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Finish turning is one of the key operations governing the residual stress of functional surfaces. The residual stress state is determined by the cutting conditions and the selected cutting tool system (macro geometry, cutting edge preparation, tool substrate, multi-layer coating...). However, this initial configuration evolves over time due to tool wear. Therefore, it seems fundamental to reproduce the wear process of the tool in order to understand the evolution of thermo-mechanical loadings applied to the machined surface. This work presents a numerical methodology for predicting the wear-induced residual stress drift in longitudinal turning. The complete 3D cutting tool is discretized into elementary 2D sections. A finite element based procedure is developed to calculate, considering each local tool geometry, the local loads withstood by the machined material. The latter are merged to generate equivalent 3D thermomechanical loadings implemented in a second macroscopic model able to calculate the residual stress state under different wear levels. Experimental cutting tests with artificially worn tools have confirmed that good agreement can be achieved. [ABSTRACT FROM AUTHOR]

Twelve healthy volunteers received two doses of amopyroquin 6 mg/kg im 24 h apart. Blood and plasma concentrations of amopyroquin and two metabolites were assayed by HPLC from 0 to 48 h. Half-life values for amopyroquin, calculated from 0 to 48 h whole-blood and plasma samples were 13.9 +/- 9.1 and 18.3 +/- 6.8 h respectively. Two metabolites were detected in blood and they had very low in-vitro activity against Plasmodium falciparum compared with the parent drug. Neither hypotension nor lengthening of QRS complex were observed in any volunteers and hepatic enzymes remained in the normal range despite a transitory increase. These results confirm that unchanged amopyroquin accounts for antimalarial activity in vivo and that two doses of 6 mg/kg are well tolerated. [ABSTRACT FROM AUTHOR]

High levels of antimalarial drugs have been shown to be inhibitory to the oxidative metabolism of human neutrophils in vitro. In this study, chemiluminescence of, and chloroquine concentrations in, neutrophils from volunteers treated with prophylactic or therapeutic malaria regimens were assessed. Although detectable chloroquine levels were found in neutrophils, their chemiluminescence was not reduced at prophylactic or at therapeutic drug levels, in comparison with controls without chloroquine treatment. At these clinically achievable concentrations, chloroquine was not found to interfere with the oxidative metabolism of neutrophils. [ABSTRACT FROM AUTHOR]

A city-state located at the heart of South East Asia, Singapore is now facing an accelerated ageing of the population, resulting from a very good health care coverage and a very low birth rate. A team of researchers from the French National Centre for Scientific Research (CNRS) is exploring the use of new technologies to improve the quality of life of elderly people in towns and cities and anticipate their health risks., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Delay for treatment of severe malaria is the cause of an important childhood mortality in Africa especially in rural zone when health facilities and accessibility are scarce. Intrarectal treatment is of particular interest in children as a non aggressive, painless and easy treatment. It can be used as early treatment and could decrease the lethality of severe malaria. We recently showed the kinetic profile, the optimal regimen and the clinical efficacy of intrarectal quinine (QIR) using Quinimax (Sanofi, Gentilly France) 20 mg/kg in solution with 2 ml of water. From 1994 to 1996 two open clinical trials were performed in Niger in children (2-15 years). QIR was compared with intraveinous infusion in cerebral malaria (n = 76) and with intramuscular quinine in severe malaria (n = 57). A three daily QIR administration (20 mg/kg followed by 15 mg/kg/8 h) was used in cerebral malaria; a two daily administration in severe malaria (30 mg/kg followed by 20 mg/kg/12 h). Symptomatic treatment was associated for hyperthermia, hypoglycemia, anemia and seizures. Results. In the cerebral malaria study 58 children presented a Blantyre coma score below 3. Four children in the IR group and 9 children in the infusion group died (P > 0.05). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 39.0 +/- 15.2 h and 37.1 +/- 16.5 h; return to consciousness 34.6 +/- 12.8 h and 33.0 +/- 14.1 h; decrease to 50% of the initial parasites count: 15.5 +/- 11.5 h and 13.8 +/- 10.0 h. Residual blood quinine concentrations at 48 hours were similar 7.4 +/- 3.7 mg/l and 7.2 +/- 2.9 mg/l. In the severe malaria study, the mortality was 0 and 7.6% in the QIR and IM group respectively (P > 0.005). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 38.7 +/- 22.8 h and 38.6 +/- 22.2 h; return to consciousness 26.8 +/- 13.9 h and 27.6 +/- 9.9 h for the 16 children in coma. The evolution under QIR treatment was also similar with that described with the other quinine routes. QIR allows an efficious treatment particularly when correct infusion cannot be performed. The efficacy, the simplicity and the good tolerance of QIR are of major concern to decrease the mortality of severe malaria due to delay for treatment and to decrease the side-effects due to intramuscular administrations of quinine in Africa.

