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Biomedical subjects

L L Gustafsson

Publications and source records attributed to L L Gustafsson.

At least 19 recordsLinked to original sources
PubMed2007

Assessing health worker performance in malaria case management of underfives at health facilities in a rural Tanzanian district.

OBJECTIVE: To study the quality of malaria case management of underfives at health facilities in a rural district, 2 years after the Tanzanian malaria treatment policy change in 2001. METHODS: Consultations of 117 sick underfives by 12 health workers at 8 health facilities in Mkuranga District, Tanzania were observed using checklists for history taking, counselling and prescription. Diagnoses and treatment were recorded. Exit interviews were performed with all mothers/guardians and blood samples taken from the underfives for the detection of malaria parasites and antimalarial drugs. Quality of care was measured using indicators adopted from the integrated management of childhood illnesses multi-country evaluation. RESULTS: Quality of care measured by indicator scores averaged 31% of what was considered optimal. The poorest results were for history taking. Nevertheless, 89% of febrile children were treated with antimalarials, in line with national guidelines for fever treatment. Of these, 61% had a parasitaemia > or =2000/microl. There was no difference in treatment given to those with parasitological malaria compared with those without parasites. Pre-treatment levels of chloroquine and sulphadoxine/pyrimethamine were low and detected in 2% and 13%, respectively. CONCLUSION: Although most febrile children were given antimalarial treatment, quality of care in terms of history taking and counselling was sub-optimal. Despite this, the study community had changed behaviour from self-treatment to seeking care at health facilities. This is encouraging for introduction of artemisinin-based combination therapies policies as one could focus resources into improving care at health facilities and still reach out with treatment to most febrile children.

Antimalarials↗
PubMed2006

Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation.

Amodiaquine (AQ) is an affordable compound, chemically related to chloroquine (CQ) but often effective against CQ resistant Plasmodium falciparum. In Uganda, a pre-packed fixed-dose combination of CQ plus sulfadoxine/pyrimethamine (CQ+SP) called Homapak is used in the home based management of fever program (HBM). We performed a single blind randomized trial to determine the efficacy of AQ+SP in comparison with the fixed-dose CQ+SP (Homapak) in the treatment of uncomplicated falciparum malaria in Ugandan children aged 6 months to 5 years. The study was done in 2004 at Walkuba Health Center, a sub-urban area in Jinja district, Uganda. Primary outcome was the day 14 per protocol clinical and parasitological response according to the WHO. A total of 183 children were included (mean age 28 months) and 90% completed 28 days of follow up. The day 14 adequate clinical and parasitological response was 70.9% for CQ+SP and 97.4% for AQ+SP (p<0.001). In those given CQ+SP, treatment failure rates for the 6 months to 2 years age group were much higher (48.2%) than in the older children (18.2%, p=0.004). The day 28 PCR adjusted parasitological failure rates were also higher in the CQ+SP (31.3%) than in the AQ+SP group (13.1%) (p=0.003), with a higher gametocyte carriage among the CQ+SP group. We conclude that the efficacy of AQ+SP was significantly superior to the fixed-dose CQ+SP (Homapak), particularly among the youngest children. Thus, AQ could be used instead of CQ in combination with SP to improve the effectiveness against falciparum malaria in Uganda.

Amodiaquine↗
PubMed2006

Pharmacokinetic interactions between chloroquine, sulfadoxine and pyrimethamine and their bioequivalence in a generic fixed-dose combination in healthy volunteers in Uganda.

