on the early course of therapy that is at higher risk of bleeding.

Purpose: Only leprosy resource centres undertake surgery for neuritis. Patients' accessibility to this surgical procedure is poor because these centres are often far from their homes. The aim of our work is to study the feasibility of neuritis surgery in the field., Methods: A surgeon trained in this surgery was recruited by Bom-Pastor hospital in Brazilian Amazonia, which is located 400 km away from the leprosy resource centre. Patients operated from May 1996 to December 1997 were enrolled in this retrospective study., Results: A total of 45 operations were carried out during 17 procedures on 13 patients, among which 12 were multibacillary cases. The decompression surgery was performed with a median delay of 1 year after leprosy diagnosis and 3.5 months after the neuritis diagnosis. Among 17 operations, 14 were performed for painful neuritis of recent onset unsuccessfully treated with corticoids or recurring during the month after corticoids were withdrawn. The other three operations were performed for long-standing neuritis with paralysis and deformity. Pain was relieved in all the cases of recent neuritis, except for one patient who suffered from a serious steroid-dependant erythema nodosum leprosum. An improvement of motor function was observed in one out of three patients with long-standing neuritis. Adverse effects were few: a scar infection with a rapid recovery and a keloid scar. Two neurites recurred 2 and 10 months after the surgery., Conclusions: In an endemic leprosy region, field access to surgery for neuritis appears to prove real progress in the management of leprosy neuritis.

Introduction: Primitive thoracic empyema or empyema secondary to pneumonia represents a significant medical problem necessitating prolonged hospitalizations and increasing the rates of morbidity and mortality. Average patient age is 55 years and remains rare in very old patients (> 85). We report here two observations in very old patients, pointing out the diversity of the clinical presentation., Exegesis: Empyema thoracis is classically associated with underlying diseases. It is often polymicrobial but Gram-positive bacteria and anaerobes are more frequent than Gram-negative bacteria. The clinical presentation may be aspecific without any parameters in favor of infectious disease: the rapidity of pleural drainage and antibiotic therapy are the main prognostic factors., Conclusion: Because of the diversity of clinical presentation in the elderly population, and because of the efficiency of rapid treatment, geriatric physicians should perform an examination of pleural fluid when pleural effusion is unknown.

We investigated the potency of digoxin-specific Fab fragments to reverse digoxin-induced Na+K+ATPase inhibition in rat brain microsomes according to (a) the extent of initial inhibition of Na+K+ATPase and (b) the neutralizing dose of antibody. Mathematical analysis of the digoxin concentration-Na+K+ATPase inhibition curve supports the existence of 2 digoxin sensitive Na+K+ATPase isoforms. The IC50 was 1.3 x 10(-4) M and 2.5 x 10(-8) M for the low (alpha 1) and high (alpha 2) digoxin affinity isoenzyme, respectively. The reversal of digoxin-induced Na+K+ATPase inhibition was dependent on the digoxin-specific Fab concentration. The maximal effect was observed when the Fab:digoxin ratio was stoichiometrical and addition of an excess of antibodies did not result in a complete reversal of inhibition at the 4 digoxin concentrations studied. This simple and rapid in vitro model will be a useful tool to predict the efficacy of a new generation of antibodies.

Three weeks before mating, two groups of SWISS OF1 mice were fed a diet that was similar but contained either peanut oil poor in alpha-linolenic acid [18:3(n-3)] (n-3 deficient = deficient mice = (n-3)-) or peanut + rapeseed oil rich in alpha-linolenic acid (n-3 nondeficient = controls = (n-3)+). Pups, fed the same diet as their dams, aged 45 to 62 days were used for brain lipid analysis and for behavioral experiments, aimed at determining whether there is a relation between the dietary intake of alpha-linolenate and a simple form of learning: habituation. The behavior of mice was compared using four models: exploration recorded in a photocell actimeter, activity in an open-field, duration of immobility in the forced swimming test and number of escape attempts from a small closed space. Habituation was measured by testing the mice in the same situation after some time had elapsed since the first test. Exploration in the photocell actimeter was significantly reduced between day 1 and 4 in nondeficient mice, but, not in deficient mice. The number of square crossings in the open-field was significantly reduced on the second test neither in the control nor in the deficient mice. In the forced swimming test, the habituation (increase in duration of immobility) was significantly greater (255%) in nondeficient than in deficient mice (163%). In the escape attempt experiment, the habituation showed a trend to be greater in controls than in deficient mice (p = 0.061) and was significantly greater in females than in males (p = 0.028). These results suggest that a simple form of learning, habituation, occurs more slowly in mice fed a diet deficient in alpha-linolenic acid.

