The Experts below are selected from a list of 36 Experts worldwide ranked by ideXlab platform

Ch B Lugt - One of the best experts on this subject based on the ideXlab platform.

  • A RANDOMIZED CONTROLLED TRIAL OF Artemotil (-ARTEETHER) IN ZAMBIAN CHILDREN WITH CEREBRAL MALARIA
    2015
    Co-Authors: Philip E Thuma, G J Bhat, C Osborne, Godfrey Biemba, G M Shakankale, Fungai G. Mabeza, Pierre A. M. Peeters, Berend Oosterhuis, Ch B Lugt
    Abstract:

    Abstract. The efficacy and safety of intramuscular Artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received Artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days

  • PHARMACOKINETIC INVESTIGATION ON THE THERAPEUTIC POTENTIAL OF Artemotil (-ARTEETHER) IN THAI PATIENTS WITH SEVERE PLASMODIUM FALCIPARUM MALARIA
    2015
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, K. Milhous
    Abstract:

    Abstract. Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1–4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1–4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5–22.4 hours on day 0 and 31.6–40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85–4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16–0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) time

  • pharmacokinetic investigation on the therapeutic potential of Artemotil β arteether in thai patients with severe plasmodium falciparum malaria
    American Journal of Tropical Medicine and Hygiene, 2004
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, Wilbur K Milhous
    Abstract:

    Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1-4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1-4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5-22.4 hours on day 0 and 31.6-40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85-4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16-0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclu- sion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate 48%) than the low-dose subjects (cure rate 23%). Despite the high accumulation and longer exposure time (9-11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including /-arteether dissolved in peanut oil used in Indian patients.

  • dose finding and efficacy study for i m Artemotil beta arteether and comparison with i m artemether in acute uncomplicated p falciparum malaria
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: Sornchai Looareesuwan, Srivicha Krudsood, Polrat Wilairatana, B Oosterhuis, B M Schilizzi, Frans A E Sollie, Ch B Lugt, P A M Peeters, James O Peggins
    Abstract:

    Aims  The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) Artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods  In part I of the study three different Artemotil dose regimens were explored in three groups of 6–9 patients for dose finding: 3.2 mg kg−1 on day 0 and 1.6 mg kg−1 on days 1–4 (treatment A), 1.6 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment B), 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment C). In part II of the study, Artemotil treatments A and C were compared in three groups of 20–22 patients with standard i.m. artemether treatment: 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment R). Results  Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two Artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of Artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial Artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to Artemotil during approximately the first 2 days of treatment, and suggested that Artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions  The optimum dose regimen for Artemotil in this study was identical to the standard dose regimen of artemether. The findings that Artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of Artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. Artemotil can be an advantage, since it may allow shorter hospitalization.

  • a randomized controlled trial of Artemotil beta arteether in zambian children with cerebral malaria
    American Journal of Tropical Medicine and Hygiene, 2000
    Co-Authors: Philip E Thuma, B Oosterhuis, Ch B Lugt, P A M Peeters, G J Bhat, G F Mabeza, C Osborne, Godfrey Biemba, G M Shakankale, V R Gordeuk
    Abstract:

    The efficacy and safety of intramuscular Artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received Artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Sornchai Looareesuwan - One of the best experts on this subject based on the ideXlab platform.

  • PHARMACOKINETIC INVESTIGATION ON THE THERAPEUTIC POTENTIAL OF Artemotil (-ARTEETHER) IN THAI PATIENTS WITH SEVERE PLASMODIUM FALCIPARUM MALARIA
    2015
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, K. Milhous
    Abstract:

    Abstract. Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1–4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1–4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5–22.4 hours on day 0 and 31.6–40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85–4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16–0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) time

  • pharmacokinetic investigation on the therapeutic potential of Artemotil β arteether in thai patients with severe plasmodium falciparum malaria
    American Journal of Tropical Medicine and Hygiene, 2004
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, Wilbur K Milhous
    Abstract:

    Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1-4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1-4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5-22.4 hours on day 0 and 31.6-40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85-4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16-0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclu- sion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate 48%) than the low-dose subjects (cure rate 23%). Despite the high accumulation and longer exposure time (9-11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including /-arteether dissolved in peanut oil used in Indian patients.

