Search PubMed⌕ Search

Biomedical subjects

Y Bergqvist

Publications and source records attributed to Y Bergqvist.

At least 37 records · Page 2Linked to original sources
PubMed1999

Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil.

Mutations in human CYP2C19 and parasite dihydrofolate reductase (dhfr) genes, related to poor metabolism of proguanil and resistance to cycloguanil, respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. To study this, 95 subjects with uncomplicated Plasmodium falciparum or Plasmodium vivax infections in Vanuatu received proguanil treatment for 3 days (adult relative dose of 300-500 mg/day) and were followed up for 28 days. A similarly high antimalarial efficacy against both infections was observed in 62 patients with CYP2C19-related poor metabolizer genotype and in 33 with extensive metabolizer genotype, even though blood cycloguanil was significantly more often detected in those with extensive metabolizer genotype than in those with poor metabolizer genotype. All 28 P. falciparum isolates had two dhfr mutations (residues 59 and 108), suggesting moderate resistance to cycloguanil. The results suggest that the parent compound proguanil has significant intrinsic efficacy against falciparum and vivax malaria independent of the metabolite cycloguanil.

Adolescent↗
PubMed1999

Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations.

The increasing resistance of falciparum malaria to common antimalarial drugs has renewed interest in the compound proguanil normally metabolized to cycloguanil, a strong dihydrofolate reductase inhibitor, via the cytochrome P450 isozyme CYP2C19. The relationship between CYP2C19 genotypes and proguanil metabolism was therefore studied in 100 uncomplicated malaria patients on Malakula island in Vanuatu, where a CYP2C19-related poor metabolizer genotype status was known to be frequent. The patients (median age, 7 years) with Plasmodium falciparum or P. vivax infections, received proguanil treatment for 3 days in daily doses corresponding to adult doses of 300-500 mg. Capillary blood samples were collected on filter paper for determining both human CYP2C19 mutations by polymerase chain reaction and mutation-specific restriction enzyme digestion and blood concentrations of proguanil and its metabolites by high-performance liquid chromatography. The frequencies of the defective alleles, CYP2C19*2 and CYP2C19*3, were 0.57 and 0.25, respectively. The patients were genotyped as 68 CYP2C19-related poor metabolizers and 32 extensive metabolizers. Proguanil concentrations were higher and cycloguanil and 4-chlorophenylbiguanide concentrations were lower in poor compared to extensive metabolizers. Among the extensive metabolizers, 27 were heterozygous and five were homozygous for unmutated alleles. The tendency of an intermediate degree of proguanil metabolism in heterozygous extensive metabolizers as compared to homozygous extensive metabolizers and poor metabolizers suggests the trend towards the existence of a gene dose effect. Mild adverse events (mainly gastro-intestinal symptoms) were often reported and positively correlated with proguanil concentrations. The incidence was, however, similar in poor and extensive metabolizers. In conclusion, our data demonstrate an association between CYP2C19 mutations and poor metabolism of proguanil.

Antimalarials↗
PubMed1998

Improved method for the simultaneous determination of proguanil and its metabolites by high-performance liquid chromatography and solid-phase extraction of 100-microl capillary blood samples dried on sampling paper.

An improved method is presented for the determination of proguanil, cycloguanil and 4-chlorophenylbiguanide in 100-microl capillary blood samples applied to sampling paper. This method also utilises a solid-phase extraction technique and high-performance liquid chromatography. Different kinds of sampling paper, such as ion-exchange and cellulose sampling paper were tested. The best elution recovery (70-80%) was obtained after treatment of cellulose sampling paper with a quaternary ammonium compound. The limit of determination was 50 nmol/l for cycloguanil and 4-chlorophenylbiguanide and 125 nmol/l for proguanil using 100 microl capillary blood. The stability of the analytes and elution performance from sampling paper was validated at different temperature and storage time. Venous blood and capillary blood concentrations of proguanil and metabolites were found to be similar.

