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Biomedical subjects

J Karbwang

Publications and source records attributed to J Karbwang.

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

Ex vivo blood schizontocidal activities of artemisinin derivatives against Plasmodium falciparum.

Serum samples collected at intervals from eight healthy volunteers after the administration of the six regimens of artemisinin derivatives were investigated for their ex vivo blood schizontocidal activities against K1 strain Plasmodium falciparum. The regimens included single doses of (a) 300 mg oral artemether; (b) 300 mg intramuscular artemether; (c) 100 mg suppository artemether; (d) 300 mg oral artesunate (Guillin formulation); (e) 300 mg oral artesunate (Arenco formulation); (f) 300 mg oral dihydroartemisinin. Sera collected after various regimens of artemisinin derivatives showed distinct degree of ex vivo blood schizontocidal activities. Activity of sera after suppository dosing was remarkably low and variable comparing to the other two formulations (oral, intramuscular). Median values for Amax (the maximum activity normalized with dose) of sera from oral dosing were 2.4- and 118-fold, while AUA (the area under activity-time curve, normalized with dose) were 0.82- and 2,370-fold of that after the intramuscular and suppository dosing, respectively. Sera from artesunate-Arenco dosing exhibited significantly higher Amax and AUA (medians: Amax 12.4 vs 5.13 nmol/l/mg dose; AUA: 21.9 vs 8.8 nmol x h/ml/mg dose), compared to that from artesunate-Guillin dosing. Among the oral formulations of artemisinin derivatives investigated (artemether, artesunate, dihydroartemisinin), sera collected following a single dose of oral dihydroartemisinin exhibited lowest bioactivity (Amax 2.35 nmol/l/mg dose; AUA: 44 nmol x h/ml/mg dose).

Administration, Oral↗
PubMed1998

Chiral chromatographic method to determine the enantiomers of halofantrine and its main chiral desbutyl metabolite in erythrocytes.

We describe a direct liquid chromatographic method with spectrofluorimetric detection to quantify the two enantiomers of halofantrine and the two enantiomers of its main chiral N-monodesbutylated metabolite in erythrocyte pellets. The method involves a Chiralpak AD column and a rapid one-step extraction procedure with acetonitrile. The method was validated for the four enantiomers within the range 0-1000 ng/ml. The absence of stereoconversion was studied in samples stored frozen for up to eight months. The optical rotation of the halofantrine and metabolite enantiomers was determined after separation on a semi-preparative Chiralcel OD column with polarimetric detection.

Administration, Oral↗
PubMed1998

Simple high-performance liquid chromatographic method with electrochemical detection for the simultaneous determination of artesunate and dihydroartemisinin in biological fluids.

A simple, rapid, sensitive, selective and reproducible high-performance liquid chromatographic method with reductive electrochemical detection is described for the simultaneous quantification of artesunate (ARS) and dihydroartemisinin (DHA) in plasma. The procedure involved the extraction of ARS, DHA and the internal standard (artemisinin, ARN) with a mixture of dichloromethane and tert.-methyl butyl ether (8:2, v/v). Chromatographic separation consisted of the mobile phase (acetonitrile-water containing 0.1 M acetic acid, pH 4.8; 45:55, v/v) running through the column (Nova-Pak C18, 150 cm x 3.9 mm I.D., 5 microm particle size). The retention times of alpha-DHA, beta-DHA, ARS and ARN were 2.9, 4.2, 4.5 and 6.0 min, respectively. The average recoveries of ARS, alpha-DHA and ARN in the concentration range of 10-800 ng/ml were 81.9, 88.2, 101.1 and 84.3%, respectively. The coefficients of variation (precision and repeatability) were below 10% for all three compounds at concentrations of 50, 200, 400 and 800 ng/ml, and below 20% at a concentration of 10 ng/ml. The limits of quantification for both ARS and alpha-DHA in spiked plasma samples were 5 and 3 ng/ml, respectively. The method was found to be suitable for application to pharmacokinetic studies of both ARS and DHA.