BACKGROUND: A pre-packaged fixed-dose formulation of chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P) combination (Homapak) is widely used for the treatment of falciparum malaria in Ugandan children. It is however a product whose pharmacokinetics and interactions have not been studied. OBJECTIVES: To explore possible pharmacokinetic interactions between CQ and S/P during co-administration, and to determine their bioavailability in the locally made Homapak compared to the Good Manufacturing Practice (GMP) made formulations. METHODS: Thirty-two adult healthy volunteers were randomized into four groups and given single oral doses of fixed-dose CQ+S/P combination (Homapak), or GMP formulations of S/P (Fansidar), CQ (Pharco), or their combination. Plasma samples were followed for 21 days, analysed by HPLC-UV methods, with pharmacokinetic modeling using the WinNonlin software. RESULTS: Sulfadoxine in Homapak was more rapidly absorbed (ka = 0.55 h(-1)) than in Fansidar + CQ (ka = 0.27 h(-1), p=0.004), but not more than S in Fansidar alone group (ka = 0.32 h(-1), p=0.03). No significant differences were observed in the other pharmacokinetic parameters of S, P and CQ when given together or separately. The relative bioavailability of CQ and S in Homapak showed bioequivalence to reference formulations. CONCLUSIONS: There were no pharmacokinetic interactions between CQ, S and P when the compounds were given together, however, more investigations would be needed to explore this further. Compared with GMP made drugs, both S and CQ are bioequivalent in Homapak, the Ugandan made fixed-dose formulation. Furthermore, the absorption of S was more rapid which could be advantageous in malaria treatment.

Administration, Oral↗
PubMed2005

Simple and cost-effective liquid chromatographic method for determination of pyrimethamine in whole blood samples dried on filter paper.

A cost-effective HPLC method for determination of pyrimethamine (PYR) in human whole blood samples dried on filter paper (Whatman) is reported. Trimethoprim (TMP) was used as an internal standard. Whole blood spiked with PYR was transferred (100 microl) onto filter paper and dried at room temperature. Capillary blood samples (100 microl) after ingestion of three tablets of sulfadoxine-pyrimethamine (SP) by one subject were also tested. PYR and an internal standard (IS) TMP were extracted into di-isopropyl ether as bases and then re-extracted with 150 microl mobile phase. A C-18 column was used and the mobile phase consisted of phosphate buffer (0.05 M, pH 5):acetonitrile:concentrated perchloric acid (750:300:2.5, v/v/v). The absorbances of PYR and IS were monitored at 270 nm. The limit of quantification was 40 ng/ml. The within- and between-assay coefficient of variations were <10% at the limit of quantification.

Antimalarials↗
PubMed2004

Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment.

A study was carried out to assess the patterns of resistance and occurrence of DHFR/DHPS genotypes of Plasmodium falciparum prior to the adoption of sulfadoxine-pyrimethamine (SP) as first-line treatment for uncomplicated malaria in Tanzania. Children under five years (n = 117) with clinical, uncomplicated malaria were randomly allocated to standard treatments of either chloroquine (CQ) (25 mg/kg) or SP (25 mg sulfadoxine and 1.25 mg pyrimethamine/kg). Patients were monitored for 28 days. Clinical recovery was achieved in 98% (n = 58) and 90% (n = 59) of the patients in the SP and CQ groups, respectively. Parasitologically, 14% of the patients in the SP group and 51% in the CQ group exhibited RII/RIII resistance. When relating pre-treatment blood drug levels to treatment outcome and the degree of parasite resistance to the number of mutations, no relationships could be detected. There was an overall significant increase in haemoglobin levels from day 0 to day 28 in both patient groups. Sulfadoxine-pyrimethamine produced an acceptable clinical response but the high degree of parasitological resistance (RII/RIII) observed two years prior to the introduction of the drug as first-line treatment is of concern, especially considering the long half-lives of sulfadoxine and pyrimethamine.

Animals↗
PubMed2004

Physicians' perceptions of possibilities and obstacles prior to implementing a computerised drug prescribing support system.

Seeks to identify physicians' perceptions of possibilities and obstacles prior to implementing a computerised drug prescribing support system. Details a descriptive, qualitative study, with semi-structured individual interviews of 21 physicians in the Accident and Emergency Department of South Stockholm General Hospital. Identifies four descriptive categories for possibilities and obstacles. Concludes that gaining access to patient drug history enables physicians to carry out work in a professional way--a need the computerised prescription support system was not developed for and thus cannot fulfil. Alerts and producer-independent drug information are valuable in reducing workload. However, technical prerequisites form the base for a successful implementation. Time must be given to adapt to new ways of working.

Attitude of Health Personnel↗
PubMed2003

High-performance liquid chromatographic method for determination of amodiaquine, chloroquine and their monodesethyl metabolites in biological samples.