Antimalarials↗
PubMed1998

Improved validated assay for the determination of proguanil and its metabolites in plasma, whole blood, and urine using solid-phase extraction and high-performance liquid chromatography.

An improved and validated method is presented for the determination of proguanil, cycloguanil, and 4-chlorophenylbiguanide in plasma, whole blood, and urine using solid-phase extraction (SPE) technique and reversed-phase high-performance liquid chromatography (HPLC). The HPLC method uses isocratic elution with acetonitrile:phosphate buffer 0.1 mol/l, pH 2.6 (21.5:78.5 vol/vol) at a flow rate of 1.0 ml/min for the separation. The recovery of proguanil and metabolites ranged from 82% to 104%. The limit of determination was 20 nmol/l for proguanil and its metabolites in plasma and approximately 50 nmol/l for proguanil and metabolites in whole blood. Different stationary phases for HPLC and SPE were tested and the best chromatographic separation from endogenous constituents and other antimalarial drugs was achieved with cyanopropyl stationary phases.

Antimalarials↗
PubMed1997

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose.

AIMS: To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers. METHODS: Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method. RESULTS: A two-compartment model adequately described the disposition of (+)RS-MQ. CL/F was 6.5 +/- 1.8 l h(-1), V(ss)/F 815 +/- 165 l, and k 0.0081 +/- 0.0023 h(-1). The kinetics of (-)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92 +/- 0.25 vs 2.14 +/- 0.63 l h(-1), 95% CI for the difference 0.86-1.60 l h(-1)) and a longer half-life (345 vs 185 h, 95% CI for the difference 47-291 h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated within subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound. CONCLUSIONS: The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.

Adult↗
PubMed1996

Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma.

OBJECTIVE: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. SETTING: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. VOLUNTEERS: Ten healthy adult Caucasian volunteers. METHODS: Drug concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (-)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. CONCLUSION: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.

Adult↗
PubMed1996

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance.

This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers (52% F) participated. AEs with some impact on activities were reported by 11.2% of participants including 7.9% of neurological/psychiatric symptoms. Women were more likely to report AEs (P = 0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic MQ levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability.

Adolescent↗
PubMed1995

Mefloquine Prophylaxis and Hearing, Postural Control, and Vestibular Functions.

Background: Mefloquine (MQ) is an important antimalarial drug. Dizziness and other adverse neuropsychiatric reactions have however restricted its use. Method: Ten healthy adult volunteers were given MQ (Lariam) 250 mg once weekly for 16 weeks. Measurement of postural sway (posturography), nystagmus recording, determinations of hearing thresholds (Bekesy audiometry), and determinations of drug concentrations were done before, after 4, 32, and 109 days of weekly MQ intake and 3 months after the last dose. Results: All volunteers were able to continue their professional work and normal daily activities. Several mild symptoms were reported. In at least one of the volunteers, these symptoms were probably caused by the MQ intake. Hearing thresholds remained normal. No significant changes were noted in the nystagmus tests. The recorded values of sway index were within the normal range (99% confidence interval) in all volunteers in all test situations, and no differences were seen at the time of maximal drug concentrations (day 109) compared to before or after the study. There was no correlation between the plasma concentrations of MQ, the two MQ enantiomers (RS and SR), or the main mefloquine metabolite and the sway index. Conclusion: Although no effect was seen on the vestibular system in the present study, further tests in a flight simulator will be needed before MQ can be recommended for pilots. (J Travel Med 2:66-69, 1995)

Journal Article↗
PubMed1994

High-performance liquid chromatographic determination of (SR)- and (RS)-enantiomers of mefloquine in plasma and capillary blood sampled on paper after derivatization with (-)-1-(9-fluorenyl)ethyl chloroformate.

