Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys.

In an effort to broaden the immune response induced by the RTS,S/AS02(A),vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1(42) and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1(42) and AMA1 vaccines formulated with the AS02(A) Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1(42) or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1(42) and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-gamma and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1(42) and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1(42) lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1(42) significantly reduced AMA1 IFN-gamma and IL-5 responses. MSP1(42) suppression of AMA1 IFN-gamma responses was not seen in animals receiving RTS,S+AMA1+MSP1(42) suggesting that RTS,S restored IFN-gamma responses. Conversely, AMA1 had no effect on MSP1(42) antibody and IFN-gamma and IL-5 responses. Neither AMA1 alone or combined with MSP1(42) affected RTS,S antibody or IFN-gamma and IL-5 responses. Immune interference by MSP1(42) on AMA1 antibody responses was also evident when AMA1, MSP1(42) and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

BACKGROUND: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. OBJECTIVE: We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. METHOD: Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). RESULTS: The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Safety and immunogenicity of the RTS, S/AS02A candidate malaria vaccine in children aged 1­4 in Mozambique

The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Changes in electroencephalogram and autonomic cardiovascular activity during induction of anesthesia with sevoflurane compared with halothane in children.

BACKGROUND: This study was design to assess clinical agitation, electroencephalogram (EEG) and autonomic cardiovascular activity changes in children during induction of anesthesia with sevoflurane compared with halothane using noninvasive recording of EEG, heart rate, and finger blood pressure. METHODS: Children aged 2-12 yr premedicated with midazolam were randomly assigned to one of three induction techniques: 7% sevoflurane in 100% O2 (group SevoRAPID); 2%, 4%, 6%, and 7% sevoflurane in 100% O2 (group SevoINCR); or 1%, 2%, 3%, and 3.5% halothane in 50% N2O-50% O2 (group HaloN2O). An additional group of children who received 7% sevoflurane in 50% N2O-50% O2 (group SevoN2O) was enrolled after completion of the study. Induction was videotaped. EEG, heart rate, and finger blood pressure were continuously recorded during induction until 5 min after tracheal intubation and analyzed in frequency domain using spectral analysis. RESULTS: Agitation was more frequent when anesthesia was induced with 100% O2 compared to the mixture of oxygen and nitrous oxide. No seizures were recorded in any group. In the four groups, induction of anesthesia was associated with an increase in EEG total spectral power and a shift toward the low-frequency bands. Sharp slow waves were present on EEG tracings of the three sevoflurane groups, whereas slow waves and fast rhythms (spindles) were observed in the halothane group. Sevoflurane induced a greater withdrawal of parasympathetic activity than halothane and a transient relative increase in sympathetic vascular tone at loss of eyelash reflex. CONCLUSIONS: Agitation observed during sevoflurane induction was not associated with seizures. Sevoflurane induction induced a marked inhibition of parasympathetic control of heart rate.

Comparison of three techniques for induction of anaesthesia with sevoflurane in children.

This study was designed to evaluate the clinical characteristics of three induction techniques using sevoflurane in children scheduled for tonsillectomy: incremental induction with sevoflurane(2,4,6,7%) in 100% O2 (group IC-O2; n=23); induction with high concentration of sevoflurane in 100% O2 (group HC-O2; n=22); and induction with high concentration of sevoflurane in a mixture of O2:N2O(50:50) (group HC-N2O; n=20). Induction was well accepted and well tolerated in most children. The addition of nitrous oxide resulted in faster loss of consciousness (P< 0.001) compared to the other induction techniques and in a tendency for reduced excitement compared with the same rapid technique without nitrous oxide (P=0.053). Time to tracheal intubation was identical in the three groups and intubation conditions were scored as good in most children. During the early induction phase, an increase in SAP and HR was observed in the three groups. Changes were maximal at two min after the beginning of induction in the three groups. SAP and HR values were back to baseline values at the time of tracheal intubation. In conclusion, the addition of nitrous oxide to a high sevoflurane concentration decreases the time to loss of eyelash reflex, tends to reduce the incidence of excitement and is not associated with an increased incidence of respiratory complications even in patients with obstructive airway.