A high-performance liquid chromatographic method for determination of amodiaquine (AQ), desethylamodiaquine (DAQ), chloroquine (CQ) and desethylchloroquine (DCQ) in human whole blood, plasma and urine is reported. 4-(4-Dimethylamino-1-methylbutylamino)-7-chloroquinoline was used as internal standard. The drugs and the internal standard were extracted into di-isopropyl ether as bases and then re-extracted into an acidic aqueous phase with 0.1 M phosphate buffer at pH 4.0 for AQ samples and at pH 2.5 for CQ filter paper samples. A C(18) column was used and the mobile phase consisted of methanol-phosphate buffer (0.1 M, pH 3)-perchloric acid (250: 747.5:2.5, v/v). The absorbance of the drugs was monitored at 333 nm and no endogenous compound interfered at this wavelength. The limit of quantification in whole blood, plasma and urine was 100 nM for AQ and DAQ (sample size 100 microliter) as well as for CQ and DCQ in blood samples dried on filter paper. For 1000 microliter AQ and DAQ samples, the limit of quantification was 10 nM in all three biological fluids. The within-assay and between-assay coefficients of variations were always <10% at the limits of quantification. Plasma should be preferred for the determination of AQ and DAQ since use of whole blood may be associated with stability problems.

Amodiaquine↗
PubMed2003

Evaluation of the quality of amodiaquine and sulphadoxine/pyrimethamine tablets sold by private wholesale pharmacies in Dar Es Salaam Tanzania.

OBJECTIVE: There are several independent reports in Tanzania of treatment failures with commercially available sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) brands. The aim of this work was to assess the quality of SP and AQ tablets marketed by wholesale pharmacies in Dar Es Salaam, Tanzania. METHODS: All eight wholesale pharmacies authorized to import medicines and located in Dar Es Salaam were included in the study. From each pharmacy, samples of all SP and AQ brands available at the time of sampling were bought, provided they had a shelf-life of at least 1 year. A sample was either an intact box of 100 tablets or a sealed tin of 100 tablets. To ensure blinding, 30 tablets of each sample were removed from their original containers, coded and sent to the quality control laboratory for analysis. The name, strength, batch number, manufacturer and the expiry dates of the tablets were recorded. In total 15 AQ and 18 SP samples were collected. Identity, assay for content of active ingredients and dissolution assay were performed as described in the United States Pharmacopoeia (USP). RESULTS: All samples passed the identity test. Among the AQ samples collected, two of 15 (13%) failed the dissolution test but all passed the assay for content, whereas two of 18 (11%) and eight of 18 (44%) SP samples failed the assay for content and dissolution tests, respectively. None of the pharmacies stocked all AQ and SP brands. CONCLUSION: This work reveals the availability of poor quality antimalarial drugs on the Tanzanian market. Use of substandard drugs could have serious clinical consequences to patients. The results support the need for continuous monitoring of the quality of marketed drugs to ensure safety and efficacy of these products in the treatment of malaria in endemic areas.

Amodiaquine↗
PubMed2002

Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity.

OBJECTIVE: There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. METHODS: Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. RESULTS: Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). CONCLUSIONS: There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.

Adult↗
PubMed2001

Simultaneous determination of quinine and four metabolites in plasma and urine by high-performance liquid chromatography.

The determination of quinine, (3S)-3-hydroxyquinine, 2'-quininone and (10R)- and (10S)-10,11-dihydroxydihydroquinine in plasma and urine samples is described. This is the first time the R and S configurations have been correctly assigned to the two metabolites of 10,11-dihydroxyquinine. One hundred microliter-plasma samples were protein precipitated with 200 microl cold methanol. Urine samples were 10-100 x diluted and then directly injected into the HPLC. A reversed-phase liquid chromatography system with fluorescence detection and a Zorbax Eclipse XDB phenyl column and gradient elution was used. The within and between assay coefficients of variation of the method for quinine and its metabolites in plasma and urine was less than 13%. The lower limit of quantitation was in the range of 0.024-0.081 microM.

Chromatography, High Pressure Liquid↗
PubMed2001

Comparative in vitro and in vivo study of a sugar-coated chloroquine preparation marketed in Tanzania versus an ordinary brand.

