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  • 1
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    Online Resource
    A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria
    Wiley ; 1998
    In:  British Journal of Clinical Pharmacology Vol. 45, No. 2 ( 1998-02), p. 123-129
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 45, No. 2 ( 1998-02), p. 123-129
    Abstract: Aims  To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. Methods  Twenty‐six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non‐compartmental methods. The time to 50% parasite clearance (PCT 50  ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic‐pharmacodynamic relationships. Results  Following i.v. bolus, ARTS had a peak concentration of 29.5 μm (11 mg l −1  ), elimination t 1/2 =2.7 min, CL=2.33 l h −1  kg −1 and V =0.14 l kg −1 . The C max for DHA was 9.3 μm (2.64 mg l −1  ), t 1/2 =40 min, CL=0.75 l h −1  kg −1 and V =0.76 l kg −1 . Following oral ARTS, relative bioavailability of DHA was 82%, C max was 2.6 μm (0.74 mg l −1  ), t 1/2 =39 min, and MAT=67 min. Overall, the PCT 50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT 50 or FCT and AUC, C max or MRT for DHA. Conclusions  Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.1365-2125.1998.00655.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 1998
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  • 2
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    Glucuronidation of Dihydroartemisinin in Vivo and by Human Liver Microsomes and Expressed UDP-Glucuronosyltransferases
    American Society for Pharmacology & Experimental Therapeutics (ASPET) ; 2002
    In:  Drug Metabolism and Disposition Vol. 30, No. 9 ( 2002-09-01), p. 1005-1012
    Details
    In: Drug Metabolism and Disposition, American Society for Pharmacology & Experimental Therapeutics (ASPET), Vol. 30, No. 9 ( 2002-09-01), p. 1005-1012
    Type of Medium: Online Resource
    ISSN: 0090-9556 , 1521-009X
    URL: Article
    DOI: 10.1124/dmd.30.9.1005
    Language: English
    Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
    Publication Date: 2002
    detail.hit.zdb_id: 186795-7
    detail.hit.zdb_id: 1500213-5
    SSG: 15,3
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  • 3
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    Pharmacokinetics and Pharmacodynamics of Intravenous Artesunate in Severe Falciparum Malaria
    American Society for Microbiology ; 2001
    In:  Antimicrobial Agents and Chemotherapy Vol. 45, No. 1 ( 2001-01), p. 181-186
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 45, No. 1 ( 2001-01), p. 181-186
    Abstract: To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT 50 ) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives ( t 1/2 ) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t 1/2 (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups ( P 〉 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT 50 range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.45.1.181-186.2001
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2001
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    SSG: 12
    SSG: 15,3
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  • 4
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    Penetration of Dihydroartemisinin into Cerebrospinal Fluid after Administration of Intravenous Artesunate in Severe Falciparum Malaria
    American Society for Microbiology ; 2003
    In:  Antimicrobial Agents and Chemotherapy Vol. 47, No. 1 ( 2003-01), p. 368-370
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 47, No. 1 ( 2003-01), p. 368-370
    Abstract: Penetration of cerebrospinal fluid (CSF) by artesunate and DHA was assessed in six adults with cerebral or severe malaria. Lumbar punctures were performed on admission and during convalescence, at 15 min (patient 1), 30 min (patient 2), 45 min (patient 3), 60 min (patient 4), 90 min (patient 5), and 120 min (patient 6) after intravenous administration of 120 mg of artesunate. No artesunate was detectable in CSF. In both studies, DHA levels in CSF increased with time while dihydroartemisinin levels in plasma fell. Dihydroartemisinin might accumulate in CSF during frequent artesunate dosing.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.47.1.368-370.2003
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2003
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
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  • 5
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    Variability in white blood cell count during uncomplicated malaria and implications for parasite density estimation: a WorldWide Antimalarial Resistance Network individual patient data meta-analysis
    Springer Science and Business Media LLC ; 2023
    In:  Malaria Journal Vol. 22, No. 1 ( 2023-06-06)
    Details
    In: Malaria Journal, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2023-06-06)
    Abstract: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood sample is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance. Methods Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an individual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/µL and age-stratified values) using estimates derived from the measured WBC value as reference. Results Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (× 1000 cells/µL) in age groups  〈  1, 1–4, 5–14 and ≥ 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for individuals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for individuals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/µL resulted in parasite density underestimation by a median (IQR) of 26% (4–41%) in infants  〈  1 year old but an overestimation by 50% (16–91%) in adults aged ≥ 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve precision of parasitaemia estimation. Imprecision of parasite clearance estimates was only affected by the within-patient WBC variability over time, and remained  〈  10% for 79% of patients. Conclusions Using an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management; but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.
