Biomedical subjects

Bernhards R Ogutu

Publications and source records attributed to Bernhards R Ogutu.

8 recordsLinked to original sources

PubMed2006

Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

OBJECTIVE: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. DESIGN: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. SETTING: The study was conducted in a rural population in Kombewa Division, western Kenya. PARTICIPANTS: Subjects were 135 children, aged 12-47 mo. INTERVENTIONS: Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine). OUTCOME MEASURES: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. RESULTS: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). CONCLUSIONS: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

Journal Article↗

PubMed2006

Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a meta-analysis.

Drug resistance in Plasmodium falciparum is a major obstacle to malaria control. Artemisinin-based combination therapy (ACT) is being advocated to improve treatment efficacy and to delay development of resistance. Here we summarise the available data on the efficacy of amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus ACTs in the treatment of uncomplicated malaria in sub-Saharan Africa. We searched for randomised trials in which patients with uncomplicated malaria treated with AQ+SP were compared with those treated with either amodiaquine plus artesunate (AQ+AS), artesunate plus sulfadoxine/pyrimethamine (AS+SP) or artemether/lumefantrine (AL). Medline, EMBASE, Cochrane Central Register of Controlled Trials and reference lists up to July 2005 were searched. Two reviewers independently extracted the data. The primary outcome measure was treatment failure by Day 28. Outcome measures were combined using a random effects model. Seven randomised trials of 4472 children were included. Trial quality was generally high. Treatment failure of AQ+SP was significantly reduced compared with AS+SP (relative risk (RR)=0.56, 95% CI 0.42-0.75), but increased compared with AL (RR=2.80, 95% CI 2.32-3.39). The overall failure rate of AQ+SP was similar compared with AQ+AS (RR=1.12, 95% CI 0.81-1.54), but there was significant heterogeneity of results across the studies. All the treatment regimens were safe and well tolerated. AQ+SP should be considered in some settings before the full implementation of an ACT.

Africa↗

PubMed2005

Determination of lorazepam in plasma from children by high-performance liquid chromatography with UV detection.

A simple, sensitive, selective, and reproducible reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the determination of lorazepam (LZP) in human plasma, using oxazepam (OZP) as internal standard. LZP and OZP were extracted from alkalinized (pH 9.5) spiked and clinical plasma samples using a single step liquid-liquid extraction with a mixture of n-hexane-dichloromethane (70:30%; v/v). Chromatographic separation was performed on a reversed-phase Synergi Max RP analytical column (150 mmx4.6 mm i.d.; 4 microm particle size), using an aqueous mobile phase (10 mM KH2PO4 buffer (pH 2.4)-acetonitrile; 65:35%, v/v) delivered at a flow-rate of 2.5 ml/min. Retention times for OZP and LZP were 10.2 and 11.9 min, respectively. Calibration curves were linear from 10 to 300 ng with correlation coefficients (r2) better than 0.99. The limits of detection (LOD) and quantification (LOQ) were 2.5 and 10 ng/ml, respectively, using 0.5 ml samples. The mean relative recoveries at 20 and 300 ng/ml were 84.1+/-5.5% (n=6) and 72.4+/-5.9% (n=7), respectively; for OZP at 200 ng the value was 68.2+/-6.8% (n=14). The intra-assay relative standard deviations (R.S.D.) at 20, 150 and 270 ng/ml of LZP were 7.8%, 9.8% (n=7 in all cases) and 6.6% (n=8), respectively. The inter-assay R.S.D. at the above concentrations were 15.9%, 7.7% and 8.4% (n=7 in all cases), respectively. Intra- and inter-assay accuracy data were within the acceptance interval of +/-20% of the nominal values. There was no interference from other commonly co-administered anticonvulsant, antimicrobial, antipyretic, and antimalarial drugs. The method has been successfully applied to a pharmacokinetic study of LZP in children with severe malaria and convulsions following administration of a single intravenous dose (0.1 mg/kg body weight) of LZP.

Anticonvulsants↗

PubMed2004

Determination of paraldehyde by gas chromatography in whole blood from children.

A rapid, sensitive and selective gas chromatographic method with flame ionization detection was developed for the determination of paraldehyde in small blood samples taken from children. Whole blood samples (300 microl) collected in a 3 ml Wheaton glass sample vial were spiked with acetone (internal standard: 15 ng) followed by addition of concentrated hydrochloric acid. The mixture was heated in the sealed airtight sample vial in a water bath (96 Celsius; 5 min) to depolymerize paraldehyde to acetaldehyde. A 2 ml aliquot of the headspace was analyzed by gas chromatography with flame ionization detector using a stainless steel column (3 m x 4 mm i.d.) packed with 10% Carbowax 20 M/ 2% KOH on 80/100 Chromosorb WAW. Calibration curves were linear from 1.0-20 microg (r2>0.99). The limit of detection was 1.5 microg/ml, while relative mean recoveries at 2 and 18 microg were 105.6 +/- 8.4 and 101.2 +/- 5.9%, respectively (n = 10 for each level). Intra- and inter-assay relative standard deviations at 2, 10 and 18 microg were <15%. There was no interference from other drugs concurrently used in children with severe malaria, such as anticonvulsants (diazepam, phenytoin, phenobarbitone), antipyretics/analgesics (paracetamol and salicylate), antibiotics (gentamicin, chloramphenicol, benzyl penicillin) and antimalarials (chloroquine, quinine, proguanil, cycloguanil, pyrimethamine and sulfadoxine). The method was successfully applied for pharmacokinetic studies of paraldehyde in children with convulsions associated with severe malaria.

