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Hardean E Achneck - One of the best experts on this subject based on the ideXlab platform.
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Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition
Journal of Thrombosis and Thrombolysis, 2019Co-Authors: Joao D. Dias, Torben Pottgiesser, Jan Hartmann, Daniel Duerschmied, Christoph Bode, Hardean E AchneckAbstract:In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG^®6s, Multiplate^®, and VerifyNow^®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG^®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow^® and Multiplate^® were able to distinguish between three and two zones, respectively. Multiplate^® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG^®6s (144–2589 ng/mL), and VerifyNow^® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG^®6s (5.0%), VerifyNow^® (8.3%), and Multiplate^® (13.3%). TEG^®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate^® (14.1%), and VerifyNow^® (17.7%). Linear models could be generated between TEG^®6s and Multiplate^®, but not VerifyNow^®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.
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Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition
Journal of Thrombosis and Thrombolysis, 2019Co-Authors: Joao D. Dias, Torben Pottgiesser, Jan Hartmann, Daniel Duerschmied, Christoph Bode, Hardean E AchneckAbstract:In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG^®6s, Multiplate^®, and VerifyNow^®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG^®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow^® and Multiplate^® were able to distinguish between three and two zones, respectively. Multiplate^® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG^®6s (144–2589 ng/mL), and VerifyNow^® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG^®6s (5.0%), VerifyNow^® (8.3%), and Multiplate^® (13.3%). TEG^®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate^® (14.1%), and VerifyNow^® (17.7%). Linear models could be generated between TEG^®6s and Multiplate^®, but not VerifyNow^®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.
Walther H Wernsdorfer - One of the best experts on this subject based on the ideXlab platform.
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Synergism between quinine and retinol in fresh isolates of Plasmodium falciparum.
Wiener Klinische Wochenschrift, 2008Co-Authors: Ariane Knauer, Gunther Wernsdorfer, Jeeraphat Sirichaisinthop, Kanungnit Congpuong, Franz F. Reinthaler, Walther H WernsdorferAbstract:Following earlier reports of synergism between retinol and various antimalarial compounds, the pharmacodynamic interaction between retinol and quinine was investigated in 38 fresh isolates of Plasmodium falciparum. The study was carried out in western Thailand, an area with quinine-resistant P. falciparum. The combination of quinine with retinol in concentrations corresponding to the 50th, 65th and 80th percentile of the physiological values in healthy subjects, significantly reduced the EC50, EC90, EC99 and GMCOC for quinine. The FIC values at EC90 and EC99 indicate increasing synergism with rising EC and retinol concentration. The mean SFIC value dropped to a level as low as 0.2420, indicating strong synergism
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Specific pharmacokinetic interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum.
Wiener Klinische Wochenschrift, 2007Co-Authors: Peter Starzengruber, Chaiporn Rojanawatsirivet, Gunther Wernsdorfer, Herwig Kollaritsch, Maria Parizek, Walther H WernsdorferAbstract:The blood schizontocidal activity of lumefantrine, monodesbutyl-benflumetol (DBB) and a 999:1 combination of both compounds has been investigated in 26 fresh isolates of Plasmodium falciparum from northwestern Thailand, using the WHO standard protocol MarkII for determining the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation (GMCOC) were 943.2 nM for lumefantrine, 146.3 nM for DBB and 182.2 nM for the 999:1 combination of lumefantrine and DBB. The EC50 values were 27.3nM for lumefantrine, 5.7 nM for DBB, and 16.5 nM for the combination, and the EC90 values 163.1 nM for lumefantrine, 44.1 nM for DBB, and 78.3 nM for the combination. Despite the very low concentration in the combination, DBB exerted significant synergistic activity with lumefantrine that was strongest at the EC90 and EC99 levels. Correlation analysis indicates that DBB is the leading determinant for the activity of the combination.
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Susceptibility to chloroquine, mefloquine and artemisinin of Plasmodium vivax in northwestern Thailand.