    Type of Medium: Online Resource
    ISSN: 1475-2875
    URL: Article
    DOI: 10.1186/s12936-023-04583-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2091229-8
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  • 6
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    The Hypothalamic-Pituitary-Adrenocortical Axis in Severe Falciparum Malaria: Effects of Cytokines 1
    The Endocrine Society ; 1997
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 ( 1997-09), p. 3029-3033
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 82, No. 9 ( 1997-09), p. 3029-3033
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.82.9.4196
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1997
    detail.hit.zdb_id: 2026217-6
    detail.hit.zdb_id: 3029-6
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  • 7
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    Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria
    Wiley ; 2001
    In:  British Journal of Clinical Pharmacology Vol. 51, No. 6 ( 2001-06), p. 541-546
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 51, No. 6 ( 2001-06), p. 541-546
    Abstract: Aims  To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria. Methods  Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n  = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n  = 8) or DHA (120 mg; Group 2, n  = 7), in a randomized cross‐over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT 50 ) and fever clearance time (FCT) also were measured. Results  In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT 50 and FCT were 2.3 and 28 h, respectively. Conclusions  The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose‐normalized C max and AUC(0,∞) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first‐pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.1365-2125.2001.01395.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2001
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    detail.hit.zdb_id: 188974-6
    SSG: 15,3
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  • 8
    Online Resource
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    Serum Vitamin A and E Concentrations in Acute Falciparum Malaria: Modulators or Markers of Severity?
    Portland Press Ltd. ; 1994
    In:  Clinical Science Vol. 87, No. 5 ( 1994-11-01), p. 505-511
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 87, No. 5 ( 1994-11-01), p. 505-511
    Abstract: 1. To assess the association between vitamin A, vitamin E and the clinical course of severe malaria, serial morning blood samples were taken from 24 Vietnamese patients, aged 18–62 years, receiving intensive treatment for complicated Plasmodium falciparum infections. A single fasting blood sample was also taken from 10 control subjects aged 22–45 years. Serum retinol, carotene and vitamin E concentrations were measured by h.p.l.c. 2. Admission serum retinol concentration was depressed relative to that of the control subjects (0.69 ± 0.35 versus 1.86 ± 0.41μmol/l mean ± SD, P & lt; 0.001) and correlated inversely with indices of hepatic function, but positively with the simultaneous serum creatinine concentration (P & lt; 0.05). During the first week of treatment, serum retinol concentration increased in parallel with improving liver function, whereas serum creatinine concentration remained elevated in the majority of patients. Serum α- and β-carotene concentrations remained depressed throughout. 3. Serum vitamin E concentration, corrected for total serum cholesterol concentration in the form of a ratio, was also depressed at presentation (3.1 ± 1.8×103 versus 4.2 ± 0.8×103 in control subjects; P & lt; 0.05), but tended to be higher than the control value at the time of discharge (0.1 & gt; P & gt; 0.05); there was a significant correlation between admission ratio and parasite clearance time (P = 0.04). 4. On the basis of this and previous studies, vitamin A replacement could be considered in selected severely ill patients without renal impairment. As found previously in animal models, depressed vitamin E levels may have a beneficial effect on the course of malarial infection.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/cs0870505
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1994
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    detail.hit.zdb_id: 1484392-4
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  • 9
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    The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria
    Wiley ; 2002
    In:  British Journal of Clinical Pharmacology Vol. 53, No. 1 ( 2002-01), p. 23-30
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 53, No. 1 ( 2002-01), p. 23-30
    Abstract: Aims  To obtain pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.m. ARTS and rectal DHA administration. Methods  Twelve Vietnamese patients with uncomplicated falciparum malaria were randomized to receive either i.v. or i.m. ARTS (120 mg), with the alternative preparation given 8 h later in an open crossover design. A further 12 patients were given i.v. ARTS (120 mg) at 0 h and rectal DHA (160 mg) 8 h later. Results  Following i.v. bolus, ARTS had a peak concentration of 42 µ m (16 mg l −1 ), elimination t 1/2  = 3.2 min, CL = 2.8 l h −1 kg −1 and V  = 0.22 l kg −1 . The C max for DHA was 9.7 µ m (2.7 mg l −1 ), t 1/2  = 59 min, CL = 0.64 l h −1  kg −1 and V  =  0.8 l kg −1 . Following i.m. ARTS, C max was 2.3 µ m (3.7 mg l −1 ), the apparent t 1/2  = 41 min, CL = 2.9 l h −1 kg −1 and V  = 2.6 l kg −1 . The relative bioavailability of DHA was 88%, C max was 4.1 µ m (1.16 mg l −1 ) and t 1/2  = 64 min. In the rectal DHA study, relative bioavailability of DHA was 16%. Conclusions  For patients with uncomplicated falciparum malaria i.m. ARTS is a suitable alternative to i.v. ARTS, at equal doses. To achieve plasma DHA concentrations equivalent to parenteral administration of ARTS, rectal DHA should be given at approximately four‐fold higher milligram doses. Further studies are needed to determine whether these recommendations can be applied to patients with severe malaria.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.0306-5251.2001.01519.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1498142-7
    detail.hit.zdb_id: 188974-6
    SSG: 15,3
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