Background: Both malnutrition and malaria affect drug disposition and are frequent among children in the tropics. We assessed their respective influence on quinine distribution., Methods: Forty children were divided into 4 groups: children with normal nutritional status without (group 1) or with (group 2) cerebral malaria, and malnourished children without (group 3) or with (group 4) cerebral malaria. All children received an infusion of 8 mg/kg of a combination solution of cinchona alkaloids that contained 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (corresponding to 4.7 mg/kg quinine base). The children with malaria then received repeated infusions every 8 hours for 3 days. Pharmacokinetic profiles of plasma and erythrocyte quinine were determined during the first 8 hours, together with quinine protein binding. Additional measurements of plasma quinine concentrations were used to simulate quinine concentrations profiles in children with malaria with and without malnutrition. Clinical recovery and parasitemia clearance times were determined in the children with malaria., Results: Compared with control children, malaria and malnutrition increased plasma concentrations of quinine and reduced both the volume of distribution and the total plasma clearance. Simultaneously, alglycoprotein plasma concentrations and protein-bound fraction of the drug were increased. Erythrocyte quinine concentrations correlated strongly with free plasma quinine but not with the extent of parasitemia. Similar effective and nontoxic quinine concentration profiles were obtained in malaria with and without malnutrition., Conclusions: Severe global malnutrition and cerebral malaria have a similar effect on quinine pharmacokinetics in children. Moderate malnutrition does not potentiate cerebral malaria-mediated modifications of quinine disposition. These results suggest that current parenteral quinine regimens can be used, unmodified, to treat children with both malaria and malnutrition.

The intrarectal route has been shown to be an alternative to parenteral therapy for the treatment of acute uncomplicated malaria. We conducted an open randomized clinical study of intrarectal Quinimax (a Cinchona alkaloids association) (20 mg/kg, then 15 mg/kg every 8 h) vs. intravenous Quinimax (8 mg/ kg infused over 4 h every 8 h) for 2 d in 76 children (39 in the intrarectal and 37 in the infusion groups) with cerebral falciparum malaria in Niger. This treatment was followed by oral chloroquine (10 mg/kg/d for 3 d). The primary end points of the study were fatal outcome and coma recovery time. In the intrarectal group, 35 children were cured (90%) and 4 died. In the infused group, 28 were cured (76%) and 9 died; mean coma recovery times were 34.6 h (SD = 12.8) and 33.0 h (SD = 14.1) for the intrarectal and infused groups, respectively. None of the differences was significant. Both treatments were well tolerated and no anal irritation was observed with intrarectal Quinimax. These findings suggest that intrarectal Quinimax can be an alternative to intravenous administration for rapid onset childhood cerebral malaria in the rural tropics, where the safety of parenteral administration cannot be guaranteed.

Twenty-four patients presenting with severe Plasmodium falciparum infection at the Kamenge Hospital in Burundi were enrolled in a double-blind study comparing the efficacy of a seven-day regimen of intravenous quinine alone or in combination with pefloxacin. The aim of this study was to assess whether pefloxacin modified chloroquine efficacy or its uptake by infected erythrocytes as shown with other antimalarials. Pefloxacin did not modify the antimalarial activity of quinine, in terms of speed of parasite or fever clearance. Moreover, pefloxacin does not appear to interact with quinine uptake by erythrocytes in humans.

In order to avoid the frequent side effects with injections of quinine in african children, empirical intrarectal administration of quinine (Quinimax, Sanofi Winthrop) has already been used successfully in Madagascar and Niger. In an attempt to optimise its use, a pharmacokinetic study was carried out with 66 children, 2 to 15 years old, admitted in pediatric unit for acute uncomplicated Plasmodium falciparum malaria, but warranting parenteral therapy. Children received Quinimax intrarectally (20 mg/kg/12h), intravenously (12,5 mg/kg in a slow infusion over 4 hours/12h) or intramusculary (12,5 mg/kg/12h). Plasma quinine concentrations were determined by HPLC. In this study, temperature and parasite clearance were similar in the 3 groups. A second randomized study was performed with 3 different dosages of intrarectal Quinimax: 8 and 13 mg/kg/8h and 20 mg/kg/12h. Temperature fell stably to normal at 36 hours with all regimens. Total clearance of parasitaemia was only obtained at 48 h with 30 mg/kg/12h regimen. Pharmacokinetic stimulation allowed to propose that intrarectal administration of Quinimax 20 mg/kg/8h would be a safe and effective regimen. A third approach studied the efficacy and pharmacokinetics of a new rectal quinine formulation (12,8 mg/kg/8h quinine gluconate) compared to IM and IV (8 mg/kg/8h) : at 36h, body temperature of all children was returned to normal and remained so until day 7. Parasitaemia expressed as a percentage of initial values was not different in the 3 groups after 48 h. At day 7, all the patients were aparasitaemics. The good tolerability and efficacy of this new intrarectal quinine formulation might allow to propose this route as an alternative to intramuscular route for the treatment of childhood malaria in Africa.