Pharmacokinetics of tiaprofenic acid in infants after a single oral dose.

Ten healthy infants (15.2 +/- 10.6 months old, range 6-35) anesthetized for minor surgery were given a single oral dose (3 mg x kg-1) of tiaprofenic acid (TA). Seven venous blood samples and 0-12 h urine were collected. TA concentrations in plasma and urine were measured by HPLC. Within the whole group the mean +/- SD kinetic parameters were: Cmax: 10.55 +/- 3.31 mg x l-1, Tmax: 1.73 +/- 0.87 h, AUC0-1 32.53 +/- 4.42 mg x l-1 x h, AUC0-infinity 35.33 +/- 4.73 mg x l-1 x h, t1/2 1.82 +/- 0.48 h, Cl/F: 0.09 +/- 0.01 l x h-1 x kg-1, VZ/F: 0.23 +/- 0.08 l x kg-1. Renal clearance was 0.030 +/- 0.009 l x h-1 x kg-1. 32% of the TA dose was recovered in urine, 60% of which was conjugated. AUC0-8h increased significantly with age. The TA kinetic parameters were close to those in 3 to 11-year-old children. The present study suggests slight differences in the TA kinetics between infants and adults. However, the lack of an evidenced direct relationship between plasma TA concentration and either efficacy or tolerance suggests that the TA dose regimen in infants may not have to be different from that in adults.

Pharmacokinetics of cetirizine in 2- to 6-year-old children.

Eight children (3.84 +/- 1.17 years old) received a single oral 5 mg cetirizine dose (0.32 +/- 0.07 mg.kg-1) as a 10 mg.ml-1 solution, 1.73 (+/- 0.64) hours before a minor surgical intervention (mean duration +/- SD = 0.90 +/- 0.25 h). Seven venous blood samples were collected before administration (t0) and 0.5 h, 1.5 h, 4 h, 8 h, 12 h and 24 h after dosing, and urine samples were collected up to 24 hours after the dose. The mean +/- SD kinetic parameters were: peak plasma level (Cmax) 607 +/- 231 micrograms.l-1 reached in 1.93 +/- 1.39 h (tmax), elimination half-life (t1/2) 5.55 +/- 0.98 h, area under the plasma concentration time curve (AUC0-infinity) 4,772.1 +/- 1,318.4 micrograms.l-1.h, mean residence time (MRT) 8.13 +/- 1.31 h, apparent plasma clearance (Cl/f) 1.27 +/- 0.80 ml.min-1.kg-1, apparent volume of distribution (Vz/f) 0.60 +/- 0.38 l.kg-1. Urinary recovery was 38.4 +/- 9.9% (n = 4) of the dose. Renal clearance was 0.42 +/- 0.10 ml.min-1.kg-1 (n = 6). No influence of age on the cetirizine parameters was evidenced among this group, except for MRT (p < 0.05) which decreases with age. When compared with results in adults, elimination half-life (t1/2) was twice as short and apparent clearance twice as great. These results suggest that a higher dosage b.i.d. may be required in children.

[Sevoflurane]. / Le sévoflurane.

Sevoflurane, a methylethylether halogenated solely with fluorine, is characterized by a low blood/gas solubility (blood/gas partition coefficient = 0.65). This feature allows in a more rapid uptake and elimination than with more soluble agents. MAC is about 2 vol% in young adults and 2.5 vol% in children of more than 6 months of age. It undergoes degradation by soda lime in various components. Among them, compound A (an olefin) produces renal toxicity in rats. Total sevoflurane metabolism represents about 5% of inhaled dose and produces inorganic fluorides. However no renal toxic effects has been reported up to now in animals and in patients. The effects on central nervous and cardiovascular systems are close to those of isoflurane. It decreases cerebral vascular resistances and cerebral oxygen consumption, but does not cause convulsive activity. It decreases myocardial contractility, systolic arterial pressure and systemic vascular resistances, but heart rate remains basically unchanged up to 1 MAC. It does not sensitize the myocardium to catecholamines. It depresses ventilation in a dose-dependent fashion, this effect being more pronounced than that of halothane but less than that of both isoflurane and enflurane. It is not irritant for the airways and has some bronchodilatory effect. In adults, recovery is more rapid than with isoflurane. In children, sevoflurane seems a promising agent owing to its good acceptance for mask induction, as well as its favourable haemodynamic profile. However due to its rapid elimination, analgesic drugs should be administered early enough to decrease the incidence of postoperative pain.