  • dose finding and efficacy study for i m Artemotil beta arteether and comparison with i m artemether in acute uncomplicated p falciparum malaria
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: Sornchai Looareesuwan, Srivicha Krudsood, Polrat Wilairatana, B Oosterhuis, B M Schilizzi, Frans A E Sollie, Ch B Lugt, P A M Peeters, James O Peggins
    Abstract:

    Aims  The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) Artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods  In part I of the study three different Artemotil dose regimens were explored in three groups of 6–9 patients for dose finding: 3.2 mg kg−1 on day 0 and 1.6 mg kg−1 on days 1–4 (treatment A), 1.6 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment B), 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment C). In part II of the study, Artemotil treatments A and C were compared in three groups of 20–22 patients with standard i.m. artemether treatment: 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment R). Results  Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two Artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of Artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial Artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to Artemotil during approximately the first 2 days of treatment, and suggested that Artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions  The optimum dose regimen for Artemotil in this study was identical to the standard dose regimen of artemether. The findings that Artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of Artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. Artemotil can be an advantage, since it may allow shorter hospitalization.

V R Gordeuk - One of the best experts on this subject based on the ideXlab platform.

  • a randomized controlled trial of Artemotil beta arteether in zambian children with cerebral malaria
    American Journal of Tropical Medicine and Hygiene, 2000
    Co-Authors: Philip E Thuma, B Oosterhuis, Ch B Lugt, P A M Peeters, G J Bhat, G F Mabeza, C Osborne, Godfrey Biemba, G M Shakankale, V R Gordeuk
    Abstract:

    The efficacy and safety of intramuscular Artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received Artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Wilbur K Milhous - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic investigation on the therapeutic potential of Artemotil β arteether in thai patients with severe plasmodium falciparum malaria
    American Journal of Tropical Medicine and Hygiene, 2004
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, Wilbur K Milhous
    Abstract:

    Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1-4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1-4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5-22.4 hours on day 0 and 31.6-40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85-4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16-0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclu- sion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate 48%) than the low-dose subjects (cure rate 23%). Despite the high accumulation and longer exposure time (9-11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including /-arteether dissolved in peanut oil used in Indian patients.

Polrat Wilairatana - One of the best experts on this subject based on the ideXlab platform.

  • PHARMACOKINETIC INVESTIGATION ON THE THERAPEUTIC POTENTIAL OF Artemotil (-ARTEETHER) IN THAI PATIENTS WITH SEVERE PLASMODIUM FALCIPARUM MALARIA
    2015
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, K. Milhous
    Abstract:

    Abstract. Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1–4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1–4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5–22.4 hours on day 0 and 31.6–40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85–4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16–0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) time

  • pharmacokinetic investigation on the therapeutic potential of Artemotil β arteether in thai patients with severe plasmodium falciparum malaria
    American Journal of Tropical Medicine and Hygiene, 2004
    Co-Authors: Ch B Lugt, Srivicha Krudsood, Polrat Wilairatana, Sornchai Looareesuwan, Suparp Vannaphan, Kobsiri Chalearmrult, Wilbur K Milhous
    Abstract:

    Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1-4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1-4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5-22.4 hours on day 0 and 31.6-40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85-4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16-0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclu- sion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate 48%) than the low-dose subjects (cure rate 23%). Despite the high accumulation and longer exposure time (9-11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including /-arteether dissolved in peanut oil used in Indian patients.

  • dose finding and efficacy study for i m Artemotil beta arteether and comparison with i m artemether in acute uncomplicated p falciparum malaria
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: Sornchai Looareesuwan, Srivicha Krudsood, Polrat Wilairatana, B Oosterhuis, B M Schilizzi, Frans A E Sollie, Ch B Lugt, P A M Peeters, James O Peggins
    Abstract:

    Aims  The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) Artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods  In part I of the study three different Artemotil dose regimens were explored in three groups of 6–9 patients for dose finding: 3.2 mg kg−1 on day 0 and 1.6 mg kg−1 on days 1–4 (treatment A), 1.6 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment B), 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment C). In part II of the study, Artemotil treatments A and C were compared in three groups of 20–22 patients with standard i.m. artemether treatment: 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment R). Results  Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two Artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of Artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial Artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to Artemotil during approximately the first 2 days of treatment, and suggested that Artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions  The optimum dose regimen for Artemotil in this study was identical to the standard dose regimen of artemether. The findings that Artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of Artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. Artemotil can be an advantage, since it may allow shorter hospitalization.