Calibration↗

PubMed2003

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus.

AIMS: Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.

Adolescent↗

PubMed2003

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions.

AIMS: Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg(-1) is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg(-1) intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. METHODS: Twelve children (M/F: 11/1), aged 7-62 months, received a loading dose of phenobarbital (15 mg kg(-1)) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg(-1) at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l(-1) for 72 h. RESULTS: All the children achieved plasma concentrations above 15 mg l(-1) by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, infinity)]: 4259 (3169, 5448) mg l(-1).h, t(1/2): 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg(-1) h(-1), Vss: 0.8 (0.7, 0.9) l kg (-1), CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9-27.9) mg l(-1). Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg(-1) followed by two maintenance doses of 2.5 mg kg(-1) at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l(-1) for 72 h. CONCLUSIONS: Phenobarbital, given as an i.v. loading dose, 15 mg kg(-1), achieves maximum plasma concentrations of greater than 15 mg l(-1) with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg(-1) at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15-20 mg l(-1) for 72 h, and may be a suitable regimen for treatment of convulsions in these children.

Anticonvulsants↗

PubMed2003

Cerebral malaria: optimising management.

Cerebral malaria is one of the most common nontraumatic encephalopathies in the world. Children living in sub-Saharan Africa bear the brunt of the disease, but cerebral malaria is being seen increasingly in adults throughout the world, including outside malarious areas. There are differences in the clinical presentation and pathophysiology between African children and nonimmune adults from any region. Mortality is high (10-20%). Parenteral antimalarials are the only interventions that have been shown to affect outcome. The cinchona alkaloids (quinine and quinidine) are the mainstay of antimalarial treatment, but the artemisinin derivatives are increasingly being used. Aggressive treatment and prevention of convulsions may be important, particularly in children. Other ancillary treatments that can be used to augment standard antimalarial drugs, such as exchange blood transfusions, osmotic diuretics and pentoxifylline, may improve outcome but have not been subjected to rigorous clinical trials. There is little support for corticosteroids or deferoxamine (desferrioxamine) in cerebral malaria. Other adjuncts have not been adequately tested. Further research is required on drugs that interfere with the pathophysiological processes to prevent neurological complications and death.

Africa South of the Sahara↗

PubMed2002

Phenytoin pharmacokinetics and clinical effects in African children following fosphenytoin and chloramphenicol coadministration.

AIMS: Some children with malaria and convulsions also have concurrent bacterial meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in children with malaria. METHODS: Multiple intravenous (i.v.) doses of chloramphenicol succinate (CAP) (25 mg kg-1 6 hourly for 72 h) and a single intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg-1 phenytoin sodium equivalents) were concomitantly administered to 15 African children with malaria. Control children (n = 13) with malaria received a similar dose of fosphenytoin and multiple i.v. doses (25 mg kg-1 8 hourly for 72 h) of cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen saturation, level of consciousness and convulsion episodes were monitored. Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined. RESULTS: The area under the plasma unbound phenytoin concentration-time curve (AUC(0, infinity ); means (CAP, CEF): 58.5, 47.6 micro g ml-1 h; 95% CI for difference between means: -35.0, 11.4), the peak unbound phenytoin concentrations (Cmax; medians: 1.12, 1.29 micro g ml-1; 95% CI: -0.5, 0.04), the times to Cmax (tmax; medians: 4.0, 4.0 h; 95% CI: -2.0, 3.7), the CSF:plasma phenytoin ratios (means: 0.21, 0.22; 95% CI: -0.8, 0.10), the fraction of phenytoin unbound (means: 0.06, 0.09; 95% CI: -0.01, 0.07) and the cardiovascular parameters were not significantly different between CAP and CEF groups. However, mean terminal elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI: 1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of the children had no convulsions during the study period. CONCLUSIONS: Concomitant administration of chloramphenicol and a single i.m. dose of fosphenytoin alters the t1/2,z but not the other pharmacokinetic parameters or clinical effects of phenytoin in African children with severe malaria. Moreover, a single i.m. dose of fosphenytoin provides anticonvulsant prophylaxis in the majority of the children over 72 h. However, a larger study would be needed to investigate the effect of concomitant administration of multiple doses of the two drugs in this population of patients.

Anti-Bacterial Agents↗