Induction and recovery characteristics and hemodynamic responses to sevoflurane and halothane in children.

The present study was designed to compare induction and recovery characteristics of sevoflurane and halothane anesthesia in children, and to assess the hemodynamic profile of both anesthetics during induction and maintenance of anesthesia. Thirty-four children (aged 9 mo-9 yr) scheduled for ambulatory surgery were allocated randomly to groups to receive either halothane (HALO, n = 17) or sevoflurane (SEVO, n = 17) in a mixture of O2 and N2O (40:60) for mask induction and maintenance of anesthesia. The inspired concentrations used for inhalation via a mask were increased every five breaths and were successively 1%, 2%, 3%, and 3.5% for HALO and 2%, 4%, 6%, and 7% for SEVO. After tracheal intubation, expired concentration was maintained at 1 minimum alveolar anesthetic concentration (MAC) corrected for age until skin closure. Analgesia was provided by epidural anesthesia using a mixture of plain 1% lidocaine and 0.25% bupivacaine. Induction and recovery characteristics as well as hemodynamic data were recorded. The two groups were identical in age, weight, and duration of anesthesia and surgery. Time to intubation was the same between groups. In the SEVO group, five children exhibited mild excitement, while in the HALO group, one mild laryngospasm and one transient cardiovascular deterioration were observed. In the SEVO group, a significant increase in heart rate (HR) was observed before tracheal intubation, but during maintenance of anesthesia HR and systolic arterial pressure (SAP) did not change compared to control values. In the HALO group, HR did not change throughout the study, whereas SAP remained significantly below control values throughout both induction and maintenance of anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective disposition of ibuprofen enantiomers in infants.

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/- 0.3 mg kg-1 dose of the racemate in 11 infants. Mean (+/- s.d.) half-lives were 1.6 +/- 0.5 h for S(+) and 1.5 +/- 0.5 h for R(-) and mean (+/- s.d.) AUC values were 31.5 +/- 14.3 mg l-1 h for S(+) and 36.6 +/- 13.8 mg l-1 h for R(-). Since plasma concentrations of the active S(+)-isomer were lower than those reported in adults, a higher dosage might be required in infants.

Correlation between fusogenicity of synthetic modified peptides corresponding to the NH2-terminal extremity of simian immunodeficiency virus gp32 and their mode of insertion into the lipid bilayer: an infrared spectroscopy study.

The amino-terminal extremity of the simian immunodeficiency virus (SIV) transmembrane protein (gp32) has been shown to play a pivotal role in cell-virus fusion and syncytium formation. We provide here evidence of a correlation between the structure and orientation of the modified SIV fusion peptide after insertion into the lipid membrane and its fusogenic activity. The sequence of the wild-type SIV peptide has been modified in such a way that the calculated angles of insertion correspond to an oblique, parallel, or normal orientation with respect to the lipid-water interface. Fourier transform infrared spectroscopy was used to gain experimental informations about the structures and orientations, of the membrane-inserted peptides with respect to the lipid acyl chains. The peptides adopt mainly a beta-sheet conformation in the absence of lipids. After interaction with large unilamellar liposomes, this beta sheet is partly converted into alpha helix. The ability of the modified peptides to promote lipid mixing was assessed by a fluorescence energy transfer assay. The data provide evidence that alpha-helix formation is not sufficient to induce lipid mixing and that the fusogenic activity of the peptide depends on its orientation in the lipid bilayer.