A sensitive, stereoselective and rapid reversed-phase liquid chromatographic method for the determination of (SR)- and (RS)-mefloquine enantiomers in 100 microliters plasma and capillary blood collected on chromatographic paper is presented. The assay involves protein precipitation from plasma, liquid-liquid extraction of mefloquine from plasma, capillary blood with methyl tert.-butyl ether under alkaline conditions and derivatization of MQ with (-)-1-(9-fluorenyl)ethyl chloroformate. Liquid chromatographic separation of the diastereomers was performed using an C18 reversed-phase column with acetonitrile-water-acetic acid 82:18:0.07 (v/v/v) as the mobile phase, and a flow-rate of 1.0 ml/min. When using 100 microliters of plasma the limit of determination is 250 nmol/l with ultraviolet- and 10 nmol/l with fluorescence detection. The present method offers several advantages over those previously reported; very low limit of determination, small sample volume, sampling onto paper and use of an inexpensive standard achiral HPLC column. No racemization during the derivatization procedure or storage of the MQ enantiomers was found.

Capillaries↗
PubMed1994

Improved method for analysis of glycated haemoglobin by ion exchange chromatography.

The Pharmacia Mono S column for glycated haemoglobin (HbA1c) was compared with Mono S HR 5/5 and three other cation exchange columns to optimize analysis of HbA1c. This column allows a significant decrease in separation time, resulting in a sample throughput of 12 samples per hour. The choice of parameters for integration of peak areas in the chromatograms is very important for reproducible results. Since pure calibrators of HbA1c are not available, the relative contribution of HbA1c to the total amount of haemoglobin is calculated. We have compared valley-to-valley integration with baseline integration to assess reproducibility. Valley-to-valley integration significantly enhances the reproducibility of the method and is therefore preferable for routine analyses of HbA1c.

Blood Proteins↗
PubMed1994

Falciparum malaria in eastern Thailand: a randomized trial of the efficacy of a single dose of mefloquine.

Reported are the results of a randomized trial of a single dose of mefloquine (15 mg/kg or 25 mg/kg body weight) for the treatment of uncomplicated multidrug-resistant falciparum malaria. Of the 110 adult patients enrolled in the study 57 were randomly assigned to the 15 mg/kg group and 53 to the 25 mg/kg group. The baseline characteristics of the patients did not differ significantly in the two groups, except that those in the 15 mg/kg group had lower haemoglobin levels. Adverse effects following treatment were commoner in the 25 mg/kg group, but not significantly so. Seven patients (6%) did not complete the 42-day follow-up. The parasitological failure rates in the 15 and 25 mg/kg groups were, respectively, 50% (28/56) and 43% (25/53) on day 28, and 62% (33/53) and 56% (28/50) on day 42. Treatment failures were not correlated with the serum mefloquine concentrations on day 2, and 13 out of 19 patients with serum mefloquine concentrations > 2000 micrograms/l on day 2 showed an R response during the follow-up. The mean ratio between the concentrations of the (SR)-(-) and (RS)-(+) enantiomers of mefloquine on day 2 was 3.37, indicating that there are differences in their pharmacokinetics. Re-treatment of patients who showed an R response with seven days of quinine (30 mg.kg-1.day-1)+tetracycline (25 mg.kg-1.day-1) was successful in 93% of the cases.

Adult↗
PubMed1993

Enantioselective high-performance liquid chromatographic determination of (SR)- and (RS)-mefloquine in plasma using N-benzyloxycarbonyl-glycyl-L-proline as chiral counter ion.

A stereoselective HPLC method is described for the determination of (SR)- and (RS)-mefloquine in plasma. The direct chiral separation is carried out on a Hypercarb-S column (porous graphitised carbon) with N-benzyloxycarbonyl-glycyl-L-proline (L-ZGP) as a chiral counter-ion in a reversed-phase system. The sample work-up included protein precipitation by addition of zinc sulphate and acetonitrile followed by liquid-liquid extraction with methyl-tert.-butyl ether. After evaporation of the organic phase, the residue is dissolved in the mobile phase and injected onto the column. Analyses of the enantiomers in plasma after a single oral dose of mefloquine indicates that the pharmacokinetics of the two enantiomers are different. The method is validated by determining the absolute recovery, linearity, accuracy, precision and inter- and intra-assay variation.