OBJECTIVE: To investigate the absorption and the quality of a sugar-coated chloroquine (CQ) marketed in Tanzania. METHOD: Twenty healthy volunteers were randomised to take either the test brand (group A) or a control chloroquine phosphate (group B). Each subject received 300 mg chloroquine base. Whole blood dried on filter papers were collected at time 0 and at 15 and 30 min and at 1, 2, 3, 4, 6, 8, 24, 36, 48, 72 and 168 h after drug intake. Urine samples were collected at time 0, 0-4 h, 4-8 h, 8-24 h, 24-48 h and 48-72 h after drug administration. In an in vitro study, six tablets from each of the two CQ preparations were checked for the amount of active drug contained in each tablet and their dissolution rates. RESULTS: The blood concentration Area Under the Curve (AUC) of group B was about 10% larger than that of group A. The total amounts of CQ plus deethylchloroquine excreted with the urine during the 72-h study period were 5% for group A and 6% for group B. None of the pharmacokinetic parameters were significantly different between the two groups. All the tablets contained the labelled amount of chloroquine; however, one tablet from the test drug failed to fulfil the required dissolution rate. CONCLUSION: We found no major difference between the AUCs of the two CQ preparations, but the sugar-coated brand has shown to have variable dissolution rate.

Adolescent↗
PubMed2001

Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity.

Debrisoquine metabolism among Tanzanians has been found to be slower than expected from the CYP2D6 genotype. In order to evaluate any genetic explanation, the coding sequence and intron-exon boundaries of the CYP2D6 gene from three Black Tanzanian volunteers with a CYP2D6*1/*1 or CYP2D6*2/*2 genotype and debrisoquine metabolic ratios (MRs) > 1 were fully sequenced to screen for new mutations. Two functional mutations, G1747 to A (causing V136I) and G3271 to A (causing V338M), were identified in the CYP2D6*2/*2 sample. Thirty-six subjects (34%) out of a total 106 subjects were heterozygous and three subjects (3%) were homozygous for the allele, yielding an allele frequency of 20%. The CYP2D6*29 allele, having also the mutations of the CYP2D6*2 allele, was subsequently expressed in yeast and mammalian COS-1 cells. No differences were seen with respect to the affinity (Km) or maximal velocity (Vmax) of the CYP2D6 substrate bufuralol between the wild-type and mutant when expression was carried out in yeast cells. By contrast, the 1'-hydroxybufuralol catalytic activity of the mutant expressed in COS-1 cells was only 26% of the wild-type (P < 0.01; Mann-Whitney U-test) and its debrisoquine hydroxylation activity was 63% of that of CYP2D6.1. The single mutants V136I and V338M had reduced capacity for bufuralol hydroxylation, but the effect was even stronger when both mutations were present together as in CYP2D6.29. Analysis of the distribution of CYP2D6*29 in subjects phenotyped for debrisoquine revealed that this allele significantly causes a reduction in the rate of debrisoquine hydroxylation in vivo. The results indicate the common existence in Tanzanians of a variant CYP2D6 form with different substrate specificity as compared to the wild-type form of the enzyme causing reduced capacity for debrisoquine metabolism.

Alleles↗
PubMed2000

Methadone, ciprofloxacin, and adverse drug reactions.

Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 and CYP3A4 activity, two of the cytochrome p450 isozymes involved in the metabolism of methadone.

Adult↗
PubMed2000

Postoperative nausea and vomiting after breast surgery: efficacy of prophylactic ondansetron and droperidol in a randomized placebo-controlled study.

Postoperative nausea and vomiting (PONV) is a common adverse phenomenon following breast surgery. The efficacy of ondansetron and droperidol in preventing post-operative nausea and vomiting in women undergoing breast surgery was compared in this randomized, double-blind, placebo-controlled study. Altogether 207 women were randomly assigned to receive either a single intravenous dose of droperidol (1.25 mg) (n = 69), ondansetron (8 mg) (n = 67) or saline (n = 71) immediately after induction of general anaesthesia with thiopental, fentanyl, atracurium, nitrous oxide in oxygen and isoflurane. Complaints of nausea, vomiting and requests for rescue antiemetics were recorded during a 24-h period postoperatively. During the initial 2 h in the postanaesthesia care unit, the incidence of postoperative nausea and vomiting was 15%, 6% and 12% in the placebo, droperidol and ondansetron groups, respectively (NS). The incidence of post-operative nausea and vomiting during the first 24 h was 61%, 48% and 45% in the placebo, droperidol and ondansetron treatment groups, respectively (NS). Postoperative analgesic requirements and the length of stay in the post-anaesthesia care unit were equal in all three treatment groups. It is concluded that the intravenous pretreatment with single doses of ondansetron or droperidol did not substantially prevent postoperative nausea and vomiting after breast surgery.