Wiener Klinische Wochenschrift, 2007Co-Authors: Birgit Woitsch, Chaiporn Rojanawatsirivet, Gunther Wernsdorfer, Jeeraphat Sirichaisinthop, Kanungnit Congpuong, Walther H WernsdorferAbstract:The in vitro study had the objectives of monitoring the sensitivity of Plasmodium vivax to chloroquine and artemisinin, and to assess its baseline sensitivity to mefloquine in northwestern Thailand in an area near the border to Myanmar. The investigations were carried out in 2004 at the malaria clinics of Mae Sot, Chedi Ko and Mae Ka Sa, all in the district of Mae Sot, Province of Tak. The in vitro tests followed the method of Tasanor. Successful tests were obtained with 45 fresh isolates of P. vivax. The EC50 and EC90 values for chloroquine were 120.9 nM and 655.7 nM, respectively, the GMCOC was 1699.7 nM. There was a significant decrease of the chloroquine sensitivity since 1998/1999. However, results of parallel investigations continue to indicate clinical-parasitological sensitivity to chloroquine. With mefloquine the EC50 and EC90 the (baseline) values were 131.6 nM and 972.6 nM, respectively, the GMCOC was 1987.0 nM. For artemisinin the EC50 and EC90 values were 8.7 nM and 105.2 nM, respectively, the GMCOC was 310.5 nM. As compared to 2002, the sensitivity of P. vivax to artemisinin has shown a slight but not significant increase.
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Pharmacodynamic interaction between atovaquone and other antimalarial compounds against Plasmodium falciparum in vitro.
Wiener Klinische Wochenschrift, 2006Co-Authors: Carola Lütgendorf, Chaiporn Rojanawatsirivet, Gunther Wernsdorfer, Jeeraphat Sirichaisinthop, Herwig Kollaritsch, Walther H WernsdorferAbstract:Atovaquone, a 2-hydroxy-1,4-naphthoquinone, was first introduced as a drug against opportunistic infections in immuno-compromised patients. Early clinical-parasitological experiences in the treatment of malaria were disappointing due to highly variable and poor absorption, a phenomenon typical for naphthoquinones. Proguanil was found to potentiate the activity of atovaquone and the combination of the two drugs was introduced as an antimalarial drug with blood schizontocidal and causal prophylactic activity. It is now widely used in therapy and prophylaxis. Despite the enhanced activity, the combination does not always overcome the problem of poor absorption of atovaquone, especially in the presence of gastro-intestinal disorders. Therefore, further combination with a fastacting blood schizontocide, e.g. one of the artemisinins, could accelerate clinical improvement and normalization of absorption. The interaction between artemisinin and atovaquone and that of artemisinin and atovaquone + proguanil has been investigated in 37 fresh isolates of Plasmodium falciparum from northwestern Thailand, an area with high prevalence of multi-drug resistance. Interaction between atovaquone and artemisinin was synergistic above the EC30, with mean ΣFIC (Berenbaum) values of 0.9679 at the EC50, 0.4014 at the EC90 and 0.2214 at the EC99. Synergism was more pronounced with the triple combination, i.e. atovaquone + proguanil and artemisinin, starting at the EC10 level. The mean ΣFIC values were 0.7626 at the EC50, 0.2939 at the EC90, and 0.1527 at the EC99. The strong synergism at the therapeutically relevant effective concentrations suggests that the therapeutic efficacy of atovaquone-proguanil can be considerably enhanced by the additional administration of a suitable artemisinin derivative, e.g. artesunate.