The schizogony of malarial parasite is a typical cyclic phenomenon where the different stages of parasite development appear at regular time intervals. Each of the stages is specifically sensitive to different antimalarial drugs. Knowledge of the details of the cycle, drug susceptibility and the pharmacokinetics of drugs, could allow the improvement of drug action by the chronotherapeutic approach: treatment at the time of appearance of the drug sensitive stage with a drug that displays rapid pharmacokinetics. Since murine malarias serve as preferable models for in vivo drug testing, the pharmacokinetics of subcutaneously (sc) administered chloroquine (CQ) were tested in the whole blood of healthy mice and in animals slightly (1.5-3.5% parasitemia) or heavily infected (21-25% parasitemia) with Plasmodium chabaudi chabaudi. The half-time of absorption was around 5 min and almost independent of parasitemia. The apparent half-time of drug concentration decay was around 40 min in healthy animals, about 90 min at low parasitemia and about 410 min in heavy infection, indicating that the concentration of CQ is a typical spike, that is prolonged by asymptomatic disease, and considerably more by the active accumulation of CQ in infected cells. The latter is confirmed by the 3-fold higher peak blood [CQ] at the trophozoite stage and < 1.5-fold increase during schizogony. In conjunction with our previous experiments which showed that a single sc injection of 5 mg/kg CQ is sufficient to eliminate the drug susceptible mid-term trophozoite stage, the present results seem to justify to propose the chronotherapeutic approach for the treatment of malaria.

The efficacy of a 12-mg/kg (of body weight) intramuscular amopyroquin (ApQ) regimen (two successive 6-mg/kg injections at a 24-h interval), previously established from kinetic studies on healthy volunteers and multicenter studies on patients with malaria, was investigated in 152 patients (children and adults) in Gabon with Plasmodium falciparum malaria. All children in the present study (ages, 1 to 14 years) showed higher degrees of parasitemia and temperatures and lower hematocrit values than did adults at the time of admission. No major side effects in the patients were observed. On day 7, all patients were apyretic; clearance of parasites was obtained in 143 of 152 patients (94%); a low level of parasitemia was observed in nine patients, all of whom were children (6%). In vitro chemosusceptibility tests carried out on P. falciparum isolates from patients demonstrated 51% of resistance to chloroquine (Cq). A correlation was found between the in vitro chemosusceptibilities to Cq and ApQ, but no relationship between the in vitro activity and the in vivo efficacy of ApQ could be found. Concentrations of ApQ in blood assayed by high-performance liquid chromatography on day 2 did not differ significantly between the groups in whom therapy was a success or a failure, although the mean ApQ concentration in blood for the group that failed therapy was 31% lower. Concentrations greater than 100 nmol of self-prescribed Cq and amodiaquine per liter, which were assayed simultaneously with ApQ, were observed in 78 patients (51%). They did not correlate with degrees of parasitemia compared with ApQ alone, which did. Successful treatment by day 7 was obtained in 69 of 74 patients (93%) who had no other 4-aminoquinolines in their blood. The results of the present study show that an ApQ regimen of 12 mg/kg over 2 days may be an alternative for the treatment of Cq-resistant malaria, at least in adult patients, in the field.

A combination of chloroquine and amlodipine, a derivative of 1,4-dihydropyridine calcium channel blocker, was tested against Plasmodium falciparum in vitro and P. yoelii in mice. The dextrorotary enantiomer of amlodipine, practically devoid of calcium channel blocking action, increased chloroquine accumulation inside the infected mouse erythrocytes and potentiated chloroquine action against the resistant strains of P. falciparum in vitro and P. yoelii in mice. Unlike the racemate, the dextrorotary amlodipine was not toxic to the host animal, even at the highest dose of 250 mg/kg. No potentiating effect was noted in the chloroquine-susceptible strains of P. falciparum. The results of this study indicate that chloroquine potentiation of amlodipine is probably independent of calcium channels and that a combination therapy of the dextrorotary enantiomer of amlodipine and chloroquine might be a potentially useful therapeutic strategy against chloroquine-resistant falciparum malaria.