Adult↗
PubMed1998

Pharmacokinetics of intramuscular artemether in patients with severe falciparum malaria with or without acute renal failure.

AIMS: The pharmacokinetics of intramuscular artemether and its major plasma metabolite-dihydroartemisinin, were investigated in patients with severe manifestations of falciparum malaria. METHODS: Six severe falciparum malaria patients with acute renal failure (ARF) and 11 without ARF were recruited into the study. They were treated with intramuscular artemether at a loading dose of 160 mg, followed by daily doses of 80 mg for another 6 days (total dose 640 mg). RESULTS: Patients with and without ARF showed a good initial response to treatment; the parasite and fever clearance times were 66(30-164) and 76(36-140) h [median(range)], respectively. None had reappearance of parasitaemia in their peripheral blood smear within 7 days of initiation of treatment. In comatose patients, the time to recovery of consciousness was 51.6(22-144) h. Artemether was detected in plasma as early as 1 h after a 160 mg dose, and declined to undetectable levels within 24 h in most cases. Patients with ARF had significantly higher Cmax [2.38(1.89-3.95) vs 1.56(1.05-3.38) ng ml(-1) mg(-1) dose], AUC [35.4(22-52.9) vs 25.2(13.4-52.9) ng ml(-1) h mg(-1) dose], and lower Vz/F [5.45(3.2-6.9) vs 8.6(4.2-12.3) l kg(-1)] and CL/F [7.4(5.4-13.8) vs 19.1(8.5-25.1) ml min(-1) kg(-1)] when compared with those without ARF. In addition, t1/2,z was significantly longer in ARF patients [7.0(5.5-10.0) vs 5.7(4.2-6.6) h]. The pharmacokinetics of dihydroartemisinin in the two groups of patients were comparable. CONCLUSIONS: ARF significantly modified the pharmacokinetics of intramuscular artemether. The changes could be attributed to either improved absorption/bioavailability, a reduction of systemic clearance, or a change in plasma protein binding of the drug.

Acute Kidney Injury↗
PubMed1998

Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients.

AIMS: To investigate the pharmacokinetic and pharmacodynamic properties of artemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinical trial. METHODS: Two hundred and sixty patients were enrolled into a randomized, double-blind, parallel group, dose-finding trial. CGP 56697 was given orally, either as: A, 4 x 4 tablets over 48 h; B, 4 x 2 tablets over 48 h or C, 3 x 4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumetol 120 mg. The pharmacokinetics were determined using a population-based approach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the derived pharmacokinetic parameters. RESULTS: The median absorption half-life of benflumetol was 5.3 h, with a tmax of 10 h and terminal elimination half-life of 4.5 days. For artemether (and its metabolite, dihydroartemisinin), the corresponding values were 1.9 (1.9) h, 1.8 (1.2) h, and 0.84 (0.43) h. The variability in bioavailability of artemether and dihydroartemisinin was large both between doses and between patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three-fold by the third and fourth doses. Higher artemether or dihydroartemisinin AUC was found to decrease parasite clearance time. Higher benflumetol AUC was found to significantly increase the chance of cure. CONCLUSIONS: Using a population-based approach it was confirmed that the pharmacokinetic and pharmacodynamic properties of benflumetol and artemether differ markedly. Benflumetol AUC is associated with cure and the effect of benflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer elimination half-life. A short course of low-dose artemether, which is rapidly absorbed and has a short elimination half-life, produced effective parasite clearance. The complementary pharmacokinetic and pharmacodynamic properties of benflumetol and artemether was the main rationale for developing a fixed-dose combination. While the 4 x 4 dose regimen is very effective in most endemic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.

Adolescent↗
PubMed1998

Plasma concentrations of artemether and its major plasma metabolite, dihydroartemisinin, following a 5-day regimen of oral artemether, in patients with uncomplicated falciparum malaria.