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In vitro interaction between artemisinin and chloroquine as well as desbutyl-benflumetol in Plasmodium vivax
Wiener Klinische Wochenschrift, 2006Co-Authors: Leila Kyavar, Chaiporn Rojanawatsirivet, Gunther Wernsdorfer, Jeeraphat Sirichaisinthop, Herwig Kollaritsch, Walther H WernsdorferAbstract:Malaria resulting from infection with Plasmodium vivax rarely causes death, however, patients usually suffer acute debilitating clinical symptoms and the recovery is slow. This study had the objective of assessing the pharmacodynamic interaction between artimisinin and chloroquine with a view of a potential acceleration of the clinicalparasitological response, and the investigation of therapeutic alternatives in the event of chloroquine resistance in Plasmodium vivax. Tests were based on the growth inhibition of Plasmodium vivax, determined by morphological differential counts of 200 asexual parasites. In total 45 isolates were evaluated successfully with parallel tests for artemisinin, chloroquine and desbutylbenflumetol (DBB) alone and combinations of artemisinin + chloroquine and artemisinin + DBB. Total inhibition was reached at a mean concentration of 1274.8 nM (95% CI 898.5 to 1808.7 nM), and 1852.2 nM (95% CI 1539.5 to 2228.6 nM) for artemisinin, and chloroquine respectively, whilst the 1:1 (m/m) combination of artemisinin and chloroquine was 1860.2 nM (95% CI 1454.4 to 2379.3 nM). EC50 and EC90 were 129.9 nM and 1058.5 nM for chloroquine, 32.6 nM and 735.5 nM for artemisinin, and 73.6 nM and 1103.0 nM for the 1:1 combination of both drugs. Interaction analysis according to Berenbaum yielded for the artemisinin + chloroquine combination at the EC50 a mean ΣFIC of 1.1126, at the EC90 a mean ΣFIC of 1.0331, and at the EC99 a mean ΣFIC of 1.1857. These results revealed marked additive interaction. For desbutylbenflumetol (DBB) the EC50 and EC90 were 1.5 nM and 28.8 nM, complete growth inhibition was observed at 90.4 nM (95% CI 75.1 to 108.7 nM). Interaction analysis indicated moderate antagonism at the lower concentration ranges, at the EC90 additive interaction with a mean ΣFIC of 1.0300, and synergism at the therapeutically most important EC99 with a mean ΣFIC of 0.5990.
Joao D. Dias - One of the best experts on this subject based on the ideXlab platform.
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Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition
Journal of Thrombosis and Thrombolysis, 2019Co-Authors: Joao D. Dias, Torben Pottgiesser, Jan Hartmann, Daniel Duerschmied, Christoph Bode, Hardean E AchneckAbstract:In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG^®6s, Multiplate^®, and VerifyNow^®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG^®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow^® and Multiplate^® were able to distinguish between three and two zones, respectively. Multiplate^® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG^®6s (144–2589 ng/mL), and VerifyNow^® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG^®6s (5.0%), VerifyNow^® (8.3%), and Multiplate^® (13.3%). TEG^®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate^® (14.1%), and VerifyNow^® (17.7%). Linear models could be generated between TEG^®6s and Multiplate^®, but not VerifyNow^®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.
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Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition
Journal of Thrombosis and Thrombolysis, 2019Co-Authors: Joao D. Dias, Torben Pottgiesser, Jan Hartmann, Daniel Duerschmied, Christoph Bode, Hardean E AchneckAbstract:In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG^®6s, Multiplate^®, and VerifyNow^®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG^®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow^® and Multiplate^® were able to distinguish between three and two zones, respectively. Multiplate^® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG^®6s (144–2589 ng/mL), and VerifyNow^® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG^®6s (5.0%), VerifyNow^® (8.3%), and Multiplate^® (13.3%). TEG^®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate^® (14.1%), and VerifyNow^® (17.7%). Linear models could be generated between TEG^®6s and Multiplate^®, but not VerifyNow^®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.
Simon L Croft - One of the best experts on this subject based on the ideXlab platform.