The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 days (schedule 2; one dose of 10 mg/kg followed by two doses of 5 mg/kg at 6-h intervals on the first day and two doses of 5 mg/kg at 12-h intervals on the second day) in terms of their clinical and parasitological efficacies, tolerance, and drug concentration-time curves. At 24 h schedule 2 gave higher chloroquine levels in blood, which induced a more rapid decrease in parasitemia. The time required for a 50% decrease in the initial parasitemia was shorter in patients on schedule 2 (14.3 +/- 1.6 h) than it was in patients on schedule 1 (35.5 +/- 5.4 h; P less than 0.01). Moreover, negative blood smears were obtained more rapidly with schedule 2 (50.8 +/- 3.7 h) than with schedule 1 (72 +/- 8.7 h). As predicted by the drug concentration-time curve, no high, potentially toxic peak drug concentration appeared and no adverse effects were observed with the loading dose regimen (schedule 2). These findings support the idea that a loading dose of 20 mg/kg given at intervals during the first 12 h is well tolerated and can be used to obtain a more rapid decrease in parasitemia and to shorten the treatment time of uncomplicated chloroquine-susceptible falciparum malaria in the field.

Chloroquine (Cq) and desethyl-chloroquine ( CqM ) levels were measured by HPLC in the blood, plasma, and erythrocytes of 9 healthy subjects under standard prophylactic treatment (100 mg/day for 10 days) and 8 malarial patients given a therapeutic regimen (10 or 25 mg/kg). Chloroquine levels in various fractions of the healthy subjects were as follows: whole blood: 1 265 +/- 598 nmol/l; plasma: 145 +/- 63 nmol/l of whole blood; erythrocytes: 827 +/- 460 nmol/l of whole blood. The CqM /Cq ratio in malarial patients varied from 0.4 to 0.8. These results show that Cq levels and Cq metabolization varied significantly from one individual to the next. Above all, they demonstrate the presence of Cq in other types of blood cells. This underlines the practical importance of the conditions of chloroquine assay in blood.

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 +/- 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 +/- 75 liters/kg and 2,063 +/- 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 +/- 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.

The disposition of amopyroquin was studied in rats after a single 50-mg/kg (body weight) oral dose of amopyroquin base. After a rapid absorption phase, the drug concentrations decreased in the plasma, with a terminal half-life of 14.5 h. The drug was widely distributed in the liver and lungs and, to a lesser extent, in the kidneys and spleen. In rabbits, the kinetic parameters were compared after a single 10-mg/kg dose of amopyroquin base through intravenous, intramuscular (i.m.), and oral routes. The similar bioavailability values (0.67 and 0.69) suggested that the drug could be used through i.m. or oral administration. Clearance and distribution volume did not differ significantly among the three modes of administration, and the terminal half-lives were 18.1 +/- 3.3, 23.9 +/- 6.7, and 25.7 +/- 5.4 h for intravenous, i.m., and oral routes, respectively. The ratio of concentrations in erythrocytes and plasma was about 5 in rats and rabbits. Three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative). The amopyroquin in vitro activity was tested against four chloroquine-susceptible and 11 chloroquine-resistant African Plasmodium falciparum strains. For all isolates, the 50% inhibitory concentrations of amopyroquin were much lower than those of chloroquine and monodesethylamodiaquine.

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes (RBC) was studied in vitro before and during culture by measuring the chloroquine gradient between the cells and medium (C/M) by high-pressure liquid chromatography. The C/M values were 5.9 +/- 2.7 (n = 23) for uninfected RBC, 13 to 34 for six chloroquine-susceptible isolates (concentration required to inhibit 50% of parasite growth, less than 100 nmol/liter) in partially infected RBC (parasitemia from 0.3 to 5%) (n = 28), and 8.4 to 4.9 for four chloroquine-resistant isolates (concentration required to inhibit 50% of parasite growth, 320 to 1,500 nmol/liter) in partially infected RBC (parasitemia from 0.4 to 5%) (n = 26). Two isolates were studied before and after adaptation to continuous culture. C/M was found to decrease (34.2 to 2.1 and 19.3 to 4.9), whereas the concentration required to inhibit 50% of parasite growth increased (35 to 1,400 and 54 to 1,500 nmol/liter), thus indicating the acquisition of chloroquine resistance. These results demonstrate that chloroquine uptake decreased in RBC in which the infective strain, initially susceptible, became resistant in culture and imply that the drug is bound to ferriprotoporphyrin IX to a lesser extent or that a parasite protein competes with ferriprotoporphyrin IX to a greater extent. We suggest that genotypic modifications in the mechanism of chloroquine uptake might occur in the parasite.