Plasma concentrations of artemether and its active plasma metabolite (dihydroartemisinin) were measured in 49 male, Thai patients with acute, uncomplicated, multidrug-resistant, Plasmodium falciparum malaria, following their treatment with oral artemether (300 mg on the first day, then 100 mg daily for another 4 days). Four patients recrudesced (on days 19-22). After the first dose, artemether became undetectable in < or = 18 h and this drug was also undetectable in samples collected immediately before each dose. Although dihydroartemisinin followed similar trends, three patients had detectable plasma concentrations of this metabolite 24 h after the first dose (i.e. immediately before the second dose). Median (range) values for plasma concentrations of dihydroartemisinin 6 h [354 (150-751) v. 196 (178-220) ng/ml] and 12 h [158 (25-420) v. 54 (25-115) ng/ml] after the initial dose, estimated antimalarial activities (calculated as dihydroartemisinin equivalents) 6 h [331 (78.2-644.1) v. 23 (183.3-270) nmol/litre] and 12 h [98.3 (10-192.2) v. 56.7 (9.8-59.4) nmol/litre] after the initial dose, and the corresponding 'areas under the curves' (AUC) [3684 (1562-8216) v. 834 (1401-2030) ng.h/ml] were all significantly higher in the patients with sensitive responses than in those who recrudesced.

Acute Disease↗
PubMed1998

Pharmacokinetic interactions of artemether and pyrimethamine in healthy male Thais.

The pharmacokinetics of a single oral dose of artemether (300 mg) and pyrimethamine (100 mg) given as each individual drug alone or as a drug combination (artemether 300 mg plus pyrimethamine 100 mg), were investigated in 8 healthy male Thai volunteers. Both artemether and pyrimethamine were rapidly absorbed after oral administration. Elimination of pyrimethamine was however, a relatively slow process compared with artemether, and thus resulted in a long terminal phase elimination half-life (50-106 hours). Pharmacokinetics of artemether and dihydroartemisinin following a single oral dose of artemether alone or in combination with pyrimethamine were similar. In contrast, coadministration of artemether resulted in significantly increased Cmax (medians of 818 vs 1,180 ng/ml) and contracted the apparent volume of distribution (medians of 3 vs 2.56 l/kg) of pyrimethamine.

Adult↗
PubMed1998

Compliance with artesunate and quinine + tetracycline treatment of uncomplicated falciparum malaria in Thailand.

A randomized, controlled, malaria-clinic-based field trial was conducted to compare compliance with a 7-day quinine + tetracycline regimen and a 5-day 700-mg artesunate regimen for the treatment of uncomplicated falciparum malaria in a community in Thailand. Of 137 patients, aged 15-60 years attending a malaria clinic, 77 received artesunate and 60 received quinine + tetracycline. Compliance and cure rates were evaluated on days 5 (artesunate) and 7 (quinine + tetracycline) using patient interview/residual pill counts and peripheral blood smear, respectively. Data were analysed using the intention-to-treat approach, and the reasons for compliance and noncompliance were investigated. Compliance was significantly higher (98.4%) with artesunate than with quinine + tetracycline (71.7%) (relative risk adjusted for sex (aRR) = 1.39 (95% C.I. = 1.15-1.68); referent: quinine + tetracycline). Cure rate (100%) was higher in those receiving artesunate than quinine + tetracycline (77.4%) (aRR = 1.32 (95% C.I. = 1.12-1.55)). Reasons for compliance included the desire to be cured and to follow the advice of malaria staff/employer, and the simple dosing regimen. Noncompliance was mostly due to adverse reactions and forgetting to take the drugs. These results can serve as a baseline for designing and evaluating new interventions to improve compliance, as well as for studying cost-effectiveness to help drug policy decision-making. We recommend a strategy which integrates a short-course, once-a-day regimen (with minimal adverse reactions), a better delivery system for antimalarial drugs and health education, and an enhanced advisory role of malaria staff. Considering the higher compliance rate and curative effectiveness of artesunate, we recommend its use instead of quinine + tetracycline for the treatment of uncomplicated malaria in clinics in Thailand.

