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Michael D. Edstein - One of the best experts on this subject based on the ideXlab platform.
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plasma concentrations of tafenoquine a new long acting Antimalarial Agent in thai soldiers receiving monthly prophylaxis
Clinical Infectious Diseases, 2003Co-Authors: Michael D. Edstein, David A Kocisko, Douglas S Walsh, Chirapa Eamsila, B G Charles, Karl H. RieckmannAbstract:We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.
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population pharmacokinetics of the new Antimalarial Agent tafenoquine in thai soldiers
British Journal of Clinical Pharmacology, 2001Co-Authors: Michael D. Edstein, David A Kocisko, Thomas G Brewer, Douglas S Walsh, Chirapa Eamsila, B G CharlesAbstract:Aims To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. Methods The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. Results A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h1, 3.20 l h1 and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. Conclusions The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent Antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.
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in vitro activities of the biguanide ps 15 and its metabolite wr99210 against cycloguanil resistant plasmodium falciparum isolates from thailand
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Michael D. Edstein, S Bahr, G. Dennis Shanks, Barbara M. Kotecka, Karl H. RieckmannAbstract:The in vitro activities of the new biguanide PS-15 and its putative active metabolite, WR99210, were determined against seven different isolates or clones of Plasmodium falciparum. The mean 50% inhibitory concentrations of PS-15 and WR99210 were 1,015 and 0.06 ng/ml, respectively. WR99210 was up to 363 times more potent than cycloguanil, the active metabolite of proguanil, against cycloguanil-resistant parasites. The pronounced activity of WR99210 against multidrug-resistant P. falciparum indicates that further studies are required to determine the value of the prodrug, PS-15, as an Antimalarial Agent.
Karl H. Rieckmann - One of the best experts on this subject based on the ideXlab platform.
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plasma concentrations of tafenoquine a new long acting Antimalarial Agent in thai soldiers receiving monthly prophylaxis
Clinical Infectious Diseases, 2003Co-Authors: Michael D. Edstein, David A Kocisko, Douglas S Walsh, Chirapa Eamsila, B G Charles, Karl H. RieckmannAbstract:We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.
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in vitro activities of the biguanide ps 15 and its metabolite wr99210 against cycloguanil resistant plasmodium falciparum isolates from thailand
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Michael D. Edstein, S Bahr, G. Dennis Shanks, Barbara M. Kotecka, Karl H. RieckmannAbstract:The in vitro activities of the new biguanide PS-15 and its putative active metabolite, WR99210, were determined against seven different isolates or clones of Plasmodium falciparum. The mean 50% inhibitory concentrations of PS-15 and WR99210 were 1,015 and 0.06 ng/ml, respectively. WR99210 was up to 363 times more potent than cycloguanil, the active metabolite of proguanil, against cycloguanil-resistant parasites. The pronounced activity of WR99210 against multidrug-resistant P. falciparum indicates that further studies are required to determine the value of the prodrug, PS-15, as an Antimalarial Agent.
Steven R. Meshnick - One of the best experts on this subject based on the ideXlab platform.
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interactions of db75 a novel Antimalarial Agent with other Antimalarial drugs in vitro
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Anne Purfield, Richard R Tidwell, Steven R. MeshnickAbstract:Pafuramidine is a novel orally active Antimalarial. To identify a combination partner, we measured the in vitro Antimalarial activities of the active metabolite, DB75, with amodiaquine, artemisinin, atovaquone, azithromycin, chloroquine, clindamycin, mefloquine, piperaquine, pyronaridine, tafenoquine, and tetracycline. None of the drugs tested demonstrated antagonistic or synergistic activity in combination with pafuramidine.
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effects of α thalassemia on pharmacokinetics of the Antimalarial Agent artesunate
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Wanida Ittarat, Sornchai Looareesuwan, Pensri Pootrakul, Petchmanee Sumpunsirikul, Phantip Vattanavibool, Steven R. MeshnickAbstract:Thalassemia is common in Southeast Asia, where artemisinin derivatives are frequently used in the treatment of malaria. It has been previously reported that artemisinin derivatives can be concentrated by uninfected thalassemic erythrocytes in vitro but not by normal erythrocytes. As a follow-up to this report, we studied the Antimalarial kinetics of intravascular artesunate (2.4 mg/kg of body weight) in 10 persons with normal hemoglobins and in 10 patients with thalassemia (2 with α-thalassemia type 1–hemoglobin Constant Spring and 8 with α-thalassemia type 1–α-thalassemia type 2). Concentrations of artesunate and its active metabolites in plasma were measured by bioassay and expressed relative to those of dihydroartemisinin, the major biologically active metabolite. Concentrations of intravascular artesunate in plasma peaked in both the normal individuals and the thalassemic individuals 15 min after injection (the first time point). Plasma drug concentrations at all time intervals, except that at 1 h, were significantly higher in thalassemic subjects than in normal subjects (P < 0.05). The area under the concentration-time curve was 9-fold higher (P < 0.001) and the volume of distribution at steady state was 15-fold lower (P < 0.001) in thalassemic than in normal subjects. In light of the potential neurotoxicity of artemisinin derivatives, these results suggest that thalassemic subjects may need a drug administration regimen different from that of normal patients.