Paclitaxel is a new antimitotic derived from yew-tree, used for the treatment of ovarian and breast cancers. The local toxicity of paclitaxel is still poorly known. We report one of the first observations of accidental subcutaneous extravastion of paclitaxel. Local epidermic necrosis was observed and evolution was good with local treatment only. Treatments of such extravasation are discussed.

The present study was aimed at determining the relative potency of various beta-blocking drugs as agonists or antagonists at 5-HT1B receptors. The behavioral model used (increase in escape attempts of isolated mice) has been previously shown to be exclusively responsive to 5-HT1B agonists such as 1-3-(trifluoromethyl) phenylpiperazine (TFMPP). Beta-blocking drugs acted in three different ways: they were either inactive, or acted as agonists or as antagonists at 5-HT1B receptors. The specific beta-blocking drugs: atenolol and betaxolol (beta-1) and ICI 118,551 (beta-2) were inactive by themselves and in interaction with TFMPP. The mixed beta-1 beta-2 blocking drug 1-penbutolol, (but not d-penbutolol), inactive alone, behaved as an antagonist: it impaired in a dose-dependent way the effect of TFMPP. (+/-)Pindolol and (-)pindolol was inactive. None of the (-), (+), or (+/-)pindolol was able to impair TFMPP effect. The increase in escape attempts induced by (+/-)pindolol was antagonized with 1-penbutolol or after a specific desensitization. Cyanopindolol and S-tertatolol (but not R-tertatolol) acted as agonists. SDZ 21009 was inactive as agonist or antagonist. It may be concluded that all beta-blocking drugs are not equivalent regarding their effect at 5-HT1B receptors. L-penbutolol was the only drug acting as an antagonist.

Using published data, we have investigated the relationship of the association constant (Ka) of 265 MAbs for haptens with molecular weights ranging from 111 to 1202 Da. The study indicates that: (1) differences of a factor 10(3)-10(5) are frequently found between the lowest and the highest value of Ka for the same hapten; (2) the relationship between log Ka and the hapten molecular weight of either the native drug or the molecular entity used for the Ka determination is described by a hyperbolic function; (3) beyond a critical molecular weight of approximately 300-325 Da, the log Ka reaches a plateau at a maximal value near 10(-12) M-1.

Cyclosporin 5-10 mg/kg daily was given for 2-8 months to twelve recently diagnosed type 1 diabetics from a mean of 49 +/- SE 14 days after the start of insulin therapy, which was regulated to give near-normal blood glucose and haemoglobin A1c values. Mean insulin dosage dropped from 46 +/- 5 U/day before cyclosporin treatment to 16 +/- 4 U/day by the 7th month. Four patients had a complete remission and the insulin needs of four more were cut by half. The remaining four did not have remissions. Initial basal and glucagon-stimulated C peptide concentrations were higher in those who went into remission than in those who did not; they rose during cyclosporin treatment in the former but not in the latter. OKT4+ lymphocyte functions were suppressed in all patients and OKT4/OKT8 ratios declined. Anti-beta-cell autoimmunity, as indicated by lymphocyte-induced inhibition of insulin release from mouse islet cells, declined in all patients who went into remission. No consistent trend was observed for anti-islet cell antibodies. In forty-four similar, but non-randomised, recently diagnosed diabetics treated with insulin alone, the incidence of remission was 6%.

Antilymphocyte sera, either allogeneic or xenogeneic, may retain the antigen used for the immunization of the animal producing the serum in the form of antigen-antibody complexes, at least when the animal is bled within the first two weeks following the last immunizing injection. Evidence for this has been obtained in vivo and in vitro (3). Thus, antilymphocyte injections may contain not only antibodies but the antigens used to prepare the serum as well, and active immunization to these antigens can result in the human or animal recipient. In the heart-allografted rat, pre-transplantation injection of immune complexes prepared from alloantisera prolongs graft survival. The filtrate from these complexes, presumably containing antigens, also prolongs graft survival when administered in conjunction with nonspecific immunosuppresive drugs after transplantation. These results, however, do not allow determination of whether the effect is active or passive, or perhaps both, nor what is the action of the complexes themselves.