Lysophosphatidylcholine mediates the mode of insertion of the NH2-terminal SIV fusion peptide into the lipid bilayer.

We report here on the interaction of a synthetic 12 residue peptide corresponding to the N-terminal sequence of gp32 from SIV with phospholipid bilayers. This peptide has been shown to induce lipid mixing of PC/PE/SM/Chol LUV (large unilamellar vesicles) at pH 7.4 and 37 degrees C [(1992) in: Advances in Membrane Fluidity, vol. 6, pp. 365-376, Wiley-Liss]. In the present study, this fusion process was inhibited by the addition of lysophosphatidylcholine (lysoPC) to the lipid bilayer of PC/PE/SM/Chol LUV. Fourier transform infrared spectroscopy (FTIR) reveals that the orientation of the SIV fusion peptide with respect to the lipid acyl chains depends on the presence of lysoPC in the lipid bilayer but that the peptide secondary structure and the amount of lipid-associated peptides do not depend on the lipid composition. The peptide is obliquely inserted into the lipid bilayer of vesicles without lysoPC, whereas it is oriented parallel to the lipid-water interface in the vesicles containing lysoPC. The data provide evidence that the orientation of the SIV fusion peptide depends on the lipid composition, and that this mediates its fusogenic activity.

[Perioperative perfusion in children: evaluation of a new perfusion solution]. / Perfusion périopératoire chez l'enfant: évaluation d'un soluté de perfusion.

A new intravenous solution (B66) containing 0.9% dextrose in water for infusion therapy in infants and children was assessed. Forty-one children, aged between 6 months and 11 years, scheduled for elective non haemorrhagic surgery, were randomly assigned to two groups: children in group I (n = 22) were given 1% dextrose in lactated Ringer's solution (RLG1), and those in group II (n = 19) the commercially available solution B66 (0.9% dextrose in lactated Ringer's solution). The fluids were administered throughout the study with volumetric infusion pumps (IVAC 541). The infusion rate was adapted to children's weight and age. Blood samples for blood glucose, sodium and protein concentration assessments were obtained at induction (T0), on arrival in the recovery room (T1), than 30 and 60 min later (T2 and T3). Preoperative blood glucose concentrations were within the normal range for all children except for two, who had asymptomatic hypoglycaemia (2.2 and 2.3 mmol.l-1). Postoperative blood glucose concentrations were higher in both groups. This increase was significantly greater in the RLG1 group than in the B66 group. The highest mean figures at T1 were 6.8 +/- 1.5 mmol.l-1 and 5.2 +/- 1.0 mmol.l-1 in the RLG1 and B66 groups respectively. Total protein levels decreased postoperatively significantly in both groups. Preoperative age-related differences in total protein concentrations were also observed postoperatively. Sodium concentrations remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anesthesia in the management of pyloric stenosis. Evaluation of the combination of propofol-halogenated anesthetics]. / Anesthésie pour sténose du pylore. Evaluation de l'association propofol-anesthésiques halogénés.

This study was aimed at evaluating haemodynamic changes during an anaesthetic sequence for full stomach, using propofol as induction agent and volatile anaesthetics for maintenance of anaesthesia in infants scheduled for surgical cure of hypertrophic pyloric stenosis. After correction of preoperative blood electrolyte and metabolic disturbances with appropriate i.v. hydrating solutions, anaesthesia was induced with propofol and suxamethonium. Infants were divided in two groups according to the volatile anaesthetic agent used for maintenance of anaesthesia after tracheal intubation: halothane (n = 16) or isoflurane (n = 15). The two groups were identical regarding weight (4.28 +/- 0.6 vs 4.14 +/- 0.76 kg), age (1.6 +/- 0.9 vs 1.5 +/- 0.6 months), preinduction heart rate (155 +/- 22 vs 151 +/- 22 b.min-1) and systolic-diastolic arterial pressure (96 +/- 18/58 +/- 12 vs 105 +/- 16/67 +/- 15 mmHg). Propofol and suxamethonium doses were identical, 3.9 +/- 1 mg.kg-1 and 1.3 +/- 0.6 mg.kg-1 respectively in halothane group, vs 4.3 +/- 0.8 mg.kg-1 and 1.3 +/- 0.4 mg.kg-1 in isoflurane group. Heart rate did not change after induction of anaesthesia, while arterial blood pressure decreased significantly (p < 0.001). However, blood pressure remained within the normal range for age throughout the procedure. Mean duration of surgery was shorter in halothane group (64 +/- 16 vs 79 +/- 17 min, p < 0.05), however time-interval from the end of surgery to tracheal extubation (12 +/- 6 vs 15 +/- 8 min) was short and identical in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two anesthesia techniques on perioperative insulin response to i.v. glucose infusion in children.