Adolescent↗
PubMed1998

Initial evaluation of low-dose phenobarbital as an indicator of compliance with antimalarial drug treatment.

Since poor compliance with antimalarial therapy is often suspected but difficult to prove, this study attempted to establish a model for predicting the plasma concentration of phenobarbital (given in low doses in conjunction with the drug) as an indicator of compliance. Phenobarbital was chosen because its value had been demonstrated as a marker of compliance in long-course therapies, any significant departure from steady-state concentrations (achieved with full compliance) indicating one or more missed doses. Therapy for uncomplicated malaria varies from 5 days with artesunate to 7 days with quinine + tetracycline. Volunteers with confirmed falciparum malaria were randomized into 5 groups and given malaria therapy as well as phenobarbital daily for 3-7 days. Plasma samples for determination of phenobarbital concentrations were taken just prior to the daily dose of phenobarbital. Although there was a clear and predictable individual pattern of blood concentrations following each dose of phenobarbital, inter-individual variation in blood levels was significant and reduced their predictive value beyond the second day's dose. The cause of the variations is not clear; it could be attributable to different sources of the drug, previous intake of phenobarbital by the patient, or differences in drug absorption and disposition in malaria patients. Results for the 5-day artesunate regimen suggest that phenobarbital may be useful as a marker of compliance if the patient stops medication after 3 days; clear differences were evident at the end of the course of treatment between plasma phenobarbital concentrations in individuals completing the 5-day course and those who stopped after 3 days. For the quinine-tetracycline regimen, results suggest that it may be possible to discriminate between subjects where there is a 3-day difference in treatment. Phenobarbital is a better discriminant when dosing is every 24 hours as with artesunate, rather than the 8-hourly regimen for quinine-tetracycline. When measuring compliance for malaria treatment, if it is important to know what proportion of patients reach 3, 5 or 7 days of compliance, then phenobarbital might have a role to play in this assessment, but further investigations in more patients would be required. Alternatively, different markers could be used for the doses to be given on these days and, as long as the patient does not mix the doses for the different days, sequential doses and determination of compliance could be based on an "all or none" detection of the marker rather than on drug levels.

Adolescent↗
PubMed1998

Plasma containing artemether-pyrimethamine has ex vivo blood schizonticidal activity against Plasmodium falciparum.

Plasma samples collected at intervals from healthy volunteers, after administration of 3 drug regimens [artemether (ART) 300 mg, pyrimethamine (PYR) 100 mg, and ART 300 mg plus PYR 100 mg] were examined for blood schizonticidal activity against K1 strain and T(9/94) clone of Plasmodium falciparum ex vivo. A synergistic effect against T(9/94), a pyrimethamine sensitive clone, was observed in plasma collected after ART+PYR administration, when the test was carried out in low p-aminobenzoic acid, low folic acid medium. The maximum activity (Amax), expressed as equivalent dihydroartemisinin concentration, for plasma samples collected after the combined ART+PYR regimen [6,935 (1,330-13,400) nmol/l] was significantly higher than those for the single ART or PYR regimens [935 (397-2,000) and 9.9 (5.6-15.6) nmol/l, respectively]. In addition, the area under the activity curve (AUA) for the combined regimen [12,8397 (39,274-19,7901) nmol.h/l] was significantly higher than those for the single ART or PYR regimens [(3618 (1406-5597) or 334 (82.3-733.3) nmol.h/l, respectively]. Microscopic observation revealed that ART in the combined regimen exerted its inhibitory effect against all erythrocytic stages and that this occurred before effects of PYR activity. Prolongation of inhibitory effects for the combined ART+PYR regimen was shown to be due to PYR activity by comparison to the activity from the single ART regimen. Results clearly demonstrated no PYR activity against K1, a pyrimethamine resistant strain, in plasma samples collected after the single PYR regimen and the ART+PYR regimen. Microscopic examination confirmed that growth inhibition of K1 was caused by ART activity only.