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Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: Docking between the Antimalarial Agent and its putative receptor
Journal of molecular graphics, 1995Co-Authors: Kanhiya L. Shukla, Tamara M. Gund, Steven R. MeshnickAbstract:Artemisinin (qinghaosu, QHS) is a promising new Antimalarial Agent that is effective against drug-resistant strains of malaria. The Antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.
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Iron-dependent free radical generation from the Antimalarial Agent artemisinin (qinghaosu).
Antimicrobial agents and chemotherapy, 1993Co-Authors: Steven R. Meshnick, Ying-zi Yang, V. Lima, F. Kuypers, Sumalee Kamchonwongpaisan, Yongyuth YuthavongAbstract:Artemisinin is an important new Antimalarial Agent containing a bridged endoperoxide. The in vitro Antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one. Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch. A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator. Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin. The combination of artemisinin and hemin also decreases erythrocyte deformability. Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron. Images
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daphnetin a novel Antimalarial Agent with in vitro and in vivo activity
American Journal of Tropical Medicine and Hygiene, 1992Co-Authors: Ying-zi Yang, Allen Ranz, Huazhen Pan, Zhinan Zhang, Xiebin Lin, Steven R. MeshnickAbstract:Abstract Daphnetin is a dihydroxycoumarin that is being used in China for the treatment of coagulation disorders. It is also a chelator and an antioxidant. In vitro, daphnetin causes a 50% inhibition (IC50) of 3H-hypoxanthine incorporation by Plasmodium falciparum at concentrations between 25 and 40 µM. Several related compounds, such as scopoletin, 2, 3-dihydroxybenzoic acid and 3, 4-dihydroxybenzoic acid show no inhibitory activity. The Antimalarial activity of daphnetin is inhibited by the addition of iron. Daphnetin does not appear to be an oxidant drug, since it does not spontaneously generate superoxide in vitro. However, it does alkylate bovine serum albumin when incubated in the presence of iron. In vivo, daphnetin significantly prolongs survival of P. yoelli—infected mice.
B G Charles - One of the best experts on this subject based on the ideXlab platform.
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plasma concentrations of tafenoquine a new long acting Antimalarial Agent in thai soldiers receiving monthly prophylaxis
Clinical Infectious Diseases, 2003Co-Authors: Michael D. Edstein, David A Kocisko, Douglas S Walsh, Chirapa Eamsila, B G Charles, Karl H. RieckmannAbstract:We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.
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population pharmacokinetics of the new Antimalarial Agent tafenoquine in thai soldiers
British Journal of Clinical Pharmacology, 2001Co-Authors: Michael D. Edstein, David A Kocisko, Thomas G Brewer, Douglas S Walsh, Chirapa Eamsila, B G CharlesAbstract:Aims To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. Methods The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. Results A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h1, 3.20 l h1 and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. Conclusions The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent Antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.
Toshiaki Sunazuka - One of the best experts on this subject based on the ideXlab platform.
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a concise total synthesis of puberulic acid a potent Antimalarial Agent
ChemInform, 2015Co-Authors: Goh Sennari, Tomoyasu Hirose, Masato Iwatsuki, Satoshi Omura, Toshiaki SunazukaAbstract:Puberulic acid (I) is prepared from D-(+)-galactose in eight steps and with 54% overall yield.
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a concise total synthesis of puberulic acid a potent Antimalarial Agent
Chemical Communications, 2014Co-Authors: Goh Sennari, Tomoyasu Hirose, Masato Iwatsuki, Satoshi ōmura, Toshiaki SunazukaAbstract:Efficient and practical total synthesis of puberulic acid has been accomplished via 8 steps, with 54% overall yield, and only two C–C bond formations, without the introduction of oxygen atoms into the core skeleton. Construction of the tropolone framework as the key transformation was achieved by multi-tandem oxidation of the aliphatic-triol, from D-(+)-galactose as the starting material.