Calibration↗
PubMed1993

High-performance liquid chromatographic method for the simultaneous determination of mefloquine and its carboxylic metabolite in 100-microliters capillary blood samples dried on paper.

A reversed-phase high-performance liquid chromatographic method is described for the analysis of mefloquine and its carboxylic metabolite in 100-microliters capillary blood spots dried on chromatographic paper. Each spot was cut into small pieces, and mefloquine and its metabolite were eluted with an ammonia-water solution (10:90, v/v). The compounds were extracted simultaneously after alkalization at pH 9.5 using tetrabutylammonium as ion-pairing agent and then separated on a C18 column with ultraviolet detection at 227 nm. The recovery of the drugs from spiked blood applied to paper and dried was 70-80%, and the inter-assay precision at 1.0-5.0 mumol/l (therapeutic range) was less than 10%. The correlation between extractions from venous whole blood and capillary blood applied to chromatographic paper was more than 0.94. The analytes were stable in dried blood spots for at least fifty days at -20 degrees C. The decrease of concentration was less than 10%, when the paper was stored at 37 degrees C for fifty days. The assay is reliable and easy to use for therapeutic monitoring of mefloquine with a lower limit of determination of 0.3-0.5 mumol/l.

Chromatography, High Pressure Liquid↗
PubMed1993

Integrating decision support, based on the Arden Syntax, in a clinical laboratory environment.

A clinical decision support system prototype have been developed in the clinical laboratory environment. The knowledge base consists of Medical Logic Modules, written in the Arden Syntax, and the work describes how these modules can be written, evoked and executed in a system, that is integrated with a laboratory information system, and facilitate real time validation of laboratory data. Tools and methods for building a decision support system are described and design aspects, such as database access, system validation and platform independence, are discussed.

Artificial Intelligence↗
PubMed1993

[Mefloquine and sulfadoxine/pyrimethamine overdose in malaria tropica].

A 39 year-old man with malaria due to Plasmodium falciparum received 3500 mg mefloquine over 3 days, in addition to 3250 mg chloroquine and 175/3500 mg sulfadoxine/pyrimethamine. He developed severe neuropsychiatric symptoms and had to be hospitalized. Treatment with diazepam, haloperidol and thioridazine achieved relief of the severe symptoms after 4 days. The patient was still suffering from discrete neuropsychiatric symptoms 8 months after treatment.

Adult↗
PubMed1992

Improving lactate analysis with the YSI 2300 GL: hemolyzing blood samples makes results comparable with those for deproteinized whole blood.

To obviate the well-documented problem of hematocrit dependency of the Yellow Springs Instruments (YSI) whole-blood lactate analyzer, we modified the dilution buffer by including a lysing reagent. This makes the results comparable with those of methods performed with deproteinized whole-blood samples. No centrifugation step is needed, thus preserving the convenience of the YSI instrument for stat and field use. The modification works equally well on plasma samples. Lactate concentrations measured in nonhemolyzed whole blood are not comparable with results for hemolyzed whole blood or protein-precipitated whole blood. We therefore recommend to all users of YSI equipment to lyse the erythrocytes before lactate determinations.

Biosensing Techniques↗
PubMed1991

Reversed-phase liquid chromatographic method for the simultaneous determination of the antimalarial drugs sulfadoxine, pyrimethamine, mefloquine and its major carboxylic metabolite in plasma.

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of sulfadoxine, pyrimethamine, mefloquine and the carboxylic metabolite of mefloquine in plasma is described. After the proteins have been precipitated with a combination of zinc sulphate and acetonitrile containing two internal standards, pyrimethamine and mefloquine are extracted as bases and sulfadoxine and the carboxylic metabolite of mefloquine as ion-pairs with tetrabutylammonium. The drugs are separated by HPLC on a 3 micron octadecylsilica column with ultraviolet detection at 229 nm. The method is simple and reliable and enables the simultaneous determination of the drugs in 600-microliter plasma samples with a sensitivity suitable for standard drug monitoring purposes.

Antimalarials↗