Adolescent↗
PubMed2000

Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype.

BACKGROUND: We have previously found decreased CYP2C19 activity in Tanzanians tested with mephenytoin and omeprazole in relation to genotype when compared with white and Asian subjects. OBJECTIVE: We investigated the impact of CYP2C19 genotype and phenotype on chloroguanide (INN, proguanil) metabolism to its metabolites cycloguanil and 4-chlorophenylbiguanide. METHODS: A single oral chloroguanide dose was given to 25 healthy Tanzanian subjects with CYP2C19 genotypes (CYP2C19*1, CYP2C19*2, and CYP2C19*3). Homozygous wild-type and mutated genotype groups were chosen randomly, but the heterozygous genotype group was chosen with a range in phenotype. We used a novel HPLC method for drug determination. RESULTS: Pharmacokinetics of chloroguanide did not differ between groups. Maximum plasma concentration (Cmax) and area under the plasma concentration versus time [AUC(0-infinity)] for cycloguanil was significantly lower (t test P < .05) in the homozygously mutated group compared with the homozygously wild-type group. There were similar significant group differences of median urinary excretion. The chloroguanide/cycloguanil ratio closely correlated (r(s) = .87) with omeprazole metabolic ratio, confirming that Tanzanian subjects are generally slower CYP2C19 metabolizers. It also confirms that CYP2C19 genotype and phenotype predicts cycloguanil formation. In addition, a 3-hour plasma sample metabolic ratio also seems to be a proper time for omeprazole phenotyping in Tanzanian subjects. Because the plasma concentrations of cycloguanil and 4-chlorophenylbiguanide covary (r(s) = .89), it is now suggested that their formation be catalyzed by the same enzyme (ie, CYP2C19) through a common intermediate, the structure of which is also presented. CONCLUSIONS: As shown in an earlier study, also with a third substrate, Tanzanians have a lower capacity to form cycloguanil than white and Asian subjects. Individuals with two mutated alleles have lower metabolic capacity than individuals with two wild-type alleles or individuals in the heterozygous group, which may lead to chloroguanide therapeutic failure. This knowledge should be important when selecting appropriate patients and doses of chloroguanide in different populations.

Antimalarials↗
PubMed2000

Changes in 2f1 - f2 acoustic distortion products in humans during quinine-induced cochlear dysfunction.

Quinine is a suitable model substance for the study of otoacoustic emissions (OAEs) as it reversibly affects the outer hair cells, thus reducing sensitivity, frequency-selectivity and various forms of OAEs. The aim of this experiment was to study quinine-induced changes in the input/output (I/O) function of 2f1 - f2 distortion product OAE (DPOAE; f2/f1 = 1.22; 750-6,000 Hz). Six volunteers with normal hearing (26-39 years old) were intravenously infused to achieve pseudostable quinine plasma concentrations (approximately12 microM) inducing an average pure-tone threshold (PTT; 750-6,000 Hz) shift of 18 dB (5-30 dB) (frequency-independent and reversible). The mean quinine-induced DPOAE shift increased continuously with decreasing equal-level primary tones, e.g. from 1.0 dB at 70 dB sound pressure level (SPL) (n = 42) to 10.5 dB (n = 22) at 40 dB SPL (pooled data, no frequency dependence). According to recruitment, the mean slope of the DPOAE I/O function (at 30-60 dB SPL) increased from 0.86 to 1.35 dB/dB. The lack of correlation between shifts in DPOAE and PTT is in stark contrast to the excellent correlation reported between shifts in transient evoked OAE detection threshold and its corresponding psychoacoustic threshold. The highly vulnerable spontaneous OAEs, in combination with the less vulnerable DPOAEs, fit into a recently proposed taxonomic classification for OAEs.

Adult↗
PubMed1999

The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo.

OBJECTIVE: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo. METHODS: In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods. RESULTS: Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05). CONCLUSION: Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.

Adult↗