Perioperative blood glucose and insulin levels were measured in children (1-9 years of age) randomly assigned to two groups according to anesthesia technique, general anesthesia (group GA) or general anesthesia combined with regional anesthesia (group RA). Children in the GA group (n = 10) received halothane and opioids, while children of the RA group received epidural anesthesia with bupivacaine (0.25%) and adrenaline combined with halothane anesthesia (n = 10). Children in both groups received 2.5% dextrose in 0.4 N saline administered by volumetric infusion pumps throughout the study period, the infusion rate being adapted to the child's age. Blood samples for glucose and insulin determinations were obtained: at induction, at the end of surgery, and 30, 60 and 120 min after surgery. In response to an identical glucose load, blood glucose levels increased significantly in both groups (P < 0.001), while no differences between groups were observed. Insulin levels did not change significantly postoperatively in the GA group (P = 0.058), while a significant increase was observed in the RA group (P < 0.001). Insulin/blood glucose ratio increased significantly only in the RA group (P < 0.05). The higher insulin secretion in response to glucose infusion in the RA group compared to the GA group may indicate an increased peripheral insulin resistance after regional anesthesia or, more likely, this secretion may be beneficial in contributing to improve postoperative nitrogen balance.

Apolipoprotein A-1 interacts with the N-terminal fusogenic domains of SIV (simian immunodeficiency virus) GP32 and HIV (human immunodeficiency virus) GP41: implications in viral entry.

Previous studies showed that apoA1, the major protein component of HDL (High Density Lipoprotein), inhibited HIV infectivity and virus-induced syncytia formation. The mechanism of inhibition is unknown. We bring here evidence that the amphipathic helices of apoA1 interact with the N-terminal peptides of SIV gp32 and HIV gp41. These peptides have been shown to be associated with the initial steps of the fusion between the host cell and the virus. Binding of apoA1 to these peptides prevents the insertion of the fusogenic domains into the cell membrane and inhibits the fusion and the entry of the virus into the host cell.

[Patient-controlled analgesia in children]. / Analgésie auto-contrôlée chez l'enfant.

This study describes the author's initial experience with "patient controlled analgesia" (PCA) in thirty school-age children for postoperative pain relief after major orthopedic surgery. The only narcotic used was morphine administered at both continuous and PCA modes. After the first eight patients, dosage regimens were changed and satisfactory postoperative analgesia was obtained in the last 20 patients with few side-effects. Recommended dosages range between 0.1 and 0.2 mg.kg-1 for loading dose, 0.01-0.02 mg.kg-1.h-1 for continuous infusion and 0.01-0.02 mg.kg-1 for PCA dose. Interest and limits of this method in children are discussed.

Serum antibodies to neurofilament antigens in patients with neurological and other diseases and in healthy controls.

A total of 529 sera from patients with a wide variety of neurological and non-neurological diseases, and 101 sera from healthy control subjects, were examined by indirect immunofluorescence for the presence of autoantibodies to neurofilament antigens. Antibodies were found in approximately 50% of sera from patients with spongiform encephalopathies, 15-30% of sera from patients with other neurological and non-neurological diseases, and 7% of sera from healthy controls. The antigenic stimulus to these autoantibodies in very diverse disease processes is unknown, but as presently assayed, they are not of sufficient specificity to be useful as an aid to clinical diagnosis.