Animals↗
PubMed1997

Determination of artemether and its major metabolite, dihydroartemisinin, in plasma using high-performance liquid chromatography with electrochemical detection.

A rapid, selective, sensitive and reproducible HPLC with reductive electrochemical detection for quantitative determination of artemether (ART) and its plasma metabolite, dihydroartemisinin (DHA: alpha and beta isomers) in plasma is described. The procedure involved the extraction of ART, DHA and the internal standard, artemisinin (ARN) with dichloromethane-tert.-methylbutyl ether (1:1, v/v) or n-butyl chloride-ethyl acetate (9:1, v/v). Chromatographic separation was performed with a mobile phase of acetonitrile-water (20:80, v/v) containing 0.1 M acetic acid pH 5.0, running through a microBondapak CN column. The method was capable of separating the two isomeric forms of DHA (alpha, beta). The retention times of alpha-DHA, beta-DHA, ARN and ART were 4.6, 5.9, 7.9 and 9.6 min, respectively. Validation of the assay method was performed using both extraction systems. The two extraction systems produced comparable recoveries of the various analytes. The average recoveries of ART, DHA and ARN over the concentration range 80-640 ng/ml were 86-93%. The coefficients of variation were below 10% for all three drugs (ART, alpha-DHA, ARN). The minimum detectable concentrations for ART and alpha-DHA in spiked plasma samples were 5 and 3 ng/ml, respectively. The method was found to be suitable for use in clinical pharmacokinetic study.

Adult↗
PubMed1997

Alternative method for determination of pyrimethamine in plasma by high-performance liquid chromatography.

A rapid, selective, sensitive and reproducible reversed-phase high-performance liquid chromatography (HPLC) procedure for the quantitative determination of pyrimethamine (PYR) in plasma is described. The procedure involved the two-step extraction of PYR and the internal standard, quinine (QN) with acetonitrile and dichloromethane at basic pH. Chromatographic separation consisted of the mobile phase (methanol-water containing 0.005 M octanesulfonic acid, 50:50, v/v) running through the column (Techopak-10 C18) at a flow-rate of 1.6 ml/min. Detection was at UV wavelength of 240 nm. The mean recoveries of PYR and QN at a concentration range of 50 and 500 ng/ml were 98.9 and 89%, and 94.7 and 96% for PYR and QN. The within-day coefficients of variation were 2.1-5.1% for PYR and 5.9% for QN. The day-to-day coefficients of variation were 2.1-4.1% for PYR and 5% for QN. The minimum detectable concentrations for PYR and QN in plasma were 3 and 10 ng/ml. The method was found to be suitable for use in clinical pharmacokinetic study.

Calibration↗
PubMed1997

Pharmacokinetics and bioavailability of oral and intramuscular artemether.

OBJECTIVE: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. RESULTS: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18-24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng.ml-1; tmax: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 micrograms.h.ml-1]. Geographic means of lag-time and absorption half-life (t1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively, t1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60). artemisinin, which is commercially available in China, Vietnam, Thailand and some African countries. The drug is administered as solution in oil for intramuscular injection or as oral tablets. The clinical efficacy of artemether is dependent on the formulation, dosing scheme, duration of treatment, and the severity of the disease [1, 2]. Oral artemether is effective but with short-term treatment, the relapse rate is high. While the efficacy of intramuscular artemether against multidrug-resistant P. falciparum in either uncomplicated or severe cases has been confirmed, its pharmacokinetic documentation is limited. Formulations with high bioavailability and low costs are essential. With high-performance liquid chromatography and electrochemical detection, more sensitive and reliable assay of artemisinin and derivatives in biological fluids has been achieved [3-4]. In the present study, we have assessed the pharmacokinetics and bioavailability of oral and intramuscular artemether, in healthy Thai males.

Administration, Oral↗
PubMed1997

Compliance with a 2 day course of artemether-mefloquine in an area of highly multi-drug resistant Plasmodium falciparum malaria.