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in vitro interactions between sitamaquine and amphotericin b sodium stibogluconate miltefosine paromomycin and pentamidine against leishmania donovani
Journal of Antimicrobial Chemotherapy, 2011Co-Authors: Karin Seifert, Jane C Munday, Tahmina Syeda, Simon L CroftAbstract:OBJECTIVES: To evaluate in vitro interactions between sitamaquine and the current antileishmanial drugs amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against intracellular Leishmania donovani amastigotes in peritoneal mouse macrophages. A second objective was to evaluate the susceptibility of antimony-resistant L. donovani isolates to sitamaquine. METHODS: Mouse peritoneal macrophages were infected with L. donovani amastigotes. Drug susceptibility was assessed in a standard 5 day assay and drug interactions with a modified fixed ratio isobologram method. Fractional inhibitory concentrations (FICs), sum FICs (∑FICs) and an overall mean ∑FIC were calculated for each combination. The nature of interaction was classified on the basis of the mean ∑FIC as follows: synergy as mean ∑FIC≤0.5, indifference as mean ∑FIC between >0.5 and ≤4 and antagonism as mean ∑FIC>4. RESULTS: Interactions between sitamaquine and amphotericin B, sodium stibogluconate, paromomycin and miltefosine were classified as indifferent at the 50% and 90% effective concentration (EC50 and EC90, respectively) levels. The sitamaquine/pentamidine combination was synergistic, with overall mean ∑FICs from 0.5 to 0.6 at the EC50 level and from 0.3 to 0.7 at the EC90 level. Sitamaquine displayed in vitro activity against L. donovani isolates resistant to sodium stibogluconate. CONCLUSIONS: This study expands the preclinical data on drug combinations and provides the basis for further studies as antileishmanial chemotherapy is moving towards multidrug treatment regimens.
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In Vitro and In Vivo Interactions between Miltefosine and Other Antileishmanial Drugs
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Karin Seifert, Simon L CroftAbstract:The interaction of miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo. In vitro interactions were indifferent for miltefosine combined with amphotericin B (mean sums of fractional inhibitory concentrations [mean summation operatorFICs] ranging from 1.22 to 1.51 at the 50% effective concentration [EC50] level and 1.08 to 1.38 at the EC90 level), sitamaquine (mean summation operatorFICs from 1.33 to 1.38 and 1.0 to 1.02, respectively), and paromomycin (mean summation operatorFICs from 0.79 to 0.93 at the EC50 and 0.77 to 1.35 at the EC90 level). Some synergy was observed for miltefosine combined with sodium stibogluconate (mean summation operatorFICs from 0.61 to 0.75 at EC50 and 0.49 to 0.97 at EC90). Different interactions were found in vivo, where the highest potentiation of miltefosine activity was achieved with amphotericin B (activity enhancement index [AEI] of up to 11.3). No significant interaction was observed when miltefosine was combined with sodium stibogluconate (AEI of up to 2.38). The potentiation of miltefosine in vivo was also achieved with the combination of miltefosine and paromomycin (AEI of up to 7.22).
Michael Ramharter - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of artemisone compared with artesunate against Plasmodium falciparum.
The American journal of tropical medicine and hygiene, 2006Co-Authors: Michael Ramharter, Dominik Burkhardt, Johannes Nemeth, Ayola A. Adegnika, Peter G. KremsnerAbstract:Artemisinins show the potential for neurotoxicity in preclinical studies. Artemisone is a leading candidate of second-generation semi-synthetic artemisinin derivatives for antimalarial therapy devoid of neurotoxicity. Artemisone showed 3-5-fold higher in vitro activity (50% effective concentration (EC50) = 0.14 nmol/L, EC90 = 2.55 nmol/L) than artesunate against fresh Plasmodium falciparum isolates from Gabon and a high-activity correlation indicates a shared drug target.
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In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum
The American journal of tropical medicine and hygiene, 2002Co-Authors: Michael Ramharter, Gunther Wernsdorfer, Gerhard Wiedermann, Harald Noedl, Krongthong Thimasarn, Walther H WernsdorferAbstract:Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.