AIMS: Multi-drug resistant Plasmodium falciparum malaria is a rapidly increasing problem in the world, particularly Thailand. Practical antimalarial regimens which are highly effective against multi-drug resistant parasites with short-term course of administration are needed. In this study, we assessed the patient compliance of a short course regimen using artemether-mefloquine. METHODS: Clinical effectiveness (efficacy, tolerability and patient compliance) of a 2-day regimen of artemether-mefloquine was evaluated in 126 patients with acute uncomplicated falciparum malaria who were attending the two malaria clinics in an area of highly multi-drug resistant P. falciparum malaria (Thai-Myanmar border). Patients were treated with a single oral dose of 300 mg artemether on the day of attendance. Two additional doses of mefloquine were given for home treatment on the following day (750 and 500 mg after breakfast and lunch, respectively). RESULTS: The combination regimen was effective, with a cure rate of 92.6%. Based upon the concentrations of whole blood mefloquine on day-2, compliance for this 2 day regimen of artemether-mefloquine was 98.1% (full compliance 86.8%, partial compliance 11.3%, non-compliance 1.9%). CONCLUSIONS: We conclude that the 2 day regimen of artemether-mefloquine is, at present, a good alternative regimen for the treatment of uncomplicated multi-drug resistant falciparum malaria.

Administration, Oral↗
PubMed1997

In vitro blood schizonticidal activity of sera containing mefloquine-quinine against Plasmodium falciparum.

Serum samples collected at intervals from healthy volunteers, after the administration of 3 drug regimens (quinine (QN) 600 mg, mefloquine (MQ) 750 mg, and MQ 750 mg plus QN 600 mg) were investigated for their blood schizonticidal activities against K1 strain Plasmodium falciparum in vitro. Superiority of activity was shown in the sera collected after the combination regimen. In the diluted sera of the QN regimen, a complete inhibitory effect was observed for only 24 hours, whereas the effect was sustained for 72 hours in the sera collected after MQ in either regimen (MQ alone or MQ/QN). The pattern of minimum inhibitory concentrations (MICs) of QNEq of the sera from QN alone was constant throughout a 24-hour period, with significantly higher concentrations than that from the combination regimen (118-150 vs 21.25-73.5 micrograms/l). In sera collected after the combination regimen, however, the MIC gradually decreased from 0.5 until 2.5 and 4 h, and thereafter gradually returned to the same levels again during a period of 6-24 hours. The MICs of MQEq when given as MQ alone or in combination appeared constant, with a significantly higher value in the former regimen (24.4-26.8 vs 17-19.2 micrograms/l).

Animals↗
PubMed1997

Effect of artemether on electrocardiogram in severe falciparum malaria.

The effect of intramuscular artemether (intramuscular loading dose of 160 mg, followed by 80 mg daily for another 6 doses), in comparison with that of quinine (intravenous infusion of loading dose of 20 mg/kg, followed by 10 mg/kg q 8 hourly for 7 days), on the electrocardiograph of severe falciparum malaria patients were investigated in 102 Thai patients (92 males, 10 females) admitted to Pra Pokklao Hospital, Chantaburi, southeast of Thailand. Fifty patients (19 with quinine and 31 with artemether) were eligible for ECG analysis. Hypotension was found significantly more common in the quinine group (13 vs 2 cases). Thirteen, 5 and 1 patients with quinine treatment, respectively, had tachycardia, non-specific T-wave change and QTc prolongation. No significant dysrhythmia was found despite high plasma quinine concentrations. Five patients died; their ECGs were not significantly different from those who survived. In the group with intramuscular artemether, 17 cases had tachycardia prior to artemether treatment. QTc prolongation and non-specific T-wave change were found in 2 and 6 cases. One patient had RBBB and second degree AV-block on Day 1, but returned to normal on Day 2. No other dysrhythmia or other significant changes in ECG tracing which would suggest any effect of artemether on cardiovascular system were observed.

Adolescent↗